CN101557751A - Methods, compositions, unit dosage forms, and kits for pharmacologic stress testing with reduced side effects - Google Patents

Abstract

Methods are presented that comprise the administration of a pharmaceutical composition comprising adenosine and dipyridamole, as well methods comprising the combined administration of dipyridamole administered as a bolus with adenosine given as an infusion, both at dosages below their respective single agent dosages, for detecting the presence and/or assessing the severity of myocardial ischemia during pharmacologic stress tests. The methods are useful for exploiting the vasodilating abilities of adenosine at doses at which side effects related to adenosine are substantially reduced while optimal coronary artery perfusion is achieved. Also presented are compositions, unit dosage forms, and kits that are useful in performing the methods.

Description

The method, compositions, unit dosage form and the medicine box that are used for pharmacology's stress test of side effect minimizing

1. background

The evaluation of the functional evaluation of cardiac muscle, the particularly oxygen condition of cardiac muscle is important in the treatment decision-making of the patient's who instructs myocardial ischemia nursing.In existing clinical practice, the most normal use Noninvasive of myocardial ischemia nuclear perfusion imaging method such as plane scintigraphy (scintigraphy) or single photon emission tomography (SPECT) are estimated, and use thallium and technetium as the most frequently used isotope.Recently, because the image of improvement and radiation still less are provided, use the positron emission tomography (PET) of rubidium-82 to obtain approval.Half invasive also is used to study the motion of ventricle wall through esophagus doppler echo cardiotokography, and Noninvasive is to measure being easy to and the method for Noninvasive of coronary flow reserve through the thorax doppler echocardiography.

Therefore heart channel that these function tests need the patient usually is called " stress test " generically and on the common saying by controlled motion (controlled exercise) or by pharmacology's means " stress (stressed) ".The pharmacology's stresser that is used for the functional evaluation cardiac muscle works-expands to a greater degree than diseased vessel by making normal blood vessels via coronary artery diastole (coronaryvasodilation), these stresser are set up shunting (shunt) or " cardiac muscle is stolen stream (myocardial steal) ", causing suffering from blood flow differential in patient's the healthy tremulous pulse of coronary artery disease and the diseased arteries increases, and makes the differentiated imaging optimization of myocardial region that needs oxygen to supply with.

Adenosine and dipyridamole are coronary artery diastole agent, and they are used for individual the use as pharmacology's stresser approval of stress test separately.Adenosine directly acts on by stimulating the adenosine purine energy P1 receptor on the arterial wall.Think that dipyridamole passes through the heavily absorption of blocking-up adenosine on cellular level but not directly effect causes the endogenous adenosine concentration in the blood to increase.Dipyridamole produces the similarly approaching maximum coronary artery hyperemia that is produced with exogenous adenosine, but is not very fast.

In order to ensure gathering cardiac image the competent time be provided near maximum coronary artery diastole and in order to give, adenosine with 140 μ g/kg weight in patients/minute dose rates (dosage rate) infusion 6 minutes; Dipyridamole was with 140 μ g/kg weight in patients/minute infusion 4 minutes.Therefore, total recommended dose of adenosine is 0.84mg/kg, and total recommended dose minimum of the dipyridamole in 4 minutes infusions is 0.56mg/kg, average out to 0.80mg/kg.If vasodilation is abundant inadequately, then the accumulated dose of the dipyridamole of using in the infusion in 6 minutes can increase to 0.95mg/kg.

Although infusion is clock in a measure only, stimulate the chemical compound of adenosine receptor to be attended by a lot of side effects.For adenosine, report that maximum is rubescent (flushing) (44%), chest pain or breast discomfort (40%), dyspnea (28%), headache (18%), throat or neck or jaw discomfort (15%) and gastrointestinal upset (13%); Other side effect are uncommon.

The side effect of adenosine is a dose dependent.When adenosine dosage in 6 minutes infusions when 60 increase to 140 μ g/kg/ minutes, symptom such as hotness, flush crimson, dyspnea and chest pain increase.Chest pain occurs when 90 μ g/kg/ minutes dosage usually, and becomes frequent in the time of 120 μ g/kg/ minutes.When 70 μ g/kg/ minutes or still less dosage, have been noted that the adenosine untoward reaction is considerably less, and be slight.Yet, when by intravenous perfusion with 70 μ g/kg/ minutes or still less or even when using in g/kg/ minute with 90-120 μ, adenosine shows to render a service and reduces, so do not recommend to be used for stress test with the dosage of this attenuating.

The side effect profile of dipyridamole is similar, but its adverse events seldom takes place.Yet the dipyridamole side effect continues more of a specified duration, and is more difficult, and therefore more frequent needs are used the intravenous aminophylline as antidote.

Because think that dipyridamole is by increasing the effect of endogenous adenosine, so taboo is used adenosine and dipyridamole with complete intravenous dosages.Similarly, avoid orally ingestible dipyridamole before adenosine pharmacology stress test usually.

In order to reduce the side effect when the most effective agonist dosage, just developing that selectively adenosine can agent (adenosinergic agent) to the A2a receptor subtype.Referring to for example United States Patent (USP) the 6th, 531,457; 6,448,235; 6,322,771; With 5,877, No. 180.Specific compound in the exploitation comprises regadenoson, binodenoson and apadenoson (BMS068645).Yet although they have receptor-selective, the side effect of having observed these chemical compounds is moderate reduction only.In addition, these chemical compounds have the acting duration longer than adenosine; So side effect such as rubescent, headache and dyspnea continue more of a specified duration.Therefore, although than adenosine specificity is arranged more, these adenosines can agent more likely trigger the side effect of prolongation than adenosine itself, and more likely need to use pharmacology's antidote, and in a single day adenosine stops to use its side effect and dissipate fast.In addition, these alternative medicines also neither one be approved for clinical use.

Therefore, there is the lasting demand to the injection (injectable agent) that can be used for pharmacology's stress test in this area, described injection has the quick acting and the of short duration half-life of adenosine, thereby can handle, and provide the side effect of maximum effectiveness and attenuating clinically in the mode identical with adenosine.

2. general introduction

Although think dipyridamole by increasing the adenosine concentration indirect action and have and the similar side effect feature of adenosine in clinical practice, the inventor has found that at present about 5%-of the dipyridamole of low-down parenteral dosage-be used for the clinically at present dosage of cardiac imaging research can strengthen the vasodilator effect of the auxiliary adenosine of using and the not corresponding enhancing of the side effect of adenosine.This allow adenosine with the dosage that lowers in order to realizing for example being used for the coronary artery diastole of functional evaluation myocardial function, with existing scheme (protocol) relatively, render a service and equate or better and side effect reduces.In addition, clinical effect and haemodynamic effect are used in back 1 minute advantageously and are stopped stopping adenosine.

Therefore, this paper has described method, compositions, unit dosage form and the medicine box (kit) that utilizes this newfound phenomenon.

In first aspect, provide realization to be used for the method for the coronary artery diastole of cardiac diagnosis (cardiac diagnosis).Described method comprises uses adenosine and dipyridamole simultaneously, wherein adenosine and dipyridamole with about 2: 1 to about 10: 1 adenosine: dipyridamole weight rate parenteral is used.

In some embodiment of this method, described adenosine: the dipyridamole ratio is about 2: 1 to 4: 1, for example 4: 1; In various other embodiments, described adenosine: the dipyridamole ratio is about 7: 1 or about 8: 1.

In the various embodiments of this method, adenosine uses with 35 to 100 μ g/kg/ minutes dose rates and dipyridamole is used with g/kg/ minute dose rates of 3.5-50 μ.In some embodiments, adenosine is used with 70 μ g/kg/ minutes dose rates and dipyridamole is used with 10 μ g/kg/ minutes dose rates; Adenosine uses with 70 μ g/kg/ minutes dose rates and dipyridamole is used with 8.75 μ g/kg/ minutes dose rates; Adenosine uses with 50 μ g/kg/ minutes dose rates and dipyridamole is used with g/kg/ minute dose rates of 12.5-25 μ.

But adenosine and dipyridamole parenteral continue to use at least about 2 minutes period, are less than about 6 minutes usually.In certain embodiments, but adenosine and dipyridamole parenteral continue to use about 4 minutes period.

In some embodiments of the method that this paper proposed, adenosine and dipyridamole are used with single compositions.In other embodiments, adenosine and dipyridamole are used by discrete sets compound (separatecompositions).

In multiple embodiments, at least a adenosine and dipyridamole are used by intravenous infusion.In some embodiments, at least a adenosine and dipyridamole by in the atrium or intra-arterial use.In some embodiments, compare with intravenous dosages, described dose dosage can use the dosage multiplier (multiplier) of 1/200-1/400 to regulate downwards.Adenosine and/or dipyridamole compare with intravenous dosages by in the embodiment of using in the coronary artery therein, and described dose dosage can use the dosage multiplier of 1/200-1/400 to regulate downwards.

In certain embodiments, described method usefully further comprises the step of assess cardiac function.Assess cardiac function can comprise uses one or more to be selected from following group technology: electrocardiography, M type sonography, the two dimension sonography, three-dimensional sonography, echo Doppler, cardiac imaging, plane (routine) scintigraphy, single photon emission tomography (SPECT), dynamic single photon emission tomography, positron emission tomography (PET), first by RAG (first pass radionuclide angiography), equilibrium activity nucleic angiography, nuclear magnetic resonance, NMR (NMR) imaging, perfusion contrast echo cardiography (perfusioncontrast echocardiography), digital subtraction angiography (DSA) and ultrahigh speed X ray computer tomography (CINE CT).In certain embodiments, functional evaluation is undertaken by SPECT; In other embodiments, described evaluation is undertaken by PET.

In some embodiment of this method of the evaluation that further comprises cardiac function, assess cardiac function comprises that isotopic parenteral uses.Described isotope usually at the same time parenteral use and be no less than 2.5 minutes after adenosine and dipyridamole begin and use.In some embodiments, isotope is no less than 2.55 minutes after can using beginning in adenosine and dipyridamole, is no less than 2.6 minutes, is no less than 2.65 minutes, is no less than 2.7 minutes, is no less than 2.75 minutes and uses.In some embodiments, isotope can be in adenosine and dipyridamole parenteral use the beginning back and used in about 2.5-2.75 minute.

In second aspect, provide realization to be used for the method for the coronary artery diastole of cardiac diagnosis.These methods comprise: (i) parenteral is used dipyridamole; (ii) after this simultaneously or in succession parenteral use adenosine receptor agonist.Dipyridamole is used to be lower than the dosage that reaches maximum coronary artery diastole required dosage when using with single medicine by identical parenteral approach separately with adenosine receptor agonist.

In some embodiments, described adenosine receptor agonist is selected from the group of being made up of following: prodrug and the pharmaceutically acceptable salt of adenosine, adenosine triphosphate (ATP), adenosine diphosphate (ADP) (ADP), adenosine monophosphate (AMP) and adenosine or AMP, ADP, ATP.

Every kind of approach that parenteral is used can independently be selected from the group of being made up of following: use in intra-arterial, intravenous and atrium.In some embodiments, dipyridamole is used by intravenous or intra-arterial bolus injection (bolus injection).In certain embodiments, dipyridamole is to be no more than 140 μ g/kg, to be no more than 50 μ g/kg, even to surpass the dosage of 40 μ g/kg and use with dosage intravenous or the intra-arterial bullet of at least 14 μ g/kg usually.For example, in some embodiments, dipyridamole is used with the dosage intravenous or the intra-arterial bullet of 23 to 60 μ g/kg (as 35 μ g/kg or 40 μ g/kg).

In different embodiments, dipyridamole is used by the intravenous infusion in 1 or 2 minute.

In some of these embodiments, described adenosine receptor agonist be applied in dipyridamole use finish the back, as beginning in 30 seconds to 2 minutes behind dipyridamole injection or infusion.

In multiple embodiments, dipyridamole is to use by the intravenous infusion of (as 4 minutes) in 2 to 6 minutes with the mixture of adenosine receptor agonist.

In typical embodiment, described adenosine receptor agonist is an adenosine, and it is used by intravenous infusion with about 35 μ g/kg/ minute-100 μ g/kg/ minutes dose rates.In these embodiments, adenosine is used with the dose rates that is no more than about 100 μ g/kg/ minutes.In some embodiments, adenosine is to be no more than about 70 μ g/kg/ minutes, even to use above about 50 μ g/kg/ minutes dose rates.In exemplary embodiment, described adenosine receptor agonist is an adenosine, and it is with at least about 35 μ g/kg/ minutes even use by intravenous infusion at least about 50 μ g/kg/ minutes dose rates.For example, in some embodiments, adenosine is used by intravenous infusion with the speed of about 50 μ g/kg/ minutes to about 70 μ g/kg/ minutes (70 μ g/kg/ minutes according to appointment).

In some embodiments, dipyridamole is used and adenosine is used through intravenous through intravenous.

In some exemplary, described adenosine receptor agonist is an adenosine, and the accumulated dose of dipyridamole is 23 to 40 μ g/kg, and the dose rates of adenosine is 50 to 70 μ g/kg/ minutes.For example, in some embodiments, the accumulated dose of dipyridamole is that the dose rates of 40 μ g/kg and adenosine is 70 μ g/kg/ minutes.

This method can further comprise the step of assess cardiac function.In some embodiments, assess cardiac function comprises that isotopic parenteral uses, and described isotope is used after 2 minutes at dipyridamole and this adenosine receptor agonist sequential application, and after dipyridamole and this adenosine receptor agonist are used 2.5 minutes simultaneously, after 2.55 minutes, after 2.6 minutes, after 2.65 minutes, after 2.75 minutes, after 2.8 minutes, after 2.85 minutes, after 2.9 minutes or after 2.95 minutes but used before 3 minutes.In some embodiments, isotope was used behind sequential application dipyridamole and this adenosine receptor agonist in about 2.5-2.75 minute.

In the third aspect, provide the pharmaceutical composition that comprises adenosine and dipyridamole.Described compositions comprises about 2: 1 to about 10: 1, for example about 2: 1 to about 4: 1 adenosine: the adenosine of dipyridamole weight rate and dipyridamole.In some embodiments, described ratio is about 7: 1 or 8: 1.

In different embodiments, adenosine and dipyridamole exist with the amount that 35 to 100 μ g/kg/ minutes dose rates is used and dipyridamole is used with 3.5 to 50 μ g/kg/ minutes dose rates to allow adenosine.

Described compositions can be a sterile fluid, for example is applicable to the sterile fluid that parenteral is used, for example intravenous is used.In some embodiments, adenosine and the dipyridamole concentration that direct intravenous is used to allow not dilute exists.

In different embodiments, adenosine and dipyridamole exist with the concentration that allows adenosine to use with 8.75 to 10 μ g/kg/ minutes dose rates with 70 μ g/kg/ minutes dose rates and dipyridamole.In some embodiments, adenosine and dipyridamole exist with the concentration that allows adenosine to use with 12.5 to 25 μ g/kg/ minutes dose rates with 50 μ g/kg/ minutes dose rates and dipyridamole.

Provide herein in a series of embodiments of pharmaceutical composition, the concentration of adenosine is about 1 to 10mg/ml.Usefully, the concentration of adenosine is about 3mg/ml or 4mg/ml, even 5mg/ml or 7mg/ml.

In certain embodiments, the concentration of dipyridamole is about 0.1 to 5mg/ml, for example: 0.375 to 0.428mg/ml; 0.5 to 0.571mg/ml; 0.625 to 0.714mg/ml; 0.75 to 0.857mg/ml; With 0.875 to 1mg/ml.For example, described concentration can be 1mg/ml.

In one aspect of the method, provide and comprise the aforesaid unit dosage form that contains the pharmaceutical composition of adenosine and dipyridamole.

In some embodiments, described unit dose comprises about 2 to 50ml the pharmaceutical composition that is mixed with the sterile fluid (being generally aseptic, apyrogeneity solution) that is suitable for parenteral and uses.In some embodiments, described unit dose comprises about 2ml, 3ml, 4ml, 7ml, 8ml or 14ml.

In some embodiments, described unit dose comprises about 5 to 60mg adenosines and about 0.5 to 30mg dipyridamole; Described compositions be can be on the physiology solid of aseptic reconstruction (reconstitution) in acceptable solvent or the solution.

In exemplary embodiment, for example, described unit dose comprises about 14mg adenosine and about 2mg dipyridamole, 21mg adenosine and about 3mg dipyridamole; About 28mg adenosine and about 4mg dipyridamole; About 35mg adenosine and about 5mg dipyridamole; About 42mg adenosine and about 6mg dipyridamole; About 56mg adenosine and about 8mg dipyridamole; About 20mg adenosine and about 5 to 10mg dipyridamoles; About 30mg adenosine and about 7.5 to 15mg dipyridamoles; About 40mg adenosine and about 10 to 20mg dipyridamoles.

Further, provide the unit dose of dipyridamole.In different embodiments, dipyridamole is with the solution supply of about concentration of 0.1 to 5mg/ml.

In certain embodiments, described dipyridamole concentration is generally about 0.5mg/ml.These embodiments have and comprise the 3mg dipyridamole in 6ml, comprise the 4mg dipyridamole in 8ml, comprise the 5mg dipyridamole in 10ml, comprise the 6mg dipyridamole in 12ml, comprise the unit dosage form of 8mg dipyridamole in 16ml.In some embodiments, described unit dose comprises usually the dipyridamole of about 5mg/ml (as 3mg/ml or 4mg/ml) extremely with the about 3mg/ml of volume, concentration of 1ml or 2ml, is provided at the unit dosage form that comprises the 6mg dipyridamole among the 2ml and comprise the 8mg dipyridamole in 2ml.

Further, provide the unit dose of adenosine.Described unit dose is with sterile fluid compositions preparation, and described dose package to allow aseptic introducing volume be at least 15% second fluid of adenosine composition volume.Second fluid comprises dipyridamole usually.

In exemplary embodiment, described unit dose comprises the 21mg adenosine, comprises the 28mg adenosine in 6ml, comprise the 42mg adenosine or comprise the 56mg adenosine in 12ml in 12ml in 6ml.

In some embodiments, described unit dose can comprise the adenosine of the about 4mg/ml of concentration.In some embodiments, described unit dose comprises the 28mg adenosine, comprises the 56mg adenosine in 14ml in 7ml.

Medicine box also is provided.Described medicine box comprises at least a unit dose of dipyridamole and at least a unit dose of adenosine.In some embodiments, at least a unit dose of described dipyridamole is above-mentioned unit dose, and the unit dose of described adenosine is above-mentioned unit dose.

3. describe in detail

3.1 summary

Although think dipyridamole by increasing the adenosine concentration indirect action and have and the similar side effect profile of adenosine in clinical practice, the inventor has found that at present about 5%-of the dipyridamole of low-down parenteral-subclinical dose-be used for the clinically at present dosage of cardiac imaging research can strengthen the vasodilator effect of the auxiliary adenosine of using and the not corresponding enhancing of the side effect of adenosine.This make adenosine with the dosage that lowers in order to realizing for example being used for the coronary artery diastole of functional evaluation myocardial function, with existing scheme relatively, render a service and equate or better and side effect that the persistent period is short reduces.

Hereinafter in first of two of detailed report clinical researches (embodiment 1), the haemodynamic effect of using dipyridamole and adenosine with pharmacology's stresser intravenous of combination (even sequential application) in 40 continuous patients that suffer ischemic heart desease with the effect of using adenosine separately relatively.The each patient is as the contrast of oneself.Dipyridamole is used in the mode of intravenous bullet.After this adenosine was used 3 minutes by continuous intravenous infusion immediately.These two kinds of medicines separately be lower than when being used for myocardial perfusion imaging as single medicine its clinically the dosage of preferred dosage use: dipyridamole is with half with its single pharmaceutical quantities speed of the 4-6% of its single medicine accumulated dose, adenosine.

Effect uses Noninvasive to measure through thorax doppler echocardiography (TTDE).Blood flow rate (being called reflexive coronary blood flow valuve) through measuring no matter-peak value or meansigma methods-all than those absolute values of after using adenosine separately, measuring low 1.5 to 4% with its standard dose speed.Yet these differences all do not have the significance (p＞0.05) on the statistics: working standard treatment-with 140 μ g/kg/ minutes independent infusion adenosines-and in succession with the 4-6% bullet of its typical single medicine accumulated dose use dipyridamole, then there not to be the difference on the statistics between the 70 μ g/kg/ minute infusion adenosine.

In addition, in 30 routine patients of first series, three (3) routine patients behind the dipyridamole bullet 2 minutes rather than after this accept the adenosine infusion immediately, and two (2) routine patients are with the injection simultaneously in the same infusion tube of " Y " type of use adapter of these two kinds of medicines.Compare with the sequential application scheme, do not observe difference.

In 40 routine patients of this research, and with the number of using report chest pain behind the adenosine in 140 μ g/kg/ minutes separately relatively, the generation of observing chest pain significantly reduces.In addition, the treatment of successive combination and standard adenosine relatively, stride across all dipyridamole dose accumulation three kinds of main adverse side effect-chest pains, dyspnea and rubescent-severity reduce 31.6%.This minimizing has the significance (p=0.001) on the statistics.

As detailed report among the embodiment 2 below, estimate 27 routine patients in having studied in II phase subsequently at present, the described II phase study compared in the coronary artery patient of experience single photon emission tomography (SPECT) imaging research as the dipyridamole-adenosine combined administration of pharmacology's stresser and independent adenosine ( Astellas).

The initial patient's data that participates in preliminary dosage exploratory development proves, with 35 μ g/kg 20-30 in second the bullet intravenous use dipyridamole, subsequently with 70 μ g/kg/ minute intravenous infusion adenosine (in 3 routine patients, testing), or use these two kinds of medicines (in 5 routine patients, testing) simultaneously with identical dosage, all provide suitable image among the patient continuously with Adenoscan (Adenoscan) (with 140 μ g/kg/ minute adenosines) in 7 examples, although scoring is lower than Adenoscan in a routine patient, in the limit accepted that this scheme limited.With regard to 10 examples and 9 examples continuously the imaging among the patients render a service with regard to (imaging efficacy), the 40 μ g/kg dipyridamoles of in 10 routine patients, testing, subsequently 70 μ g/kg/ minute adenosines combination stresser or in 9 routine patients, test they use (adenosine 70 μ g/kg/ minutes with dipyridamole 10 μ g/kg/ minutes) in same dose and demonstrate respectively and be equal to Adenoscan and sometimes than the better result of Adenoscan.

Observe dipyridamole-adenosine combination and compare with independent adenosine, the generation and the severity of chest pain significantly reduce, and the ST on the EKG changes and reduces.

The digital proof of these two researchs, use dipyridamole-, cause side effect still less simultaneously with 28 to 40 μ g/kg bullets in succession well below equivalence in the coronary artery diastole of the accumulated dose of dipyridamole infusion during-be provided for 70 μ g/kg/ minute infusion adenosine (50% is less than its common dose) subsequently imaging research as single medicine stresser.These data prove that also dipyridamole and adenosine can be with single infusion combination in 4 minutes to reach similar effect.The danger of chest pain and obvious cardiempharaxis is at the row of the side effect that combination of the present invention reduced.

Therefore, this paper describes method, pharmaceutical composition, unit dosage form and the medicine box utilize this discovery, so that the common adverse effect of some of adenosine and dipyridamole-and the dosage of significantly cardiac side effects-significantly reduce, be kept for the simultaneously best coronary artery diastole of diagnosis of myocardial ischemia makes up adenosine and dipyridamole.

3.2 realize the method for coronary artery diastole

In first aspect, provide realization to be used for the method for the coronary artery diastole of cardiac diagnosis.

In typical embodiment, described method comprise parenteral use dipyridamole and after this while or in succession parenteral use adenosine receptor agonist.Dipyridamole is used to be lower than the dosage that reaches maximum coronary artery diastole required dosage when medicine is used by identical parenteral approach separately separately separately with adenosine receptor agonist.Dipyridamole and this adenosine receptor agonist were used with the amount and the persistent period of the weight rate that is enough to realize required treatment or diagnosis effect.

Typical program control syringe pump or Micropump are used to promote the parenteral with exact dose to use effectively in clinical practice.

As hereinafter further describing, the approach that parenteral is used is selected according to required clinical effect.In certain embodiments, at least a of dipyridamole and adenosine receptor agonist used by intravenous infusion.In other embodiments, at least a of dipyridamole and adenosine receptor agonist used by infusion in endoarterial infusion such as the coronary artery or by infusion in the atrium.In these latter embodiment, as hereinafter further describing, these active matters are to use than lower speed of intravenous infusion and lower dosage.And in other embodiment, at least a of these active matters used with infusion liquid.

In some embodiments, dipyridamole and adenosine receptor agonist is at least a at least 1 minute, common infusion in period of at least 2 minutes, 3 minutes, 4 minutes, 5 minutes even at least 6 minutes.This paper employed " continuous infusion " is meant infusion at least 2 minutes period.

In some embodiments, dipyridamole is used by intravenous infusion with 3.5 μ g/kg/ minutes to 50 μ g/kg/ minutes infusion rates.All dosage ranges as herein described comprise described higher limit and lower limit and non-integral intermediate value.Therefore, in some embodiments, dipyridamole is with at least about 3.5 μ g/kg/ minutes, at least about 4 μ g/kg/ minutes, at least about 5 μ g/kg/ minutes, at least about 6 μ g/kg/ minutes, at least about 7 μ g/kg/ minutes, at least about 7.5 μ g/kg/ minutes, at least about 8 μ g/kg/ minutes, at least about 8.75 μ g/kg/ minutes, at least about 9 μ g/kg/ minutes, at least about 10 μ g/kg/ minutes, at least about 11 μ g/kg/ minutes, at least about 11.25 μ g/kg/ minutes, at least about 12 μ g/kg/ minutes, at least about 12.5 μ g/kg/ minutes, at least about 13 μ g/kg/ minutes, at least about 13.75 μ g/kg/ minutes, at least about 14 μ g/kg/ minutes, at least about 15 μ g/kg/ minutes, at least about 16 μ g/kg/ minutes, at least about 16.25 μ g/kg/ minutes, at least about 17 μ g/kg/ minutes, with at least about 17.5 μ g/kg/ minutes, at least about 18 μ g/kg/ minutes, at least about 19 μ g/kg/ minutes, at least about 20 μ g/kg/ minutes, at least about 21 μ g/kg/ minutes, at least about 22 μ g/kg/ minutes, at least about 23 μ g/kg/ minutes, at least about 24 μ g/kg/ minutes, at least about 25 μ g/kg/ minutes, at least about 26 μ g/kg/ minutes, at least about 27 μ g/kg/ minutes, at least about 28 μ g/kg/ minutes, at least about 29 μ g/kg/ minutes, at least about 30 μ g/kg/ minutes, at least about 31 μ g/kg/ minutes, at least about 32 μ g/kg/ minutes, at least about 33 μ g/kg/ minutes, at least about 34 μ g/kg/ minutes, at least about 35 μ g/kg/ minutes, at least about 36 μ g/kg/ minutes, at least about 37 μ g/kg/ minutes, at least about 38 μ g/kg/ minutes, at least about 39 μ g/kg/ minutes, at least about 40 μ g/kg/ minutes, at least about 41 μ g/kg/ minutes, at least about 42 μ g/kg/ minutes, at least about 43 μ g/kg/ minutes, at least about 44 μ g/kg/ minutes, at least about 45 μ g/kg/ minutes, at least about 46 μ g/kg/ minutes, at least about 47 μ g/kg/ minutes, at least about 48 μ g/kg/ minutes, at least about 49 μ g/kg/ minutes, at least about 50 μ g/kg/ minutes speed infusions with the intermediate value of allowing.

In some embodiments, dipyridamole is to be no more than about 50 μ g/kg/ minutes, be no more than about 49 μ g/kg/ minutes, be no more than about 48 μ g/kg/ minutes, be no more than about 47 μ g/kg/ minutes, be no more than 46 μ g/kg/ minutes, be no more than about 45 μ g/kg/ minutes, be no more than about 44 μ g/kg/ minutes, be no more than about 43 μ g/kg/ minutes, be no more than about 42 μ g/kg/ minutes, be no more than about 41 μ g/kg/ minutes, be no more than about 40 μ g/kg/ minutes, be no more than about 39 μ g/kg/ minutes, be no more than about 38 μ g/kg/ minutes, be no more than about 37 μ g/kg/ minutes, be no more than about 36 μ g/kg/ minutes, be no more than about 35 μ g/kg/ minutes, be no more than about 34 μ g/kg/ minutes, be no more than about 33 μ g/kg/ minutes, be no more than about 32 μ g/kg/ minutes, be no more than about 31 μ g/kg/ minutes, be no more than about 30 μ g/kg/ minutes, be no more than about 29 μ g/kg/ minutes, be no more than about 28 μ g/kg/ minutes, be no more than about 27 μ g/kg/ minutes, be no more than about 26 μ g/kg/ minutes, be no more than about 25 μ g/kg/ minutes, be no more than about 24 μ g/kg/ minutes, be no more than about 23 μ g/kg/ minutes, be no more than about 22 μ g/kg/ minutes, be no more than about 21 μ g/kg/ minutes, be no more than about 20 μ g/kg/ minutes, be no more than about 19 μ g/kg/ minutes, be no more than about 18 μ g/kg/ minutes, be no more than about 17.5 μ g/kg/ minutes, be no more than about 17 μ g/kg/ minutes, be no more than about 16.25 μ g/kg/ minutes, be no more than about 16 μ g/kg/ minutes, be no more than about 15 μ g/kg/ minutes, be no more than about 14 μ g/kg/ minutes, be no more than about 13.75 μ g/kg/ minutes, be no more than about 13 μ g/kg/ minutes, be no more than about 12.5 μ g/kg/ minutes, be no more than about 12 μ g/kg/ minutes, be no more than about 11.25 μ g/kg/ minutes, be no more than about 11 μ g/kg/ minutes, be no more than about 10 μ g/kg/ minutes, be no more than about 9 μ g/kg/ minutes, be no more than about 8.75 μ g/kg/ minutes, be no more than about 8 μ g/kg/ minutes, be no more than about 7.5 μ g/kg/ minutes, be no more than about 7 μ g/kg/ minutes, be no more than about 6 μ g/kg/ minutes, be no more than about 5 μ g/kg/ minutes, be no more than about 4 μ g/kg/ minutes, the speed intravenous infusion of the intermediate value that was no more than about 3.5 μ g/kg/ minutes and allowed.

In some embodiments, dipyridamole is used with bullet in the period of second at about 20-30 usually.

In some of these embodiments, dipyridamole is used in the mode of intravenous bullet.In this embodiment, dipyridamole is used with the dosage of 14 μ g/kg to 140 μ g/kg.In different embodiments, dipyridamole is used with the dosage intravenous bullet of 28 μ g/kg to 40 μ g/kg.

Therefore, in certain embodiments, dipyridamole is with at least about 14 μ g/kg, at least about 20 μ g/kg, at least about 25 μ g/kg, at least about 28 μ g/kg, at least about 29 μ g/kg, at least about 30 μ g/kg, at least about 31 μ g/kg, at least about 32 μ g/kg, at least about 33 μ g/kg, at least about 34 μ g/kg, at least about 35 μ g/kg, at least about 36 μ g/kg, at least about 37 μ g/kg, at least about 38 μ g/kg, at least about 39 μ g/kg, at least about 40 μ g/kg, at least about 45 μ g/kg, at least about 50 μ g/kg, at least about 55 μ g/kg, at least about 60 μ g/kg, at least about 65 μ g/kg, even at least about 70,80,90,100,110,120, the dosage of 130 even 140 μ g/kg and the middle dosage intravenous bullet of allowing are used.

In some embodiments, dipyridamole is to be no more than about 140 μ g/kg, 130 μ g/kg, 120 μ g/kg, 110 μ g/kg, 100 μ g/kg, 90 μ g/kg, 80 μ g/kg, 70 μ g/kg, even do not surpass about 60 μ g/kg, even do not surpass about 55 μ g/kg, be no more than about 50 μ g/kg, be no more than about 45 μ g/kg, be no more than about 40 μ g/kg, be no more than about 39 μ g/kg, be no more than about 38 μ g/kg, be no more than about 37 μ g/kg, be no more than about 36 μ g/kg, be no more than about 35 μ g/kg, be no more than about 34 μ g/kg, be no more than about 33 μ g/kg, be no more than about 32 μ g/kg, be no more than about 31 μ g/kg, be no more than about 30 μ g/kg, be no more than about 29 μ g/kg, be no more than about 28 μ g/kg, be no more than about 25 μ g/kg/, be no more than about 20 μ g/kg/, the dosage intravenous bullet of the intermediate value that is no more than about 14 μ g/kg and allows is used.

When the people was used, the dosage that is used for the dipyridamole of the inventive method can multiply by individual weight by the dosage of representing with μ g/kg, represents with μ g.For example, be the people of 50kg for weight, the dosage that is used for the dipyridamole of this method can be expressed as the scope of 700 to 7,000 μ g; For weight is the people of 60kg, and the dosage of described dipyridamole can be expressed as the scope of 840 to 8,400 μ g; For weight is the people of 75kg, and the dosage of described dipyridamole can be expressed as the scope of 1,050 to 10,500 μ g; And for weight is the people of 100kg, and described dosage can be expressed as the scope of 1,400 to 14,000 μ g.

In different embodiments, dipyridamole be no more than about 0.07 μ g/kg/ minute, be no more than about 0.06 μ g/kg/ minute, be no more than about 0.05 μ g/kg/ minute, be no more than about 0.04 μ g/kg/ minute, be no more than about 0.03 μ g/kg/ minute, the infusion rates endoarterial infusion of the intermediate value that was no more than about 0.02 μ g/kg/ minute or was no more than about 0.01 μ g/kg/ minute and allow.

In different embodiments, adenosine receptor agonist is selected from the group of being made up of adenosine and adenosine donor (can be metabolized to the chemical compound of adenosine), described adenosine donor comprise natural donor (as separately with adenosine triphosphate (ATP), the adenosine diphosphate (ADP) (ADP) and adenosine monophosphate (AMP) of the roughly the same dosage of adenosine) become any synthetic molecules of adenosine and pharmaceutically acceptable salt thereof with energy metabolism.

Normally, use adenosine.For convenience, after this its concrete purposes is being described, but this is not described method will be limited to thus to use adenosine as adenosine receptor agonist.

In some embodiments, adenosine is used by intravenous infusion with 35 μ g/kg/ minutes to 100 μ g/kg/ minutes infusion rates.Therefore, in some embodiments, adenosine is with at least about 35 μ g/kg/ minutes, at least about 40 μ g/kg/ minutes, at least about 45 μ g/kg/ minutes, at least about 50 μ g/kg/ minutes, at least about 55 μ g/kg/ minutes, at least about 60 μ g/kg/ minutes, at least about 65 μ g/kg/ minutes, at least about 70 μ g/kg/ minutes, at least about 75 μ g/kg/ minutes, at least about 80 μ g/kg/ minutes, at least about 85 μ g/kg/ minutes, at least about 90 μ g/kg/ minutes, at least about 95 μ g/kg/ minutes with at least about the speed infusion of 100 μ g/kg/ minutes and the intermediate value of allowing.

In different embodiments, adenosine is to be no more than about 100 μ g/kg/ minutes, be no more than about 95 μ g/kg/ minutes, be no more than about 90 μ g/kg/ minutes, be no more than about 85 μ g/kg/ minutes, be no more than about 80 μ g/kg/ minutes, be no more than about 75 μ g/kg/ minutes, be no more than about 70 μ g/kg/ minutes, be no more than about 65 μ g/kg/ minutes, be no more than about 60 μ g/kg/ minutes, be no more than about 55 μ g/kg/ minutes, be no more than about 50 μ g/kg/ minutes, be no more than about 45 μ g/kg/ minutes, be no more than about 40 μ g/kg/ minutes, the speed intravenous infusion of the intermediate value that was no more than about 35 μ g/kg/ minutes and allowed.

When the people was used, the dose rates of adenosine can multiply by individual weight and represent with μ g/ minute by the dose rates with expression in μ g/kg/ minute.For example, be the people of 50kg for weight, the dosage of adenosine that is used for the practice of the inventive method can be expressed as 1,750 to 5,000 μ g/ minute scope; For weight is the people of 60kg, and the dose rates of described adenosine can be expressed as 2,100 to 6,000 μ g/ minutes scope; For weight is the people of 75kg, and the dosage of described adenosine can be expressed as 2,625 to 7,500 μ g/ minutes scope; And for weight is the people of 100kg, and the dosage of described adenosine can be expressed as 3,500 to 10,000 μ g/ minutes scope.

In some embodiments, adenosine is used by endoarterial infusion (as infusion in the coronary artery) to be lower than about 200 times to the 400 times infusion rates of intravenous infusion.Therefore, in some embodiments, adenosine with at least about 0.50 μ g/kg/ minute, at least about 0.45 μ g/kg/ minute, at least about 0.40 μ g/kg/ minute, 0.35 μ g/kg/ minute, at least about 0.30 μ g/kg/ minute, at least about 0.25 μ g/kg/ minute, at least about 0.20 μ g/kg/ minute, at least about 0.15 μ g/kg/ minute, at least about the speed infusion of 0.10 μ g/kg/ minute and the intermediate value of allowing.

In different embodiments, adenosine is with endoarterial infusion, particularly be no more than about 0.10 μ g/kg/ minute, be no more than about 0.15 μ g/kg/ minute, be no more than about 0.20 μ g/kg/ minute, be no more than about 0.25 μ g/kg/ minute, be no more than about 0.30 μ g/kg/ minute, be no more than about 0.35 μ g/kg/ minute, be no more than about 0.40 μ g/kg/ minute, be no more than about 0.45 μ g/kg/ minute, even surpassed about 0.50 μ g/kg/ minute and the infusion rates coronary artery of the intermediate value of allowing in infusion.

In different embodiments, method as herein described comprises that parenteral uses dipyridamole; And after this simultaneously or in succession with about 2: 1 to about 10: 1 adenosine: (A: D) the weight rate parenteral is used adenosine receptor agonist (as adenosine) to dipyridamole.In different embodiments, described method comprises with about 2: 1 to about 10: 1 adenosine: the dipyridamole ratio is used adenosine and dipyridamole simultaneously.

In some embodiments, described ratio is about 2: 1,3: 1,4: 1,5: 1,6: 1,7: 1,8: 1,9: 1 even 10: 1, and the non-integer ratio of allowing between 2: 1 to 10: 1.In certain embodiments, described method comprises with about 6: 1 to 8: 1, preferred about 7: 1 A: the D ratio is infusion adenosine and dipyridamole simultaneously.For some method that hereinafter further describes, embodiment usefully comprises with about 2: 1 to 4: 1 A: the D weight rate is parenteral infusion adenosine and dipyridamole simultaneously.

In some embodiments, dipyridamole is used by infusion in the coronary artery: in this embodiment, dipyridamole is usually to be about adenosine infusion rates 1/7 and to be that 0.01 to 0.07 μ g/kg/ minute infusion rates is used.Therefore, in some embodiments, dipyridamole with at least about 0.01 μ g/kg/ minute, at least about 0.02 μ g/kg/ minute, at least about 0.03 μ g/kg/ minute, at least about 0.04 μ g/kg/ minute, at least about 0.05 μ g/kg/ minute, at least about 0.06 μ g/kg/ minute, at least about 0.07 μ g/kg/ minute speed endoarterial infusion.

In different embodiments, dipyridamole use in the mode of intravenous bullet and after this adenosine use in the mode of intravenous infusion.

In some this embodiment, dipyridamole is used in second and about 2 to 6 minutes of infusion adenosine after this at about 20-30.

In these embodiments, the accumulated dose of the dipyridamole that gives of intravenous bullet be generally when dipyridamole its total proposed standard dosage during as single medicine (the single pharmaceutical quantities of standard: 0.56mg-0.80mg/kg) 1/16 to 1/24, for example 1/20 (5%).In these embodiments, the accumulated dose of intravenous infusion adenosine be generally when adenosine when single medicine its total proposed standard dosage (the single pharmaceutical quantities of standard: 0.84mg/kg) 25% to 50%.

In typical embodiment, dipyridamole with the dosage of 14 to 60 μ g/kg 20-30 in second the IV bullet use, immediately (that is, and fast as far as possible clinically, usually in about 5 to 30 seconds) with 35 to 100 μ g/kg/ minutes 3 to 6 minutes periods of dosage infusion adenosine.The persistent period that adenosine is used is determined by selected formation method well-known in the art.

In some embodiments, immediately-promptly, fast as far as possible clinically behind the intravenous dipyridamole bullet of 28-40 μ g/kg, usually in about 5 to 30 seconds-with g/kg/ minute intravenous infusion adenosine of 50-70 μ 2 to 6 minutes.In certain embodiments, used adenosine 4 minutes with 70 μ g/kg/ minute intravenouss immediately behind the IV dipyridamole bullet of 40 μ g/kg.

In the sequential application embodiment, the adenosine infusion can be delayed to behind the dipyridamole bullet 2-10 minute, is no more than 5 minutes usually behind the dipyridamole bullet.

In the sequential application embodiment, dipyridamole can be via the manual bolus injection of syringe, although program control using (for example, passing through Micropump) also is possible.When using by Micropump, dipyridamole can be before the adenosine infusion 1 or injection in 2 minutes.The adenosine infusion uses program control device to realize so that guarantee that it is through transporting of measuring usually.

In some embodiments, dipyridamole and adenosine are used simultaneously.

Use simultaneously in the embodiment at some, dipyridamole and adenosine are in discrete (separate) unit dosage form, and using preceding mixing, with single compositions infusion together.

For example, in some embodiments, sampling is corresponding to the volume of the dipyridamole of the dosage of 14 to 60 μ g/kg and take a sample similarly corresponding to the volume of the adenosine of 35 to 100 μ g/kg/ minutes dosage, and both are mixed in same syringe.Then with infusion in this mixture in 3 to 6 minutes.The persistent period that intravenous is used is determined by selected formation method well-known in the art.

In some embodiments, sampling is corresponding to the volume of the dipyridamole of 28-40 μ g/kg and take a sample similarly corresponding to the volume of the adenosine of 50 to 70 μ g/kg/ minutes dosage, and both are mixed in same syringe.Then with infusion in this mixture in 3 to 6 minutes.In certain embodiments, sampling is corresponding to the volume of the dipyridamole of 40 μ g/kg and take a sample similarly corresponding to the volume of the adenosine of 70 μ g/kg/ minutes dosage, and both are mixed in same syringe.Then with this mixture infusion in 4 minutes.Therefore, as hereinafter further as described in, in one aspect of the method, provide the specific unit dosage form of the adenosine that the specific unit dosage form of land used and dipyridamole packs altogether, be beneficial to take a sample in succession and two kinds of active matter mixing in same syringe.

In other embodiments, the cumulative volume of dipyridamole unit dosage form is injected to adenosine phial (vial) and both are mixed.Therefore, as mentioned below, in one aspect of the method, the unit dosage form of adenosine that the invention provides packing is to allow the dipyridamole of aseptic introducing proper volume.

Before using two kinds of active matters are mixed in the embodiment of single compositions, the volume of using uses adenosine dose form as a reference effectively to calculate.

In other embodiments, dipyridamole and adenosine are used simultaneously by the discrete sets compound.Usefully, two kinds of active matters can be introduced into the same infusion tube (with dosage same as described above) of using Y type adapter.

3.3 the method for pharmacology's stress test

The vasodilation of realizing according to above-mentioned method is usually as the pharmacology's stresser in the cardiac stress testing.Therefore, in certain embodiments, described method further comprises the step of assess cardiac function.

Can use any method that is suitable for assess cardiac function in cardiac stress testing.

In different embodiments, for example, assess cardiac function comprises uses one or more to be selected from following group technology: electrocardiography, sonography (M type, two and three dimensions), echo Doppler, cardiac imaging comprise plane (routine) scintigraphy, single photon emission tomography (SPECT), dynamic single photon emission tomography (D-SPECT ^TMCardiacScan), positron emission tomography (PET), RAG (for example utilizing passing through first and balance studies of technetium-99 m labeled erythrocyte), nuclear magnetic resonance, NMR (NMR) imaging, perfusion contrast echo cardiography, digital subtraction angiography (DSA) and ultrahigh speed X ray computer tomography (CINE CT).

There are some advantage in SPECT and PET.

SPECT research can use the known any isotope that is suitable for this research such as thallium-201, technetium sestamibi, tetrofosmine to carry out.PET research can use known any isotope such as rubidium-82, nitrogen-13, fluoro-18, carbon-11, boron-11 and the oxygen-15 that is suitable for this research to carry out.

Normally, isotope is injected during the infusion adenosine, and begins after being imaged on the infusion end.In some embodiments, described isotope is no less than about 2.5 minutes and uses after the adenosine infusion begins.

3.4 pharmaceutical composition

In one aspect of the method, be provided for the pharmaceutical composition of said method.

In typical embodiment, described pharmaceutical composition comprises with about 2: 1 to about 10: 1 adenosines with centre (the comprising non-integer) value of allowing: dipyridamole (A: D) adenosine of weight rate and dipyridamole.In some embodiment that adenosine expection was used with 70 μ g/kg/ minutes, middle ratio and non-integer ratio that described ratio is generally about 7: 1,8: 1,9: 1 and 10: 1 and allows.Will be at adenosine with in 50 μ g/kg/ minutes or other embodiments of still less using, A: the D ratio is generally about 2: 1,3: 1 and 4: 1 and middle ratio and non-integer ratio between allow 2: 1 and 4: 1.For some clinical method, described compositions comprises usually with about 7: 1 A: the adenosine of D weight rate and inosine.

In certain embodiments, described pharmaceutical composition is suitable in intravenous, the atrium or endoarterial infusion.

For example, described compositions can be the form of aseptic, apyrogeneity, fluid composition.

In typical fluid embodiment, the concentration of described adenosine is at least about 1mg/ml, 2mg/ml, 3mg/ml, 4mg/ml and may be 5mg/ml and the intermediate value of allowing, non integer value.These embodiments have about 3.5 to about 8 pH usually.In having other typical fluid embodiments of lower pH (for example pH2-3.5) easily, adenosine concentration can be higher even be at least about 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml and even be 10mg/ml and the intermediate value of allowing, non integer value.In typical pharmaceutical composition embodiment, adenosine exists with the concentration of about 3mg/ml, 4mg/ml, 5mg/ml or 7mg/ml.

In various fluid embodiments, the concentration of described dipyridamole is at least about 0.1mg/ml, and can be usefully up to 2.5mg/ml, even 5mg/ml.In certain embodiments, described concentration can be at least about 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1mg/ml or comprises for example 1.1mg/ml more, 1.2mg/ml, 1.3mg/ml, 1.4mg/ml, 1.5mg/ml, 1.6mg/ml, 1.7mg/ml, 1.8mg/ml, 1.9mg/ml, 2mg/ml, 2.1mg/ml, 2.2mg/ml, 2.3mg/ml, or 2.4mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml, the 5mg/ml and the intermediate value of allowing and non integer value (for example 0.43,0.57,0.71 or 0.86mg/ml).

In certain embodiments, described compositions comprises with the adenosine of the concentration of about 3mg/ml with the dipyridamole of the concentration of about 0.375-0.428mg/ml (this can be rounded up to the 0.38-0.43mg/ml) (A of 8: 1 and 7: 1: the D ratio).For example, in one embodiment, described compositions comprises with the adenosine of the concentration of about 3mg/ml with the dipyridamole (ratio 7: 1) of the concentration of about 0.43mg/ml.In another embodiment, described compositions comprises with the adenosine of the concentration of about 4mg/ml with the dipyridamole (about 8: 1 to 7: 1 ratio) of the concentration of about 0.5-0.57mg/ml.In another embodiment, described compositions comprises with the adenosine of the concentration of about 5mg/ml with the dipyridamole of the concentration of about 0.62-0.71mg/ml (8: 1 and 7: 1 ratio).In another embodiment, described compositions comprises with the adenosine of the concentration of about 6mg/ml with the dipyridamole (ratio 7: 1) of the concentration of about 0.86mg/ml.In another embodiment, described compositions comprises with the adenosine of the concentration of about 7mg/ml with the dipyridamole (ratio 7: 1) of the concentration of about 1mg/ml, or the like, up to adenosine concentration up to 10mg/ml.

In other embodiments, described compositions is done, and is adapted at by adding dipyridamole and the easily molten sterile fluid of adenosine being rebuild before the infusion.Usefully, described compositions comprises to be suitable for allowing adenosine and the dipyridamole of rebuilding the amount of extremely above-mentioned adenosine and dipyridamole concentration in the container of sealing.

No matter fluid or do, described pharmaceutical composition can further be included in and well-known in the artly be suitable in intravenous, the atrium or carrier and excipient that intra-arterial is used.In these excipient, be useful on those of the dipyridamole of present approval and adenosine composition, as tartaric acid, hydrochloric acid and Polyethylene Glycol (macrogol 600).Other allow, for example mannitol.Referring to http://www.adenosin.com/en/en_SPC_05.pdf (Item Development AB, 2005), it incorporates this paper by reference into.Also referring to Remington:The Science and Practice of Pharmacy(Lei Mingdun: the science of medicament with put into practice), the 21st edition. (2005), Lippincott Williams﹠amp; Wilkins (ISBN:0781746736), it incorporates this paper by reference into.

Described compositions can further comprise other active matter, and in some embodiments, can further comprise contrast agent, comprises ultrasonic and the MRI contrast agent.

Be expected in the embodiment of continuous intravenous infusion in the said method, adenosine is usually to allow adenosine to be present in the pharmaceutical composition with the concentration or the weight of about 35 μ g/kg/ minutes to about 100 μ g/kg/ minutes speed infusion.

In some of these embodiments, adenosine is to allow with at least about 35 μ g/kg/ minutes, at least about 40 μ g/kg/ minutes, at least about 45 μ g/kg/ minutes, at least about 50 μ g/kg/ minutes, at least about 55 μ g/kg/ minutes, at least about 60 μ g/kg/ minutes, at least about 65 μ g/kg/ minutes, at least about 70 μ g/kg/ minutes, at least about 75 μ g/kg/ minutes, at least about 80 μ g/kg/ minutes, at least about 85 μ g/kg/ minutes, at least about 90 μ g/kg/ minutes, at least about 95 μ g/kg/ minutes with exist at least about the amount of the speed infusion of 100 μ g/kg/ minutes and the intermediate value of allowing and non integer value.

In some embodiments, adenosine is to allow to be no more than about 100 μ g/kg/ minutes, be no more than about 95 μ g/kg/ minutes, be no more than about 90 μ g/kg/ minutes, be no more than about 85 μ g/kg/ minutes, be no more than about 80 μ g/kg/ minutes, be no more than about 75 μ g/kg/ minutes, be no more than about 70 μ g/kg/ minutes, be no more than about 65 μ g/kg/ minutes, be no more than about 60 μ g/kg/ minutes, be no more than about 55 μ g/kg/ minutes, be no more than about 50 μ g/kg/ minutes, be no more than about 45 μ g/kg/ minutes, be no more than about 40 μ g/kg/ minutes, the amount of the intermediate value that was no more than about 35 μ g/kg/ minutes and allowed and the speed infusion of non integer value is present in the compositions.

In the embodiment of the continuous intravenous infusion of expection, dipyridamole is usually to allow dipyridamole to be present in the pharmaceutical composition with the concentration or the weight of about 3.5 μ g/kg/ minutes to 50 μ g/kg/ minutes speed infusion.

In some of these embodiments, dipyridamole is to allow with at least about 3.5 μ g/kg/ minutes, at least about 4 μ g/kg/ minutes, at least about 5 μ g/kg/ minutes, at least about 6 μ g/kg/ minutes, at least about 7 μ g/kg/ minutes, at least about 7.5 μ g/kg/ minutes, at least about 8 μ g/kg/ minutes, at least about 8.75 μ g/kg/ minutes, at least about 9 μ g/kg/ minutes, at least about 9.25 μ g/kg/ minutes, at least about 9.50 μ g/kg/ minutes, at least about 10 μ g/kg/ minutes, at least about 11 μ g/kg/ minutes, at least about 11.25 μ g/kg/ minutes, at least about 12 μ g/kg/ minutes, at least about 12.5 μ g/kg/ minutes, at least about 13 μ g/kg/ minutes, at least about 13.75 μ g/kg/ minutes, at least about 14 μ g/kg/ minutes, at least about 15 μ g/kg/ minutes, at least about 16 μ g/kg/ minutes, at least about 16.25 μ g/kg/ minutes, at least about 17 μ g/kg/ minutes with at least about 17.5 μ g/kg/ minutes, at least about 18 μ g/kg/ minutes, at least about 19 μ g/kg/ minutes, at least about 20 μ g/kg/ minutes, at least about 21 μ g/kg/ minutes, at least about 22 μ g/kg/ minutes, at least about 23 μ g/kg/ minutes, at least about 24 μ g/kg/ minutes, at least about 25 μ g/kg/ minutes, at least about 26 μ g/kg/ minutes, at least about 27 μ g/kg/ minutes, at least about 28 μ g/kg/ minutes, at least about 29 μ g/kg/ minutes, at least about 30 μ g/kg/ minutes, at least about 31 μ g/kg/ minutes, at least about 32 μ g/kg/ minutes, at least about 33 μ g/kg/ minutes, at least about 34 μ g/kg/ minutes, at least about 35 μ g/kg/ minutes, at least about 36 μ g/kg/ minutes, at least about 37 μ g/kg/ minutes, at least about 38 μ g/kg/ minutes, at least about 39 μ g/kg/ minutes, at least about 40 μ g/kg/ minutes, at least about 41 μ g/kg/ minutes, at least about 42 μ g/kg/ minutes, at least about 43 μ g/kg/ minutes, at least about 44 μ g/kg/ minutes, at least about 45 μ g/kg/ minutes, at least about 46 μ g/kg/ minutes, at least about 47 μ g/kg/ minutes, at least about 48 μ g/kg/ minutes, at least about 49 μ g/kg/ minutes, amount at least about the speed infusion of 50 μ g/kg/ minutes and the intermediate value of allowing and non integer value exists.

In some embodiments, dipyridamole is to allow to be no more than about 50 μ g/kg/ minutes, be no more than about 49 μ g/kg/ minutes, be no more than about 48 μ g/kg/ minutes, be no more than about 47 μ g/kg/ minutes, be no more than about 45 μ g/kg/ minutes, be no more than about 44 μ g/kg/ minutes, be no more than about 43 μ g/kg/ minutes, be no more than about 42 μ g/kg/ minutes, be no more than about 41 μ g/kg/ minutes, be no more than about 40 μ g/kg/ minutes, be no more than about 39 μ g/kg/ minutes, be no more than about 38 μ g/kg/ minutes, be no more than about 37 μ g/kg/ minutes, be no more than about 36 μ g/kg/ minutes, be no more than about 35 μ g/kg/ minutes, be no more than about 34 μ g/kg/ minutes, be no more than about 33 μ g/kg/ minutes, be no more than about 32 μ g/kg/ minutes, be no more than about 31 μ g/kg/ minutes, be no more than about 30 μ g/kg/ minutes, be no more than about 29 μ g/kg/ minutes, be no more than about 28 μ g/kg/ minutes, be no more than about 27 μ g/kg/ minutes, be no more than about 26 μ g/kg/ minutes, be no more than about 25 μ g/kg/ minutes, be no more than about 24 μ g/kg/ minutes, be no more than about 23 μ g/kg/ minutes, be no more than about 22 μ g/kg/ minutes, be no more than about 21 μ g/kg/ minutes, be no more than about 20 μ g/kg/ minutes, be no more than about 19 μ g/kg/ minutes, be no more than about 18 μ g/kg/ minutes, be no more than about 17.5 μ g/kg/ minutes, be no more than about 17 μ g/kg/ minutes, be no more than about 16.25 μ g/kg/ minutes, be no more than about 16 μ g/kg/ minutes, be no more than about 15 μ g/kg/ minutes, be no more than about 14 μ g/kg/ minutes, be no more than about 13.75 μ g/kg/ minutes, be no more than about 13 μ g/kg/ minutes, be no more than about 12.5 μ g/kg/ minutes, be no more than about 12 μ g/kg/ minutes, be no more than about 11.25 μ g/kg/ minutes, be no more than about 11 μ g/kg/ minutes, be no more than about 10 μ g/kg/ minutes, be no more than about 9.25 μ g/kg/ minutes, be no more than about 9.50 μ g/kg/ minutes, be no more than about 9 μ g/kg/ minutes, be no more than about 8.75 μ g/kg/ minutes, be no more than about 8 μ g/kg/ minutes, be no more than about 7.5 μ g/kg/ minutes, be no more than about 7 μ g/kg/ minutes, be no more than about 6 μ g/kg/ minutes, be no more than about 5 μ g/kg/ minutes, be no more than about 4 μ g/kg/ minutes, be no more than about 3.5 μ g/kg/ minutes and and the amount of the speed intravenous infusion of the intermediate value of allowing and non integer value be present in the compositions.

3.5 unit dosage form

3.5.1 dipyridamole: the compositions of adenosine combination

Pharmaceutical composition described herein is usefully packed with the unit dosage form that is suitable for using in said method.

At described pharmaceutical composition is to be suitable in the embodiment of form of liquid of parenteral infusion, and for example, described compositions can be packaged into the volume of 2-50ml.Unit dosage form comprises 2 to 14ml, common 2,3,4,5,6,7,8 or 14ml easily.Comprise the unit dosage form that is low to moderate the 1ml volume and comprise higher volume (as 15 or 20ml) unit dosage form also be possible.Intermediate volume and non-integer volume are permissible.

Below table 1 list adenosine as herein described: the unit dosage form embodiment that some of dipyridamole pharmaceutical composition is useful.

Therefore, in some embodiments, described unit dosage form usefully comprises 14mg adenosine and 2mg dipyridamole in 2ml; 3 or 7ml in comprise 21mg adenosine and 3mg dipyridamole; 4 or 7ml in comprise 28mg adenosine and 4mg dipyridamole; 5 or 7ml in comprise 35mg adenosine and 5mg dipyridamole; 6 or 7ml in comprise 42mg adenosine and 6mg dipyridamole; 8 or 14ml in comprise 56mg adenosine and 8mg dipyridamole.

For the light patient of body weight (for example child), multiple embodiments is usefully packed 9mg or 12mg adenosine respectively in 3ml or 4ml.Other embodiment is usefully packed 20mg adenosine (20mg/5ml), usefully packs 24mg (24mg/6ml) and usefully pack 25mg (25mg/5ml) in the 6ml cumulative volume in the 5ml cumulative volume in the 5ml cumulative volume.The multiple unit dose embodiment of pharmaceutical composition as herein described comprises 30mg adenosine (30mg/6ml), 30mg/10ml or 32mg/8ml in the 6ml cumulative volume.Other unit dose delivery scheme usefully comprises adenosine with 36mg/9ml, 40mg/10ml, 40mg/8ml, 44mg/11ml, 45mg/15ml and 50mg/10ml.

In certain embodiments, described unit dosage form comprises the dipyridamole (for example for the A of 8: 1 and 7: 1: the D ratio is 3.75mg or 4.28mg) of 30mg adenosine and 3 to 5mg dipyridamoles and intermediate quantity of allowing and non-integral quantity in 10ml altogether.In other embodiments, 6ml phial or ampoule comprise 24mg adenosine and 3mg dipyridamole (ratio 8: 1).In other embodiments, 8ml phial and ampoule usefully comprise the dipyridamole (for example for the ratio of 8: 1 and 7: 1, being 4mg to 4.57mg) of 32mg adenosine and 3.2 to 5.3mg dipyridamoles and intermediate quantity of allowing and non-integral quantity.

The container that is used for the unit dose embodiment is suitable for using with standard intravenous infusion utensil usually.

In other embodiments, described unit dosage form is included as solid adenosine and the dipyridamole that is suitable for rebuilding.

No matter liquid or do, described unit dosage form is usually aseptic and apyrogeneity.

3.5.2 dipyridamole unit dosage form

In the typical embodiments of method as herein described, dipyridamole is used with about 5% of the dosage used with single medicine at present.Therefore, in one aspect of the method, the invention provides the novel unit dosage form of dipyridamole.

The unit dosage form easily of dipyridamole (as the single-activity thing) is phial, ampoule or pre-filled syringe, usefully has the 0.1ml scale, comprises the dipyridamole with the concentration of 0.5mg/ml.With the dipyridamole dosage of 35-40 μ g/kg, 5mg/10ml phial, ampoule or pre-filled syringe are enough to satisfy nearly all clinical needs, and are convenient to direct and dosage adjusting accurately.The unit dosage form that comprises the dipyridamole of 4mg/8ml, 3.5mg/7ml, 3mg/6ml, 5mg/10ml, 6mg/12ml and 8mg/16ml also is useful.

Comprise unit dosage form with the dipyridamole of the concentration of 1mg/ml-for example, in 6ml, comprise the unit dosage form of 6mg dipyridamole, 5mg/5ml, 4mg/4ml, 3mg/3ml-also can use, but fine adjustments dosage may be more difficult under this higher concentration.In these embodiments, adjusting realizes in saline solution after being preferably in the dilution dipyridamole.

Contain concentration and surpass 1mg/ml, be feasible as the preparation (preparation) of the dipyridamole of 2mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml even 5mg/ml, and be expected at when whole dipyridamole unit dose being mixed to the adenosine unit dose before using convenient especially.In this case, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/2ml or 8mg/2ml unit dosage form (or pre-filled syringe) are useful especially.

In other embodiments, the dipyridamole unit dosage form comprises the dipyridamole of low concentration such as 0.1mg/ml.Usefully, this unit dosage form comprises 6mg dipyridamole (6mg/60ml), 5mg/50ml, 4mg/40ml and 3mg/30ml in 60ml.With 0.2,0.3 and the dipyridamole formulation of the concentration of 0.4mg/ml also allow.

3.5.3 adenosine unit dosage form

As mentioned above, in some embodiments, dipyridamole and adenosine are usefully supplied with discrete pharmaceutical composition, are using preceding combination then.In some of these embodiments, the dipyridamole compositions is usefully introduced the unit dose of adenosine, use the compositions of this combination then.

Therefore, provide the unit dosage form of adenosine, wherein adenosine is mixed with the sterile fluid compositions, and wherein this dose package to allow aseptic introducing volume be at least 15% second fluid of adenosine composition volume.

Adenosine can exist with its direct packing or any concentration that is present in aforementioned pharmaceutical compositions that after this realizes after the dipyridamole compositions of introducing appropriate amount, for example usefully from 1mg/ml to 5mg/ml.

For example, in one embodiment, the adenosine unit dosage form comprises 21mg adenosine (21mg/6ml) in 6ml.It will be reconstructed into required 21mg adenosine/7ml (3mg/ml adenosine) compositions after introducing 1ml 3mg/ml dipyridamole (the whole unit dose of dipyridamole that for example comprise the dipyridamole of 1ml 3mg/ml).In another embodiment, the adenosine unit dosage form comprises 42mg/12ml.It will be reconstructed into required 42mg/14ml (3mg/ml) adenosine after introducing 6mg/2ml dipyridamole unit dose.In another embodiment, described adenosine unit dosage form comprises 28mg adenosine/6ml, and it will be reconstructed into 28mg/7ml (4mg/ml adenosine) after introducing 4mg/ml dipyridamole unit dose.In another embodiment, described adenosine unit dosage form comprises 56mg adenosine/12ml, and it will be reconstructed into 56mg/14ml (4mg/ml adenosine) after introducing 8mg/2ml dipyridamole unit dose.In another embodiment, described adenosine unit dosage form comprises 28mg/3ml or 35mg/4ml, and it will be reconstructed into 28mg/4ml and 35mg/5ml (7mg/ml adenosine) respectively after introducing 4 or 5mg/ml dipyridamole unit dose.In another embodiment, described adenosine unit dosage form comprises 42mg/4ml or 56mg/6ml, and it will be reconstructed into 42mg/6ml and 56mg/8ml (7mg/ml adenosine) after introducing 6mg/2ml or 8mg/2ml dipyridamole unit dose respectively.Following table has been summed up exemplary unit dosage form.

In certain embodiments, dipyridamole and adenosine are taken a sample from discrete unit dosage form in succession, and mix in same syringe.In these embodiments, the adenosine unit dosage form has the 28mg adenosine and 56mg adenosine (4mg/ml adenosine) is arranged in 14ml in 7ml easily.

Normally, after this according to the adenosine sheet but not Zantine is determined administration and sampling.

3.6 medicine box

The medicine box of one or more unit dose of dipyridamole wherein (as above-mentioned those) one or more unit dose with adenosine (as above-mentioned those) packing is provided in one aspect of the method.Normally, this medicine box comprises the dipyridamole and the adenosine dosage of equivalent.

In some embodiments, the dipyridamole unit dose packaging is in prefilled syringe (pre-packedsyringe), and the adenosine unit dose packaging becomes to have the phial of injection port such as barrier film (septum), allows the aseptic adenosine dosage that is introduced into of dipyridamole.

In different embodiments, this medicine box further comprises one or more dose forms of adenosine, one or more syringe needle, diluent and infusion utensil.

4. embodiment

4.1 embodiment 1

Intravenous use as the effect of the dipyridamole of pharmacology's stresser of combination (even sequential application) and adenosine in 40 continuous patients that suffer ischemic heart desease with the effect of using adenosine separately relatively.In combined administration, these two kinds of medicines separately be lower than when being used for myocardial perfusion imaging as single medicine its clinically the dosage of preferred dosage use.Effect uses Noninvasive to measure through thorax doppler echocardiography (TTDE).

The main terminal point of rendeing a service is peak expansion flow velocity (diastolic flow velocity) and average expansion flow velocity (being measured as reflexive coronary blood flow valuve).Secondary endpoints is the toleration of patient to described program.The following design of scheme.

Recruitment suffers the continuous patient of 40 (40) of ischemic heart desease.The each patient is as the contrast of oneself.

Adenosine was used by the IV infusion with the single medicine infusion rates of 140 μ g/kg/ minutes standard in 3 minutes.

Behind 5 minutes stable phases, the patient uses the IV injection of accepting dipyridamole with the accumulated dose of 23 μ g/kg, 28 μ g/kg or 35 μ g/kg, with the bullet of about 20-30 in second then.These accumulated doses are about 4-6% (be 0.56mg/kg, infusion in 4 minutes) altogether of minimum single medicine accumulated dose of dipyridamole.

Behind the bolus injection dipyridamole, immediately with 70 μ g/kg/ minutes IV infusion adenosines 3 minutes.This dosage is half of the single pharmaceutical quantities speed of 140 μ g/kg/ minutes standard.

Blood flow speed in left anterior descending coronary artery (LAD) in four point in time measurement: (i) before adenosine infusion originally (the spontaneous flow velocity of tranquillization); (ii) during 140 μ g/kg/ minute adenosine infusion originally; (iii) before sequential application dipyridamole and adenosine (at stable phase); (iv) during 70 μ g/kg/ minute adenosine infusion, after the dipyridamole bolus injection.

The result provides in table 3-6.The abbreviation of using in table is as giving a definition:

ADE: adenosine 140 μ g/kg/ minutes separately

SC: dipyridamole is adenosine 70 μ g/kg/ minutes successive combination subsequently

PV: peak speed (cm/ second)

MV: average speed (cm/ second)

Maximum: the speed under stress state

Minimum: the speed during tranquillization (under the baseline state)

(): standard deviation

D%: speed poor (peak or on average) accounts for the percentage ratio of maximum peak speed or average speed

Table 3 be presented among the 30 routine patients with dipyridamole 28 μ g/kg IV bullets (at 20-30 in second), subsequently with 70 μ g/kg/ minute adenosine infusion (" DIP5 " successive combination) with 140 μ g/kg/ minutes the standard independent infusion adenosine of single pharmaceutical quantities result relatively.

Table 4 be presented among the 5 routine patients with dipyridamole (35 μ g/kg) bullet (using in second) at 20-30, subsequently with 70 μ g/kg/ minutes speed by infusion use adenosine (" DIP4 " successive combination) with 140 μ g/kg/ minutes the standard independent infusion adenosine of single pharmaceutical quantities result relatively.

Table 5 be presented among the 5 routine patients will with 20-30 in second bullet use dipyridamole (23 μ g/kg), subsequently with 70 μ g/kg/ minutes speed by infusion use adenosine (" DIP6 " successive combination) with 140 μ g/kg/ minutes the standard independent infusion adenosine of single pharmaceutical quantities result relatively.

Table 6 is represented from the cumulative result of all 40 routine patients:

On absolute value, the blood flow speed (no matter peak speed or average speed) through measuring is than those low 3-4% of independent adenosine (referring to table 3 to 6).Yet, estimated (table 3-5) separately or stride across all dipyridamole dose accumulation (table 6) no matter try every kinds of dipyridamole dosage to three kinds, these differences do not have the significance (all P value＞0.05) on the statistics: standard care-with 140 μ g/kg/ minutes independent infusion adenosines-and in succession bullet use dipyridamole (with the 4-6% of its typical single medicine accumulated dose), then there not to be the difference on the statistics between the 70 μ g/kg/ minute infusion adenosine.

Table 7 is presented to use number of times and the frequency that modal three kinds of adverse events (chest pain, dyspnea and rubescent) take place in the clinical practice behind the adenosine in 140 μ g/kg/ minutes separately in all 40 routine patients.

Table 8 shows descriptive statistics and the analysis (every kind of scoring is 0 to 10, and general comment is divided into 30) that the average international vision analogy scale (meanglobal visual analogue scale) of three kinds of main adverse events (VAS) is marked.VAS marks provides measuring of patient's self evaluation of painful intensity/discomfort.

Although tabulation shows in table 8, successive combination compares with independent adenosine, and the severity of striding three kinds of main ill symptomses of all dipyridamole dose accumulation reduces 31.6%.This minimizing has the significance (p=0.001) on the statistics.As in the various dose of dipyridamole, not observing difference: with 140 μ g/kg/ minutes independent adenosines relatively, reduce average severity according to all successive combination of every kind VAS of three kinds of main ill symptomses.

As be displayed in Table 7, successive combination treatment and adenosine separately the adverse events relevant with the stimulation of A1 receptor, mainly are that the number of times (and frequency) of chest pain reduces 44% and its severity (not shown) decline 60% relatively.The adverse events relevant, mainly be that dyspnea and rubescent number of times (and frequency) do not reduce with the stimulation of A2a receptor.But successive combination compares with independent adenosine, and their severity (not shown) descends 24 and 38% respectively.

The 40 routine patients' that recruit in this research average coronary flow reserve (maximum-coronary flow " CBF " of being excited equals peak and mean blood flow velocity ratio with the ratio of baseline-tranquillization CBF) is higher than 2, this shows that it is drug dependence that the observed side effect of successive treatments reduces, and is not subjected to the study population's of institute ischemic state to influence (flawed).

Although do not show in tabular data, the single medicine adenosine of successive treatments and standard compares, and EKG does not have the difference on the statistics, and remains unchanged in all patients.The vital sign of two kinds of methods (heart rate, systolic blood pressure and diastolic blood pressure) changes similar.Yet adenosine is more not obvious separately for the heart rate increase of successive combination and blood pressure drops.

It should be noted that, in the 30 routine patients (DIP5 group) of first series, three (3) routine patients accepted the adenosine infusion in 2 minutes behind the dipyridamole bullet, two (2) routine patients are with two kinds of medicines (dipyridamole and adenosine) injection simultaneously in the same infusion tube of " Y " type of use adapter.These two kinds of medication patterns are effective equally, and with the sequential application scheme is the same effective immediately.

In first controlled trial, 5 routine patients treat according to the adjustment of testing program, wherein, after this be second single medicine adenosine infusion, and do not use dipyridamole with 140 μ g/kg/ minutes originally to be five (5) minutes stable phases behind 140 μ g/kg/ minutes the adenosine infusion.The result is displayed in Table 9.The abbreviation of using in table is as giving a definition:

PV: peak speed (cm/ second)

MV: average speed (cm/ second)

Maximum: the speed under stress state

Minimum: tranquillization speed (under the baseline state)

ADE1: the first adenosine infusion

ADE2: the second adenosine infusion

Observe the significant difference (P＞0.05) that does not have between the velocity measurement of the first and second adenosine infusions on the statistics.That observes subjective symptom does not have a significant difference (data not shown).The bibliographical information that these data acknowledgements are previous: the adenosine of acute administration is not induced tachysynthesis (tachyphylaxis).These data help the proof scheme design.

In second group of controlled trial, with 140 μ g/kg/ minute infusion adenosine after three minutes, dipyridamole is applied to 5 routine patients with the dosage of 28,35 or 40 μ g/kg separately by bolus injection, use once more behind 3 minutes stable phases.Data are shown in the table 10.

Dipyridamole does not change peak rate of expansion and average rate of expansion.There is not semiography in the time of during 10 minutes tracking (follow-up).These data acknowledgements the dipyridamole used as single medicine of intravenous bullet in being used for the dosage range of testing program, do not have detectable effect; Do not induce significant hematodinamics and clinical effect with the dipyridamole dosage of 28 to 40 μ g/kg separately.

4.2 embodiment 2

Starting the II phase study, with comparison in the coronary artery patient of experience single photon emission tomography (SPECT) imaging research as pharmacology's stresser dipyridamole-(this paper is also referred to as Adenosoft to the adenosine combined administration ^TM, all dosage all are) and independent adenosine (

Astellas).Just the research of carrying out is single center, single blind, parallel (2-arm), cross matching.

According to the standard clinical scheme, all patient experiences are with the SPECT imaging research of use in 140 μ g/kg/ minutes as the adenosine of the single medicine of pharmacology's stresser.Announce only to detect that those patients of ischemic region are qualified carries out second test, and if satisfy other choice criteria, then recruit to this research.

In second test, the pharmacology stress by using when bullet is used dipyridamole, 70 μ g/kg/ minutes subsequently adenosine infusion or they in second at 20-30 for qualified patient.Obtain the SPECT image according to the standard method of carrying out the last week.

Randomization and two blind property evaluators (blindedreader) that per 10 routine patients carry out the SPECT image analyze those images.Anonymous and randomized image uses standard 17 segment models (17-segment model) and estimates based on the sxemiquantitative vision point system of 5 point scales (5-point scale) (0 to 4).The safety of operation is as analyzing in the aforementioned hematodinamics research (embodiment 1) of using the vision scale, pays close attention to viewed three common symptons of adenosine and EKG are changed and other cardiac parameters commonly used.

This research is carried out.It comprises about 60 routine patients altogether.PRELIMINARY RESULTS is as follows.

About 10 routine patients' participation is finalized a text this research approach detailed content, and they have been excluded outside the research statistics.But they provide following message, are summarized as follows.

70 μ g/kg/ minute adenosines+28 μ g/kg dipyridamoles are combined among the 3 routine patients and provide the image that is provided with Adenoscan suitable image, but scoring is poor in two routine patients, are to think unacceptable level according to this research approach.70 μ g/kg/ minute adenosines+35 μ g/kg dipyridamoles are combined among 7 continuous patients the image suitable with Adenoscan are provided, although scoring is lower than Adenoscan in a routine patient, in the limit accepted that this scheme limited.

In 5 routine patients of this initial series, before using with adenosine with dipyridamole mixes and infusion in 4 minutes.This medication pattern successfully is used for all patients.

In 19 routine patients, (use) the combination stresser of test 40 μ g/kg dipyridamoles and 70 μ g/kg/ minute adenosines for 10 in succession with 9 simultaneously, show into picture and render a service and equate with Adenoscan and sometimes than the better result of Adenoscan.Table 11 shows the preceding 10 routine patients' of this 40 μ g/kg series (name " serial I-sequential application ") (stress score) (relevant with the ischemic defective) of stress marking.

" stress mark " is the image of the ischemia among 17 heart sections one or more, as to use following scale be 0 to 4 by blind property evaluator scoring: normal perfusion=0, and counting slightly reduces=1, and counting moderate reduction=2 seriously reduce=3, not picked-up=4.Normally, when record scoring 〉=4, then ischemic region is determined.Stress mark and amount to the scoring of all abnormal section.

" A stress mark " is stress state between independent adenosine and the image diversity of values between the quiescent condition." B stress mark " be combination stresser-with 40 μ g/kg the dipyridamole bullet of 20-30 in second, subsequently with 70 μ g/kg/ minutes adenosine infusion-stress state and quiescent condition between the image diversity of values." Δ scoring " is the difference between " A stress mark " and " B stress mark ".It also needn't＞2.

Owing to think that at present thallium is that the best isotope and the technetium sestamibi (sestamibi) of test tranquillization myocardial viability is the best isotope that detects myocardium defective under stress state, so dual-isotope cardiac muscle scintigraphy is used for this research.

Shown in data at table 11, there is not patient's Δ scoring to surpass 2: promptly not have patient's combination stresser to finish to such an extent that significantly be worse than Adenoscan.In three (3) routine patients, the Δ scoring is negative value, and this ischemic defective development that shows combination stresser is better than independent Adenoscan.Total Δ scoring of 10 routine patients (it is main research terminal point) is lower than 2, even is negative value.

The 2 40 μ g/kg series that expection is used corresponding to adenosine 70 μ g/kg/mn and dipyridamole 10 μ g/kg/mn the time provides similar result (preliminary analysis that the technical staff did that has neither part nor lot in test shows that image is suitable in all patients).But, also do not carry out stochastic analysis and the corresponding Δ scoring (a routine patient fail reach 10) of two blind property evaluators to this image series.

About the patient tolerability of operation, play firstfruits as being displayed in Table 12 (n=27 example patient).These data that play firstfruits show between the 40 μ g/kg dipyridamoles of 35 μ g/kg dipyridamoles of (i) and the combination of 70 μ g/kg/ minutes adenosines and (ii) adenosine combination in 70 μ g/kg/ minutes does not have a lot of symptomatology differences.Therefore, result accumulation, and comprise with 35 μ g/kg dipyridamoles+with 8 routine patients of adenosine treatment in 70 μ g/kg/ minutes with 19 routine patient's data of 40 μ g/kg dipyridamoles+treat (SC) with 70 μ g/kg/ minutes adenosines.Suppose to produce similar side effect feature that then present preferred 40 μ g/kg dipyridamole dosage are because it is tending towards showing bigger effectiveness.As implied above, all 27 routine patients use independent Adenoscan (ADE) imaging first.

Annotate: accept the decreased number-45% of the middle chest pain incident of patient (n=19) of dipyridamole 40 μ g/kg and adenosine 70 μ g/kg/mn, the number of other adverse events does not have difference.

The #=number

Table 13 provides according to preceding 27 routine patients' vision scale (from 0 to 10) being estimated adverse events severity accumulation scoring.

Annotate: accept % among the patient (n=19) of dipyridamole 40 μ g/kg and adenosine 70 μ g/kg/mn and change and be very similar to those that show.

Point at this moment, A ₂The difference of the generation of the side effect that receptor is relevant or the severity of symptom is not as becoming obviously clear between compositions stresser and Adenoscan.On the contrary, chest pain (A ₁The side effect that receptor is relevant) become obvious among the generation (43%) and the minimizing pro-27 routine patients of severity (69%).ST on the EKG changes also and reduces, and comparing still less with Adenoscan with this variation during the described composite test and more not serious: in 27 routine patients of test up to now, only 6 patients have the ST variation.The difference of each patient's ST variation is not remarkable separately, but total variances has reached significance, and visible trend helps described combination.In following table (table 14), ST variation/baseline is represented with millimeter.

4.3 embodiment 3

Study and estimate the A that contains with 7: 1: the pharmacological property of the adenosine of D weight rate and the pharmaceutical composition of dipyridamole.Particularly, study to estimate and comprise with the concentration adenosine of 7mg/ml with the character of the compositions of the concentration dipyridamole of 1mg/ml.This particular formulations is very convenient, also contains multiple needs because it allows to be used for the use of the common figure (plain figure) of calculating concentration, maximum volume and weight-its administration error-while that is used to reduce clinical setting, and is as shown in the table:

Dipyridamole is insoluble in saline, and medium-term and long-term unstable at the solvent of pH＞4.Therefore adenosine composition pH＞4 that are used for clinical practice at present are unsuitable for adding dipyridamole.Therefore, select more tart pH.Lower pH also makes the increase of adenosine dissolubility be higher than 4mg/ml, and this is the upper limit that can accept adenosine concentration in the saline.

Prepare following compositions:

After 10 minutes, solution becomes got clarification fully ultrasonic 2 minutes and magnetic agitation, wherein pH be 3.6 and osmolality (osmolality) be 151mosmol/kg.

In a word, (Adenoscan is to be used for cardiac imaging to induce the standard pharmacology's stresser near maximum coronary artery diastole Astellas) to adenosine.When it uses with 140 μ g/kg/ minutes recommended dose speed with a lot of side effects.The digital proof of these researchs, use dipyridamole-well below when the accumulated dose of dipyridamole infusion during-with 28 to 40 μ g/kg bullets in succession subsequently with 70 μ g/kg/ minute infusion adenosine as single medicine stresser, equivalence causes side effect still less simultaneously in the coronary artery diastole that is provided for imaging research.These data prove that also dipyridamole and adenosine can be with single infusion combination in 4 minutes to reach similar effect.The danger of chest pain and obvious cardiempharaxis is at the row of the side effect that combination of the present invention reduced.

The full content of all publications, patent, patent application and the alternative document of being quoted among the application is incorporated this paper into by reference for all purposes, reaches as each independent publication, patent, patent application or alternative document to point out the degree incorporated into by reference for all purposes separately.

Although example and describe various specific embodiments it should be understood that, under without departing from the spirit and scope of the present invention, can carry out various variations.

Claims (115)

1. pharmaceutical composition, it comprises about 2: 1 of weight rate to about 10: 1 adenosine: the adenosine of dipyridamole and dipyridamole.

2. pharmaceutical composition according to claim 1, wherein said ratio are about 2: 1 to about 4: 1.

3. pharmaceutical composition according to claim 1, wherein said ratio are about 7: 1.

4. pharmaceutical composition according to claim 1, wherein said ratio are about 8: 1.

5. according to each described pharmaceutical composition of claim 1-4, wherein adenosine and dipyridamole exist with the amount that allows adenosine and use with 35 to 100 μ g/kg/ minutes dose rates and allow dipyridamole to use with 3.5 to 50 μ g/kg/ minutes dose rates.

6. pharmaceutical composition according to claim 5, wherein said compositions is a sterile fluid.

7. pharmaceutical composition according to claim 6, wherein adenosine and dipyridamole exist with the concentration that allows direct intravenous to use.

8. according to claim 6 or the described pharmaceutical composition of claim 7, wherein adenosine and dipyridamole exist with the concentration that allows adenosine to use with 8.75 to 10 μ g/kg/ minutes dose rates with 70 μ g/kg/ minutes dose rates and dipyridamole.

9. according to claim 6 or the described pharmaceutical composition of claim 7, wherein adenosine and dipyridamole exist with the concentration that allows adenosine to use with 12.5 to 25 μ g/kg/ minutes dose rates with 50 μ g/kg/ minutes dose rates and dipyridamole.

10. according to each described pharmaceutical composition of claim 6-9, wherein the concentration of adenosine is about 1 to 10mg/ml.

11. pharmaceutical composition according to claim 10, wherein the concentration of adenosine is about 3mg/ml.

12. pharmaceutical composition according to claim 10, wherein the concentration of adenosine is about 4mg/ml.

13. pharmaceutical composition according to claim 10, wherein the concentration of adenosine is about 5mg/ml.

14. pharmaceutical composition according to claim 10, wherein the concentration of adenosine is about 7mg/ml.

15. according to each described pharmaceutical composition of claim 6-14, wherein the concentration of dipyridamole is about 0.1 to 5mg/ml.

16. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is about 0.375 to 0.428mg/ml.

17. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is about 0.5 to 0.571mg/ml.

18. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is about 0.625 to 0.714mg/ml.

19. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is about 0.75 to 0.857mg/ml.

20. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is about 0.875 to 1mg/ml.

21. pharmaceutical composition according to claim 15, wherein the concentration of dipyridamole is 1mg/ml.

22. a unit dose, its comprise about 2 to 50ml according to each described compositions of claim 1-21, wherein said compositions is a sterile fluid.

23. unit dose according to claim 22, it comprises about 2ml.

24. unit dose according to claim 22, it comprises about 3ml.

25. unit dose according to claim 22, it comprises about 4ml.

26. unit dose according to claim 22, it comprises about 5ml.

27. unit dose according to claim 22, it comprises about 7ml.

28. unit dose according to claim 22, it comprises about 8ml.

29. unit dose according to claim 22, it comprises about 14ml.

30. a unit dose, it comprises about 5 to 60mg adenosines and about 0.5 to 30mg dipyridamole, wherein compositions be can be on the physiology solid of aseptic reconstruction in acceptable solvent or the solution.

31. unit dose according to claim 30, it comprises about 21mg adenosine and about 3mg dipyridamole.

32. unit dose according to claim 30, it comprises about 28mg adenosine and about 4mg dipyridamole.

33. unit dose according to claim 30, it comprises about 35mg adenosine and about 5mg dipyridamole.

34. unit dose according to claim 30, it comprises about 42mg adenosine and about 6mg dipyridamole.

35. unit dose according to claim 30, it comprises about 56mg adenosine and about 8mg dipyridamole.

36. unit dose according to claim 30, it comprises about 20mg adenosine and about 5 to 10mg dipyridamoles.

37. unit dose according to claim 30, it comprises about 30mg adenosine and about 7.5 to 15mg dipyridamoles.

38. unit dose according to claim 30, it comprises about 40mg adenosine and about 10 to 20mg dipyridamoles.

39. the unit dose of a dipyridamole, it comprises concentration is 0.1 to 5mg/ml dipyridamole.

40. according to the described unit dose of claim 39, wherein said dipyridamole concentration is about 0.5mg/ml.

41. according to the described unit dose of claim 40, it comprises the 3mg dipyridamole in 6ml.

42. according to the described unit dose of claim 40, it comprises the 4mg dipyridamole in 8ml.

43. according to the described unit dose of claim 40, it comprises the 5mg dipyridamole in 10ml.

44. according to the described unit dose of claim 40, it comprises the 6mg dipyridamole in 12ml.

45. according to the described unit dose of claim 40, it comprises the 8mg dipyridamole in 16ml.

46. according to the described unit dose of claim 39, it comprises the dipyridamole of the about 3mg/ml of concentration to about 5mg/ml.

47. according to the described unit dose of claim 46, wherein said dipyridamole concentration is about 3mg/ml.

48. according to the described unit dose of claim 46, wherein said dipyridamole concentration is about 4mg/ml.

49. according to the described unit dose of claim 47, it comprises the 6mg dipyridamole in 2ml.

50. according to the described unit dose of claim 48, it comprises the 8mg dipyridamole in 2ml.

51. the unit dose of an adenosine, it is mixed with the sterile fluid compositions, and it is at least 15% second fluid of described adenosine composition volume that wherein said dose package allows aseptic introducing volume.

52. according to the described unit dose of claim 51, it comprises the 21mg adenosine in 6ml.

53. according to the described unit dose of claim 51, it comprises the 28mg adenosine in 6ml.

54. according to the described unit dose of claim 51, it comprises the 42mg adenosine in 12ml.

55. according to the described unit dose of claim 51, it comprises the 56mg adenosine in 12ml.

56. the unit dose of an adenosine, it is mixed with the sterile fluid compositions, and it comprises the adenosine of the about 4mg/ml of concentration.

57. according to the described unit dose of claim 56, it comprises the 28mg adenosine in 7ml.

58. according to the described unit dose of claim 56, it comprises the 56mg adenosine in 14ml.

59. a medicine box, it comprises at least a unit dose of dipyridamole and at least a unit dose of adenosine.

60. according to the described medicine box of claim 59, at least a unit dose of wherein said dipyridamole is according to each described unit dose of claim 39-50.

61. according to claim 59 or 60 described medicine boxs, at least a dosage of wherein said adenosine is according to each described unit dose of claim 51-58.

62. a realization is used for the method for the coronary artery diastole of cardiac diagnosis, described method comprises: use adenosine and dipyridamole simultaneously, wherein adenosine and dipyridamole with about 2: 1 to about 10: 1 adenosine: dipyridamole weight rate parenteral is used.

63. according to the described method of claim 62, wherein said adenosine: the dipyridamole ratio is about 7: 1.

64. according to the described method of claim 62, wherein said adenosine: the dipyridamole ratio is about 8: 1.

65. according to the described method of claim 62, wherein said adenosine: the dipyridamole ratio is about 4: 1.

66. according to the described method of claim 62, wherein said adenosine: the dipyridamole ratio is about 2: 1 to 4: 1.

67. according to the described method of claim 62, wherein adenosine is used with 35 to 100 μ g/kg/ minutes dose rates, and dipyridamole is used with g/kg/ minute dose rates of 3.5-50 μ.

68. according to the described method of claim 67, wherein adenosine is used with 70 μ g/kg/ minutes dose rates, and dipyridamole is used with 10 μ g/kg/ minutes dose rates.

69. according to the described method of claim 67, wherein adenosine is used with 70 μ g/kg/ minutes dose rates, and dipyridamole is used with 8.75 μ g/kg/ minutes dose rates.

70. according to the described method of claim 67, wherein adenosine is used with 50 μ g/kg/ minutes dose rates, and dipyridamole is used with g/kg/ minute dose rates of 12.5-25 μ.

71. according to each described method of claim 62-70, wherein adenosine and dipyridamole parenteral continue to use the period at least about 2 minutes.

72. according to the described method of claim 71, wherein adenosine and dipyridamole parenteral continue to use and are less than 6 minutes.

73. according to the described method of claim 72, wherein adenosine and dipyridamole parenteral continue to use about 4 minutes period.

74. according to each described method of claim 62-73, wherein adenosine and dipyridamole are used with single compositions.

75. according to each described method of claim 62-73, wherein adenosine and dipyridamole are used by the discrete sets compound.

76. according to each described method of claim 62-75, wherein adenosine and dipyridamole compositions are used by intravenous infusion.

77. according to each described method of claim 62-75, wherein adenosine and dipyridamole compositions at least a by in the atrium or intra-arterial use, wherein by in the atrium or at least a compositions used of intra-arterial use with the dosage of regulating by 1/200 to 1/400 dosage multiplier separately.

78. according to the described method of claim 62-77 each each, it further comprises the step of assess cardiac function.

79. according to the described method of claim 78, wherein assess cardiac function comprises and uses one or more to be selected from following group technology: electrocardiography, M type sonography, the two dimension sonography, three-dimensional sonography, echo Doppler, cardiac imaging, plane (routine) scintigraphy, single photon emission tomography (SPECT), dynamic single photon emission tomography, positron emission tomography (PET), pass through RAG first, equilibrium activity nucleic angiography, nuclear magnetic resonance, NMR (NMR) imaging, perfusion contrast echo cardiography, digital subtraction angiography (DSA) and ultrahigh speed X ray computer tomography (CINE CT).

80. according to the described method of claim 79, wherein functional evaluation is undertaken by SPECT.

81. according to the described method of claim 79, wherein said evaluation is undertaken by PET.

82. according to each described method of claim 78-81, wherein assess cardiac function comprises that isotopic parenteral uses, and wherein said isotope at the same time parenteral use and be no less than 2.5 minutes after adenosine and dipyridamole begin and use.

83. 2 described methods according to Claim 8, wherein said isotope parenteral are at the same time used adenosine and dipyridamole and are begun the back and used in about 2.5 minutes.

84. a realization is used for the method for the coronary artery diastole of cardiac diagnosis, described method comprises:

Parenteral is used dipyridamole; And

After this simultaneously or in succession parenteral is used adenosine receptor agonist,

Wherein dipyridamole is used to be lower than the dosage that reaches maximum coronary artery diastole required dosage when using with single medicine by identical parenteral approach separately with described adenosine receptor agonist.

85. 4 described methods according to Claim 8, wherein said adenosine receptor agonist is selected from the group of being made up of following: adenosine, adenosine triphosphate, adenosine diphosphate (ADP), adenosine monophosphate with and prodrug and pharmaceutically acceptable salt.

86. 4 or 85 described methods according to Claim 8, wherein every kind of approach using of parenteral independently is selected from by intra-arterial, intravenous and atrium and uses the group of forming.

87. 6 described methods according to Claim 8, wherein dipyridamole is used by intravenous or intra-arterial bolus injection.

88. 7 described methods according to Claim 8, wherein dipyridamole is used with the dosage intravenous or the intra-arterial bullet that are no more than 140 μ g/kg.

89. 8 described methods according to Claim 8, wherein dipyridamole is used with the dosage intravenous or the intra-arterial bullet that are no more than 50 μ g/kg.

90. 9 described methods according to Claim 8, wherein dipyridamole is used with the dosage intravenous or the intra-arterial bullet that are no more than 40 μ g/kg.

91. each described method of 4-90 according to Claim 8, wherein dipyridamole is used with dosage intravenous or the intra-arterial bullet of at least 14 μ g/kg.

92. according to the described method of claim 91, wherein dipyridamole is used with dosage intravenous or the intra-arterial bullet of 23 to 60 μ g/kg.

93. according to the described method of claim 92, wherein dipyridamole is used with dosage intravenous or the intra-arterial bullet of 35 μ g/kg.

94. according to the described method of claim 93, wherein dipyridamole is used with dosage intravenous or the intra-arterial bullet of 40 μ g/kg.

95. each described method of 4-94 according to Claim 8, wherein dipyridamole is used by the intravenous infusion in 1 or 2 minute.

96. each described method of 4-95 according to Claim 8, being applied in of wherein said adenosine receptor agonist begins after dipyridamole is used end.

97. according to the described method of claim 96, wherein adenosine receptor agonist is applied in half a minute to 2 minute beginning behind dipyridamole injection or the infusion.

98. 4 described methods according to Claim 8, wherein dipyridamole is to use by the intravenous infusion in 2 to 6 minutes with the mixture of described adenosine receptor agonist.

99. according to the described method of claim 98, wherein said mixture is used by the intravenous infusion in 4 minutes.

100. each described method of 4-99 according to Claim 8, wherein said adenosine receptor agonist is an adenosine, and it is used by intravenous infusion with the dose rates that is no more than about 100 μ g/kg/ minutes.

101. according to the described method of claim 100, wherein adenosine is used with the dose rates that is no more than about 70 μ g/kg/ minutes.

102. according to the described method of claim 101, wherein adenosine is used with the dose rates that is no more than 50 μ g/kg/ minutes.

103. each described method of 4-102 according to Claim 8, wherein said adenosine receptor agonist is an adenosine, and it is to use by intravenous infusion at least about 35 μ g/kg/ minutes dose rates.

104. according to the described method of claim 103, wherein adenosine is to use by intravenous infusion at least about 50 μ g/kg/ minutes dose rates.

105. according to the described method of claim 103, wherein adenosine is used by intravenous infusion with about 35 μ g/kg/ minute-100 μ g/kg/ minutes speed.

106. according to the described method of claim 105, wherein adenosine is used by intravenous infusion with about 50 μ g/kg/ minutes to about 70 μ g/kg/ minutes speed.

107. according to the described method of claim 106, wherein adenosine is used by intravenous infusion with about 70 μ g/kg/ minutes speed.

108. each described method of 4-107 according to Claim 8, wherein dipyridamole is used and adenosine is used through intravenous through intravenous.

109. according to the described method of claim 108, wherein said adenosine receptor agonist is an adenosine, the accumulated dose of dipyridamole is 23 to 40 μ g/kg, and the dose rates of adenosine is 50 to 70 μ g/kg/ minutes.

110. according to the described method of claim 109, wherein the accumulated dose of dipyridamole is 40 μ g/kg, and the dose rates of adenosine is 70 μ g/kg/ minutes.

111. each described method of 4-110 according to Claim 8, it further comprises the step of assess cardiac function.

112. according to the described method of claim 111, wherein the described step of assess cardiac function comprises and uses one or more to be selected from following group technology: electrocardiography, M type sonography, the two dimension sonography, three-dimensional sonography, echo Doppler, cardiac imaging, plane (routine) scintigraphy, single photon emission tomography (SPECT), dynamic single photon emission tomography, positron emission tomography (PET), pass through RAG first, equilibrium activity nucleic angiography, nuclear magnetic resonance, NMR (NMR) imaging, perfusion contrast echo cardiography, digital subtraction angiography (DSA) and ultrahigh speed X ray computer tomography (CINE CT).

113. according to the described method of claim 112, wherein functional evaluation is undertaken by SPECT.

114. according to the described method of claim 112, wherein said evaluation is undertaken by PET.

115. according to each described method of claim 111-114, wherein assess cardiac function comprises that parenteral uses isotope, and wherein said isotope is used after 2 minutes at sequential application dipyridamole and described adenosine receptor agonist, and uses dipyridamole and described adenosine receptor agonist at the same time after 2.5 minutes but used before 3 minutes.