MXPA01001877A - Amelioration of apomorphine adverse effects - Google Patents

Abstract

Symptoms of Parkinson's disease and psychogenic male erectile dysfunction (MED) can be ameliorated through the use of apomorphine. The adverse side effects of apomorphine administration, such as nausea, vomiting, yawning, and cardiovascular effects, can be significantly reduced by a dose escalating method of acclimatization. An initial dose of apomorphine is administered to the patient, and subsequently increased over a period of time until a final apomorphine dose in excess of a desired therapeutic dose has been received by the patient. Thereafter a therapeutic dose of apomorphine, less than the final apomorphine dose, is administered to the patient with attendant reduced side effects.

Description

IMPROVING THE ADVERSE EFFECTS OF APOMORPHINE FIELD OF THE INVENTION This invention relates to the improvement of adverse effects, such as nausea, yawning, vomiting and cardiovascular effects, caused to human patients when taking apomorphine for Parkinson's disease, erectile dysfunction or other similar diseases.

BACKGROUND OF THE INVENTION Apomorphine has been used to treat patients with Parkinson's disease. See, for example, Deffond et al., J. Neurology, Neurosurgery, and Psychiatry 56 ^: 101-103 (1993) and Durif et al., Clinical Neuropharmacology 16. (2): 157-166 (1993). Additionally, apomorphine has been considered for the treatment of alcoholism, schizophrenia, dystonia m us cul orum deformans, hallucinations, migraine headaches, hiccups, Huntington's chorea, tardive dyskinesia and, more recently, male erectile dysfunction. Administration of large doses of apomorphine to mammals such as humans, dogs and the like, usually results in nausea and vomiting, and it is believed that this is due to the action of apomorphine in the chemoreceptor activation zone (CTZ) of the medulla oblongata, a structure of the central nervous system of mammals. It is also believed that additional chemoreceptors that activate vomiting are present in the gastrointestinal tract as such. Impotence or male erectile dysfunction is defined as the inability to achieve and sustain an erection sufficient for sexual contact. Impotence in any given case can result from psychological (psychogenic) disorders of physiological abnormalities in general (organic), neurological (neurogenic) disorders, hormonal (endocrine) deficiencies or a combination of the preceding. However, these descriptions are not exact. Currently there is no standardized diagnosis or treatment method. As used herein, psychogenic impotence is defined as functional impotence without forceful, apparent organic base. It may be characterized by the ability to have an erection in response to certain stimuli (for example, masturbation, spontaneous nocturnal stimulation, spontaneous early morning stimulation, erotic videos, etc.) but not others. (for example, the attention of the couple or husband). The effect of apomorphine on penile tumescence in male patients suffering from psychogenic impotence has also been studied.

These studies show that although apomorphine can effectively induce an erection in a psychogenic male patient, the dose of apomorphine required to achieve a significant erectile response is usually accompanied by nausea or other serious, undesirable side effects, including hypertension, flushing and diaphoresis. (sweating). However, the specific mechanisms by which apomorphine acts to produce an erectile response in a human patient are not yet fully understood. In addition, it has been shown that apomorphine has a very poor oral bioavailability. See, for example, Baldessarini et al., In Gessa et al., Eds., Apomorphine and Other Dopaminomimeti cs, Ba si c Pha rma col ogy, Vol. 1, Raven Press, N.Y. (1981), pp. 219-228. In this way, the search continues for an effective treatment of psychogenic impotence in male patients, as well as diagnostic methods that can identify these patients. It has now been found that certain delivery systems for apomorphine can provide a practical therapeutic and / or diagnostic "window", while reducing the likelihood of undesirable side effects. Acute and sub-acute analysis of apomorphine hydrochloride have been reported in some studies, with daily doses ranging up to more than 300 milligrams per kilogram (mg / kg) in lower vertebrates (amphibians and birds), and up to 10 mg / kg. kg in higher mammals (primates). In • mammals, it seems that doses of apomorphine hydrochloride are tolerated up to values of approximately 13 milligrams / kilogram in a single subcutaneous bolus injection. It has been reported that doses in this amount or above it are lethal in the mouse, although the LD50 is significantly higher (> 50mg / kg) in this species. The continuous infusion of apomorphine has been tolerated and doses of 420 μg / kg / hour have been reported for 14 days. It was found that higher doses ((1,500 μg / kg / hour) are minimally lethal during the study of 14 days). In primates, multiple doses of apomorphine hydrochloride have been administered for up to four days at a rate of 100-400 μg / kg without major adverse effects. • However, in 1995, The Pha rma col ogy of Sexual l Fun cti on and Dysfunct on (JJ Bancroft, editor), in an article, on pages 25-229 entitled "Dopamine agonists and their effect on the human penile erectile response" (Dopamine agonists and their effect on the human penile erectile response) for R. T .. Segraves, M.D., summarizes the evidence concerning the use of dopamine agonists, especially apomorphine, to induce erectile responses in human males. The article concludes that "clearly, apomorphine has too many side effects to have therapeutic utility". Despite the Segraves article, it has been • found that the dosage forms of 5 apomorphins are effective in the treatment of Parkinson's disease, as well as in male patients suffering from psychogenic erectile dysfunction, for the induction and maintenance of an erection sufficient to achieve sexual contact (it is say, vaginal penetration). Although to dosages • relatively minor, apomorphine can be administered without nausea or other undesirable side effects, those side effects manifest themselves as the dosages of apomorphine. When the plasma concentration of apomorphine is maintained at values no greater than about 5.5 nanograms per milliliter (ng / ml), the incidence of adverse side effects is min. That monitoring, of course, requires any invasive procedure, such as blood analysis or urinalysis, to determine the appropriate dosage requirements. The present method is provided for the improvement of the adverse effects, due to the use of apomorphine, without the invasive characteristic of the previous methods.

SUMMARY OF THE INVENTION ^ fc The adverse effects of apomorphine, such as nausea, vomiting, yawning, cardiovascular effects, etc., in a human patient, are minimized by the administration of an escalation dosage of apomorphine, through a time frame. The method begins with the administration of a threshold or initial dose of ^^ 10 apomorphine, followed by periodic increasing doses of apomorphine, until a final dose in excess of a therapeutic dose is administered. The patient is then given a therapeutic dose of apomorphine for treatment purposes. In a preferred embodiment for the treatment of psychogenic impotence, sublingual doses of apomorphine are periodically administered. The final dose of apomorphine is • preferably in excess than what is needed to produce an erection in the patient, rigid enough. The therapeutic sublingual dose is less than the final dose of apomorphine but is still sufficient to produce an erection with sufficient rigidity for vaginal penetration without the substantial adverse effects taken care of. Preferably, the sublingual threshold dose of apomorphine, for a human patient, can be in the range of about 2 to about 8 milligrams (mg), and more preferably about 4 mg. The increased dosage occurs preferably at • ratio of approximately 2 mg per day for a period of not less than three days, administering the therapeutic dose of apomorphine after the final dose is given. The final dose of apomorphine, administered to a human patient suffering from psychogenic erectile dysfunction, is approximately 8 to 10 mg. The therapeutic dose Sublingual of apomorphine is preferably 6 mg and may vary depending on the patient, in the range from about 35 to about 74 micrograms per kilogram (μg / kg) of the patient's body weight and, most preferably, within the range of from about 50 to about 74 micrograms per kilogram (μg / kg) of body weight. • For patients with the disease Parkinson's, a subcutaneous therapeutic dose, ie, sufficient to improve the symptoms of Parkinson's disease, may be as high as approximately 8 mg, usually approximately 3 to 5 mg, per administration. A dose Sublingual therapy for the treatment of Parkinson's disease symptoms can be as high as about 60 mg, usually from about 20 to about 40 mg. Subcutaneous threshold doses may be in the range of about 1.25 mg to about 5 mg AF, usually about 3 mg. Notwithstanding the dosage form, The plasma concentration of apomorphine is preferably maintained in the range from about 3 to about 20 nanograms per milliliter, for the treatment of the symptoms of Parkinson's disease. ^^ 10 For patients with female sexual dysfunction, the administration of apomorphine has been shown to increase the nervous stimulation of the clitoral intracavernous blood flow and the blood flow of the vaginal wall, each of which is associated respectively with intensified clitoral erection and vaginal congestion in a female. A A dosage form of sublingual apomorphine, which usually contains from about 2 to about 12 mg, preferably from about 2 to about 8 mg of apomorphine, is effective to produce sexual disposition in human females, without inducing nausea or other substantial effects undesirable side effects. Sublingually, administration is preferably carried out from about 15 to about 20 minutes before sexual activity. The plasma concentration of apomorphine is maintained at values no greater than about 5.5 ng / ml, preferably from about 0.3 to about 4 ng / ml, and more preferably from about 1 to about 2 ng / ml, to maintain an apomorphine level in circulating serum and in the middle brain tissue, during the period of sexual activity, sufficient to maintain vaginal congestion, its associated lubrication and erection clitoridea, during intercourse. • For patients who have been diagnosed with social phobia, a dopaminergic agonist such as apomorphine reduces the patient's inability to engage in social interactions, which characterizes social phobia. Treatment regimens that achieve a white plasma concentration of apomorphine, in the range from about 0.5 ng / ml to about • 10 ng / ml to one Cmax, with chronic therapy of 2 or more treatments, provide a therapeutically effective dose that produces the improvement of social phobia in a patient.

BRIEF DESCRIPTION OF THE FIGURES 25 Figure 1 is a graph of the duration of nausea / attempt to vomit and vomit, against time, for dogs, at a dose of acclimation of apomorphine, of 0.05 mg / kg; Figure 2 is a graph of the duration of nausea / attempt to vomit and vomit, against time, for dogs, at a dose of acclimatization of • apomorphine, 0.4 mg / kg; Figure 3 is a graph, through several days, of the number of dogs that experienced vomiting in the first five minutes followed by the administration of apomorphine, at three different doses of apomorphine; 10 Figure 4 is a graph, through • several days, of the number of dogs that experienced vomiting in three periods of time following the administration of 0.04 mg of apomorphine per kilogram of dog weight; Figure 5 is a graph, through several days, of the number of dogs that experienced vomiting in three periods of time followed by the administration of 0.1 mg of apomorphine per kilogram of dog weight, Figure 6 is a graph, through several days, the number of dogs that experienced vomiting in three periods of time followed by the administration of 0.4 mg of apomorphine per kilogram of dog weight; Figure 7 is a graph of mean arterial pressure versus time, for dogs that received three different dosages of apomorphine, measured after 5 months of daily administration of apomorphine; Figure 8 is a graph of the rhythm • Cardiac against time, for dogs that received three different dosages of apomorphine, measured after 5 months of daily administration of apomorphine, Figure 9 is a graph of mean plasma concentrations of apomorphine, ^^ 10 against time, for dogs that received 0.04 mg of apomorphine per kilogram of weight; Figure 10 is a graph of mean plasma concentrations of apomorphine, versus time, for dogs that received 0.1 mg 15 of apomorphine per kilogram of weight; Figure 11 is a graph of mean plasma concentrations of apomorphine, versus time, for dogs that received 0.4 mg apomorphine per kilogram of weight; Figure 12 is a bar graph depicting the incidence of nausea (an adverse event) in humans, in each dosage administered, as a percentage of the doses administered; Figure 13 is a bar graph depicting the incidence of vomiting (an adverse event) in humans, at each dosage administered, as a percentage of the doses administered; Figure 14 is a line chart representing the average RIGISCANMR score for human participants at each dose level and • for each type of video (that is, erotic and neutral); Figure 15 represents a sample home questionnaire from a study of sexual function, for the male participant, that needs to be filled in a time from about 12 to about 24 hours after administering a sublingual dose of apomorphine; • Figure 16 represents a sample home questionnaire, from a study of sexual function, for the female partner of the male participant, who needed to be filled in a time of approximately 12 to approximately 24 hours after the administration of the sublingual dose of apomorphine, and Figure 17 represents a sample questionnaire, of Visual Analogue Scale, used for determine the patient's sense of well-being, the level of sedation, reassurance, anxiety, excitement and any change in the yawning compartment.

DESCRIPTION OF THE PREFERRED MODALITIES Although the present invention is susceptible to modalities in many different forms, a preferred embodiment of the invention is described below. However, it should be understood that the present description should be considered as an exemplification of the principles of the invention and • that it does not intend to limit the invention to the 5 specific modalities illustrated. Apomorphine is a dopamine receptor agonist that has a recognized use as a hemetic, when administered subcutaneously, at approximately a dose of 5 milligrams. For For the purposes of the present invention, apomorphine is administered in an amount sufficient to excite the cells of the middle brain region of a patient. It is believed that this cellular excitement is part of a cascade of stimulation that probably includes neurotransmission with serotonin and oxytocin. Dopamine receptors, in the middle brain region of a patient, can be stimulated to a sufficient degree to cause a erection, by sublingual administration of apomorphine. Apomorphine, also known by the chemical name (R) -5, 6, 6a, 7-tetrahydro-6-methyl-4H-dibenzo- [de, g] quinoline-10, 11-diol, has the following chemical structure: 25 Sublingual administration is usually carried out in a period of time in the range from about 2 to about 10 minutes, or longer. The amount of apomorphine administered sublingually through this period • of time, it is preferably in the range from about 35 to about 74 micrograms per kilogram (μg / kg) of the patient's body weight, and most preferably within the range of from about 50 to about 74 μg / kg of body weight. Acclimation to side effects The usual results that result from the chronic administration of apomorphine can be achieved by using a regimen and route wherein the patient is conditioned to the drug through blood levels where the drug is at a plasma concentration, or close to it, that produces these effects. The administration of apomorphine for acclimation may take the form of parenteral, oral or sublingual routes of administration. The sublingual route is preferred for patients suffering from dysfunction psychogenic erectile. For the quick acclimatization a sensible, personalized regime is preferred. The therapeutic dose is preferably identified as the smallest dose of apomorphine, at which the • Patient experiences related adverse effects. The threshold dose is repeated until no side effects are found. The frequency of repeated administrations of apomorphine may vary, but is preferably in the range from about 1 day to approximately 1 week per administration. • Subsequently the dose of apomorphine is increased until the adverse effects are experienced again. Now the administration of the increased dosage is repeated, until the patient do not experience more adverse effects. For scaling of subsequent doses, the previously tolerated dose is preferably doubled. The scaling of the dosage is • repeat until the dosage level of apomorphine exceeds the therapeutic dose for the white medical condition. Illustrative acclimation programs are presented below in Table la.

Table the dosing program for acclimatization to Apomorphine Concentration range Threshold or plasma1 Dosage Dosage (ng / ml) initial final Frequency2 Route Uses 0. 25-4.0 Tablet Tablet 1 per day sublingual Dysfunction of 2 mg of 6 mg sexual 3. 0-25 0.25 mg 3.0 mg 1 per subcutaneous Weekly Parkinson's disease 4. 0-30 Tablets Tablet 1 per day sublingual Disease of 8 mg of 40 mg of Parkinson's Notes: 1 The plasma range is the therapeutic target and is based on the therapeutic Cmx in nanograms of apomorphine per milliliter of plasma. 2 The frequencies are average intervals between the doses provided. A higher frequency is desired in routes where the plasma concentration has a shorter life time, for example subcutaneous or continuous infusion. Doses may be administered every hour for patients who require very high apomorphine plasma concentrations, such as in Parkinson's disease. For a more convenient distribution and management of the mass, a more structured acclimation regime is preferred. In one embodiment of the present invention for the treatment of psychogenic impotence, sublingual doses of apomorphine are administered, according to the acclimation regime presented in Table Ib.

Table Ib Treatment for Impotence - Program of dosing for acclimatization to the Apomorf ina Dosage Dosage Increased threshold dose Therapeutic final dose1 Day (week 1) (week 1) (week 3) (week 4) 1 Tablet of 2 mg Tablet of 3 mg Tablet of 4 mg Therapeutic tablet 2 mg tablet 3 mg tablet 4 mg tablet Therapeutic tablet 3 Tablet of 2 mg Tablet of 3 mg Tablet of 4 mg Therapeutic tablet 4 Tablets of 2 mg Tablets of 3 mg Tablets of 4 mg Therapeutic tablet Tablet of 2 mg Tablet of 3 mg Tablet of 4 mg Therapeutic tablet 6 Tablet of 2 mg Tablet of 3 mg Tablet of 4 mg Therapeutic tablet 7 Tablet of 2 mg Tablet of 3 mg Tablet of 4 mg Therapeutic tablet It has been found that 2 mg tablets, required for 1 week, are a threshold dose for most patients with impotence. The sublingual therapeutic dose required in week 4 is less than the final two weeks of apomorph but is still sufficient to produce an erection with sufficient rigidity for vaginal penetration. Without violating this restriction, the therapeutic dose may vary according to the patient. The following Table represents an acclimatization regime for the treatment of the symptoms of Parkinson's disease.

Table treating Parkinson's disease symptoms - Dosing schedule for Apomorphine acclimation Dosage Dosage Increased threshold dose Therapeutic final dose1 Day (week 1) (week 1) (week 3) (week 4) 1 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet 2 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet 3 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet 4 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet 6 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet 7 Tablet of 20 mg Tablet of 30 mg Tablet of 40 mg Therapeutic tablet The therapeutic sublingual dose required in week 4 is less than the final dose of apomorphine but still sufficient to substantially reduce the symptoms of Parkinson's disease. Structured acclimation regimes, • presented in Tables Ib and I, have advantages for acceptance and compliance by the patient. The necessary sublingual tablets can be placed in a distributor of calendar-card-type tablets. ^^ 10 ANIMAL STUDIES This invention is further illustrated by the following examples.

Example 1: Vomiting and attempting to vomit in dog, 15 followed by daily subcutaneous administration of apomorphine hydrochloride measuring the duration of vomiting and attempting to vomit after the • dosage. 20 In this dose-defining study, subcutaneous apomorphine hydrochloride was administered to dogs, starting at a rate of 0.05 or 0.4 mg / kg. The dosages were eventually scaled. The duration of nausea / attempt to vomit and vomit, 25 were monitored and captured in Figures 1 and 2. It is known that dogs are 5 to 10 times more sensitive than humans to vomiting induced by apomorphine.

At the lowest doses, the acclimatization of the animals, evidenced by the incidence of attempted vomiting and vomiting, occurred within 3 days of • the initial dose. After 12 days the animals were challenged with a dose 100% higher than their acclimated dose. Only a small increase in the duration of vomiting was observed, which was normalized at the end of the study. At the dose of 0.4 mg / kg / day, acclimation was evident after about 10 days (see Figure 2). In the next 21 days of treatment at 0.4 mg / kg / day, the dose was scaled to 0.8 mg / kg / day without any evidence of an increase in vomiting / attempt to vomit. On day 28 the dose was scaled to 1.2 mg / kg / day. This dose produced a modest increase in the duration of vomiting and the attempt to vomit. However, this dose produced significant disorders in locomotion and coordination due to the effect of the drug in the center of movement nigra-str iatal. The dose was reduced to 0.8 mg / kg / day where the movement disorders were observed again. It was believed that this was the result of the upregulation of the dopamine receptor system in the upper brain, also observed in other species. Once supersensitivity was achieved in the central nervous system, a washout period of approximately 4 to 6 weeks is required to establish homeostasis.

This study indicates that the period of treatment with apomorphine hydrochloride that produces a significant reduction in vomiting and intent • by vomiting, depends on the dose. In general, the average duration of the period of the attempt to vomit / vomit followed by the initial dose was approximately 30 minutes. This duration was markedly reduced to approximately 5 minutes followed by daily administration. In addition, once acclimatization had been established, the increase in • the dose in 100% acclimation dose, did not produce a corresponding increase in the duration of the attempt to vomit and vomiting.

Example 2: Time Measurement for the Maximum Number of Animals Acclimated to the Side Effects of the Daily Administration of Subcutaneous Apomorse. • The number of animals with 20 attempts to vomit or vomit during the selected time periods was recorded after subcutaneous administration of apomorphine hydrochloride. Specifically, the presence of attempt to vomit or vomit was recorded for the following periods 25 after the administration of apomorphine: from 0 to 5 minutes, from 5 to 30 minutes and from 30 to 60 minutes. This study provides a different view of the data recorded in Example 1. The data studied in Example 1 revealed the average period of attempt to vomit and vomit, while in this example the number of affected animals • It was examined in selected periods. 5 Observations were made at three different dosage levels, 0.04, 0.1 and 0.4 mg / kg / day. In this study, a dose escalation was not attempted. A group of five dogs was used for the analyzes at each level of dosage. The number of dogs in each group of • Dosage, as an episode of attempt to vomit or vomit in each period of time after administration, was recorded for daily administration for approximately 180 days. They were calculated averages of 10 days and plotted (see from figures 3 through 6). At the highest dosage level, from 0.4 achieve an 80 percent acclimation level • effective, required daily treatment by approximately 3 months. The results shown in Figures 3 through 6 indicate that individual variations occur effectively in a relatively refractory subject, and that acclimation can be achieved by repeated treatment at an intolerated dose. Acclimation time is a function of the dose provided and the predisposition of the individual subject to vomiting. Since many of the known side effects are the result of peripheral vasodilation, blood pressure after administration and heart rate were measured, • for each dosage group, followed by 5 months 5 of chronic treatment (around day 150). Blood pressure and heart rhythms of a group of untreated dogs were evaluated for comparison purposes. The results are reported graphically in figures 7 and 8. It was observed that it sometimes occurs tachycardia followed by the administration, although • Net changes in blood pressure are not significantly different from controls. Following the daily administration of apomorphine, peripheral vasodilation appears to be compensated by an increase in cardiac output. Initially, badicardia was registered in certain subjects exposed to apomorphine hydrochloride. This effect is lost by the acclimatization of the vagal nerve dopamine receptor, which produces a signal compensated that invokes an increase in heart rate to respond to the decrease in blood pressure. To assess whether the reduction in side effects could be attributed to changes in the After the pharmacokinetic response, a study of the plasma concentration profile was carried out for each dosage group on day 1, day 90 and day 180. Specifically, the plasma concentration of apomorphine was measured at intervals over a period of 8 hours followed by the administration. The results are presented in figures from 9 to • the 11. 5 There was no evidence of significant changes in the area under the curve (AUC), in the distribution or in the elimination of apomorphine between the plasma concentration data for the measurements of 1, day 90 or day 180. Therefore, the observed decrease in side effects by • Apomorphine, are not the result of significant changes in pharmacokinetics.

Example 3: Comparison of Sublingual, Oral and Subcutaneous Administration of Apomorphine Hydrochloride in Dog. The dogs were exposed to a single dose of apomorphine hydrochloride, first by • subcutaneous administration of 0.04 mg / kg, then subsequently at 3-day intervals at 0.2 mg / kg for the sublingual route and 0.2 mg / kg for the oral route. The control of incidents of vomiting and / or attempted vomiting is presented in Table II below.

Table II Duration of secondary effects is guided by the A subcutaneous, sublual, and oral administration of • cl orhidr; apomor tie • f ina en perrc > 3 5 Time from Subcutaneous Sublingual Oral Dose 8 minutes 4 0 0 15 minutes 2 1 0 30 minutes 0 1 0 Average Severity 150. 00% 50. 00% 0. 00% • 3 Number of animals that have nausea / vomiting in the set time interval; 4 animals per group.

The preceding results indicate that in the Initial treatment with a subcutaneous injection of apomorphine, at approximately six times the bioavailable sublingual dose, acclimatized the dogs to this subsequent dose. The pharmacokinetic analysis ^ of the data is shown in Table III below.

It was found that the bioavailability of the drug is approximately 13% through sublingual administration. This value is consistent with the human discoveries previously reported. 20 Table III Bioavailability of Apomorphine by Administration Route in Subcutaneous Dog (0.04 mg / kg) 483.56 ng / ml (min) Sublingual Bioavailability (0.2 mg / kg) 327.1 ng / ml (min) 13.53% Oral (0.2 mg / kg) 94.59 ng / ml (min) 3.91% STUDY IN HUMANS Example 4: Pharmacokinetic Comparison of a 4 mg and 8 mg Sublingual Tablet with an Intravenous Injection of 1 mg of Apomorphine Hydrochloride This study compares the plasma concentration of apomorphine followed by two sublingual doses of 4 or 8 mg tablets with an injection intravenous bolus of 1 mg. The study was carried out in seven healthy volunteer males. The plasma was prepared and tested using the method of Bianchi & Landi (J. Chromatography, 1985). The results are presented in Table IV below.

Table IV Comparison Pharmacokinetics Intravenous Tablet tablet of 1 mg apomorphine apomorphine 4 mg 8 mg Sublingual sublingual intravenous route Number of subjects 7 7 7 Tablet (s) x concentration 1 x 1 8 Dosage (mg / kg) 0.01 0.06 0.11 Crax (ng / mg) 8.3 0.83 2.07 Tmax (min) 2.2 17.5 52.5 AUC (ng / ml / min) 207 31.6 283 Cl (L / h / kg) 4.37 - - Vd (L / kg) 3.35 2.33 2.07 MRT (min) 340.3 64.2 143.7 T72 (min) 39.4 89.2 176.3 F _ 4.00% 0.21 AUC = Area under the curve Cl = Elimination Vd = Volume of distribution @ stage ß. Cd (SS) = Volume of steady state distribution MRT = Average residual time A plasma drug concentration of approximately 2.5 nanograms / milliliter is considered the threshold concentration (Cmax) at which the onset of adverse effects such as nausea occurs in human male subjects. When apomorphine is administered parenterally as apomorphine hydrochloride the threshold is easily exceeded. However, through the sublingual administration of • tablets containing at most 8 mg of apomorphine hydrochloride, the concentration of plasma drug can be maintained more easily at approximately Cmax.

Example 5: Study of Tolerance to the Scaling of the Dosage with Sublingual Tablets • Apomorphine Hydrochloride, for the Treatment of Male Psychogenic Erectile Dysfunction Example 5-Summary. This clinical study carried out in three phases. In Phase 1, subjects were selected among patients who complained of impotence, through a thorough physiological and psychological evaluation. For example, a stage • of the evaluation process required that the candidates were subjected to a Rigiscan measurement of stiffness and penile circumference followed by the administration of a placebo tablet in the single-blind form. Phase 2 consisted of escalation of the dose (tablets of 4, 6 and 8 mg) administ adas in 4 visits. An outpatient phase was carried out, known as phase 3. Patients were given apomorphine hydrochloride tablets to use at home. Adverse events (side effects) attributable to apomorphine hydrochloride were recorded in all three phases for the study. Table IV below is a summary of the frequency of side effects for the number of patients in the escalation phase (phase 2) compared with the outpatient phase (phase 3). During the escalation phase of the dose, it was observed that the frequency of side effects increased from 61.5% to 105.8% and began to decline, for the • 8 mg tablet, up to 94.2%. The frequency of side effects at doses of 4 and 6 mg were approximately one half and one third, respectively, compared with those of patients who had initial exposure at these doses. The evidence of acclimation demonstrates here the usefulness of scaling up the dose, for the reduction of global side effects. The • Side effects presented in this study were: nausea, fatigue, vertigo, sweating, yawning, hypotension and vomiting.

Table IV Summary of the Human Study Incidence of Secondary Effects Registered • During the Dose Escalation and Treatment of External Patients with Sublingual Tablets of Apomorphine Hydrochloride Phase 2 Phase 3 Dose (mg / week) 4 6 8 4 6 8 Total Number of 31 58 50 15 13 8 Adverse Events • 10 Table IV shows that a weekly dose escalation of apomorphine will initially be followed by an increase in side effects until acclimation is achieved. The number and severity of the effects secondary subjects presented by the subjects subsequently decreased. Example- 5 Detailed Description (Clinical Study # 94-03-01). The study in humans was carried out in three separate phases. Phase 1 consisted of appropriately select the objects and obtain baseline information of sexual performance for each subject. Phase 2 consisted of escalation of the dose in which the subjects were administered increasing doses of apomorphine during a period of four weeks. Finally, Phase 3 consisted of a five-week home trial, where patients self-administered constant doses of apomorphine, before sexual contact.

Phase 1: Selection of Subjects 5 The participating patients were selected from those who initially presented complaints of impotence. These patients underwent a thorough urological evaluation by a urologist, as well as an evaluation by a psychiatrist (See "baseline" column in Table VII). • Diagnostic analysis for erectile difficulties was extensive and included the following: biochemical profile, night penile tumescence (TPN) monitoring, flow studies Doppler, biotesiometry, body calibration analysis with intracorporeal injection of triple therapy and dynamic cavernosometry. These analyzes were used to exclude any arterial causality, • peripheral venous or neural impotence. Any patient with abnormalities in any of these three areas was excluded from entering the trials. Patients were also excluded for evidence of erectile dysfunction due to non-psychogenic causes (eg, discord relational), any personal history of endocrine disease (eg, Diabetes mel lit us), multiple sclerosis, cancer, heart disease, drug or alcohol abuse in the past 12 months, any history of hypogonadism or hyperprolactinemia, the use of penile prostheses, and many other conditions. Table VI below is not an exhaustive list of inclusion / exclusion criteria for the present study.

Table VI Inclusion / Exclusion Criterion A, INCLUSION CRITERIA 1. Written and signed consent has been obtained; 2. The subject is a heterosexual male between the ages of 18 and 65; 3. Diagnosis of psychogenic impotence evidenced by the documentation of: a. Unsuccessful sexual contact with your partner for at least six months before entering the study; b. Documented report of the ability to achieve or maintain an erection of sufficient quality and duration to have a sexual relationship during the 3 months prior to entering the study, evidenced by morning erections, masturbation and / or sexual erotic stimulation. 4. The subject currently has a stable heterosexual relationship; The subject and his partner agree to at least one attempt at vaginal intercourse every week during the study; • The subject and his partner agree to maintain effective birth control to prevent pregnancy during the study; The subject has a good general health; The subject wishes to comply with the study procedures. 10 • B EXCLUSION CRITERIA: There is no evidence in the subject of male erectile dysfunction due to non-psychogenic causes such as relational discord, physiological or organic dysfunction, Previous concomitant use of any of the following medications or treatments within the restricted time period, as follows: • • Presence of any disease related to non-psychogenic impotence, including but not limited to the following conditions: a. Endocrine disease (Di abe tes mel l i t us, Addison's disease, etc.,); b. Multiple sclerosis; c. Neurological illness or damage (damage or spinal cord injury, neuropathy, etc. ); d. Vascular disease (Leriche syndrome, aneurysm, atherosclerosis, cerebrovascular disease, etc.); 15 e. Cancer; F. Renal disease; g. Liver disease; h Cardiac disease (including hypotension, angina, history of MI, angioplasty, CABG, arrhythmia, etc.); i. Illness, trauma or pelvic damage; and • j. psychiatric disorder other than psychogenic impotence (including antisocial disorders, depression, schizophrenia, etc.); 4. History of hypogonadism or hyperprolactinemia (serum prolactin> 30 ng / ml + conversion YES); • 5. Documented history of testosterone level in the serum OOO or > 1000 ng / dL + SI conversion (above or below the normal range for the laboratory) in the 3 previous months 15 to enter the study. 6. Use of penile prostheses sometime in the past; 7. Presence of postural hypotension evidenced by a resting blood pressure < 90/50 • mmHg in the sitting position or hypertension evidenced by resting blood pressure > 170/110 mmHg; 8. History of drug or alcohol abuse within the past year; 9. Subject who does not wish to comply with the 25 study procedures.

The male patients who met all the criteria were diagnosed as having impotence, mainly of a psychogenic origin. If there were no known medical contraindications for the use of a dopaminergic drug, they were • offered to enter an APO trial.

• • • Table VII Program of Study Parameters * Seven days before the treatment period Fifty men who had been diagnosed with psychogenic male erectile dysfunction (MED) enrolled in the three-pass trial • from four different analysis sites, as shown in Table VII below.

Table VIII Subject Responsibility The investigations were conducted by Dr. Jeremy Heaton, M.D., at site # 1 (Kingston General Hospital, Kingston, ON, Canada); Dr. Magdy M. Hassouna, M.D., on site # 2 (Royal Hospital of Victoria, Montreal, PQ, Canada); Dr. Ridwan Shabsigh, M.D., at site # 3 (Columbia Presbyterian Medical Center, New York, New York); and Dr. Emil Tanagho, M.D., at site # 4 (University of California at San Francisco, San Francisco, California). The penile erectile response of each of the selected subjects was evaluated (measured with the outpatient tumescence monitor of RIGISCANMR) using the scoring system presented in Table IX, below.

Table IX RIGISCAN MR 10 score Maximum increase • 2. Maximum penile rigidity in the penile circumference Circumference (cm) Score Rigidity (%) Score 0.0 - < 0.5 0 0 - < 10 0 0.5 - < 1.0 1 10 - < 20 1 1.0 - < 1.5 2 20 - < 30 2 1.5 - < 2.0 3 30 - < 40 3 2.0 - < 2.5 hard < 1 min. 4 40 - < 50 4 2.5 or more, it lasts < 1 min. 5 50 - < 60 5 • 2.0 - < 2.5, hard > 1 min. 60 - < 70 6 6 70 - < 80 7 2.5 or more, hard > 1 min. 7 80 - < 90 3.0 or more, hard > 5 min 8 90 - 100 3.0 or more, hard > 10 minutes. Maximum increase in: Maximum Score: Score A: circumference of the A. stiffness of the penile tip penile tip B. Circumference of the B. stiffness of the base penile base penile The combination of the scores of A, B, C and D of Table IX produces a total score for each subject. A total score of less than 16 for • Individual subject indicates erectile dysfunction. 5 To complete this phase each of the subjects received a placebo tablet for sublingual administration and then watched a video, for 30 minutes, consisting of two erotic sequences of 10 minutes, separated by a sequence neutral 10 minutes. Subsequently the subjects • filled out a visual analogue scale (VAS) questionnaire, such as the one shown in Figure 17, about their feelings and well-being. After dialing in each of the thirteen categories of data, placing a small vertical line at some point on the horizontal line between the two opposite conditions, a score was given based on the distance of the mark, from • the left end of the horizontal line. The scores were noted in the box to the right of each category and subsequently 'used for statistical analysis. VAS data collected from fifty subjects, were used in the study as information for the baseline, as shown in Tables X a-c. Table Xa provides the mean, SEM median and range scores for various demographic categories for all sites combined, as well as for each individual site listed in Table VIII above. Table Xb shows the average SEM scores, • median and range for all sites combined and for each individual site, relative to the satisfaction of the subject with his erection and recent and global sexual performance. Table Xc shows the scores for the SEM mean, median and range for all sites combined, and for each site individual, concerning the results of the • erection and frequency of sexual intercourse of the subject.

Table Xa Information for the baseline regarding sexual performance All patients All sites combined Site 1 Site 2 Site 3 Site 4 Number of patients 50 11 16 14 9 Age (years) Mean 48.7 49.4 49.8 49.4. 45.1 SEM 1,433 3,540 2,446 2,655 3,310 Median 50.5 46.0 53.5 51.5 46.0 Range 26 - 69 33 - 69 33 - 62 26 - 62 30 - 60 N 50 11 16 14 9 Asian Race 1 (2.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (11.1%) Black 6 (12.0%) 0 (0.0%) 2 (12.5%) 3 (21.4%) 1 (11.1%) Hispanic 3 (6.0%) 0 (0.0%) 0 (0.0%) 3 (21.4%) 0 (0.0%) Blanca 40 (80.0%) 11 (100.0%) 14 (87.5%) 8 (57.1%) 7 (77.8%) Height (cm) Average 175.4 175.1 169.3 178.8 181.5 SEM 1.123 1.331 1.690 2.150 1.934 Medium 175.0 175.0 171.3 179.7 180.3 Rank 149.5 - 196 168 - 180 149.5 - 176 165.1 - 196 174.8 - 193 N 50 11 16 14 9 Weight (kg) Average 81.7 81.3 78.3 87.5 79.2 SEM 1,691 2,666 2,797 3,677 4,032 Median 80.0 83.9 75.0 85.9 80.4 Range 60 - 111.2 68 - 96 65.8 - 104.5 63.6 - 111.2 60 - 97.6 N 50 11 16 14 9 Table Xb Information for the baseline regarding sexual performance • All patients All sites combined Site 1 Site 2 Site 3 Site 4 Overall Satisfaction level with sexual performance within the last two months [1] Mean 17.7 16.3 16.3 24.6 10.9 SEM 2,491 4,249 3,398 6,342 4,880 • Medium 14.0 16.0 16.0 12.0 4.0 Range 0 - 62 1 - 46 0 - 51 0 - 62 0 - 39 N 49 11 15 14 9 Level of Satisfaction with the most recent sexual intercourse attempt [1] Mean 22.5 17.3 21.0 32.2 16.1 SEM 3.720 6.716 7.223 8.113 6.033 Median 9.0 5.0 7.0 21.0 8.0 Range 0 - 100 0 - 69 0 - 87 0 - 100 0 - 52 N 49 11 15 14 9 Results of the erection during the most recent sexual intercourse attempt [2] Mean 38.3 32.9 25.3 49.0 50.0 SEM 4,653 8,857 8,143 8,152 12,119 Medium 30.0 22.0 12.0 41.0 50.0 Range 0 - 100 1 - 80 1 - 96 7 - 100 0 - 100 N 49 11 15 14 9 [1] Visual analogue scale Extremely dissatisfied, 100 = Extremely satisfied [2] Visual Analogue Scale: 0 = No Erection, 100 Rigid erectile appropriate for penetration • Table Xc Baseline information on sexual performance All patients All sites combined Site 1 Site 2 Site 3 Site 4 Results of the total erection when the sexual act is attempted [2] Mean 41.1 32.3 42.1 41.9 48.9 SEM 4,093 5,985 8,836 7,642 9,866 Median 40.0 29.0 21.0 38.0 49.0 Range 0 - 100 0 - 54 3 - 100 4 - 100 1 - 96 N 49 11 15 14 9 Sexual relationship successfully completed during the most recent attempt? (No answer) 1 (2.0%) 0 (0.0%) 1 (6.3%) 0 (0.0%) 0 (0.0%) NO 35 (70.0%) 10 (90.9%) 13 (81.3%) 6 (42.9%) 6 (66.7%) YES 14 (28.0%) 1 (9.1%) 2 (12.5%) 8 (57.1%) 3 (33.3%) Frequency of sexual intercourse attempts, RARELY 0 NEVER 3 (6.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 3 (33.3%) 2 - . 2 - . 2 - 6 TIMES AT YEAR 4 (8.0%) 0 (0.0%) 1 (6.3%) 2 (14.3%) 1 (11.1%) ONE TO THE MONTH 5 (10.0%) 1 (9.1%) 0 (0.0%) 2 (14.3%) 2 (22.2%) 2 - 3 TIMES PER MONTH 16 (32.0%) 5 (45.5%) 5 (31.3%) 3 (21.4%) 3 (33.3%) 4 - . 4 - 5 TIMES PER MONTH 10 (20.0%) 2 (18.2%) 7 (43.8%) 1 (7.1%) 0 (0.0%) 6 -. 6 - 7 TIMES PER MONTH 7 (14.0%) 3 (27.3%) 2 (12.5%) 2 (14.3%) 0 (0.0%) 8 TIMES OR MORE? L MONTH 5 (10.0%) 0 (0.0%) 1 (6.3%) 4 (28.6%) 0 (0.0%) [2] Analog Visual Scale: 0 = No erection, 100 = Proper Rigid Erection for penetration Phase II: Dose with escalation The investigating physician provided instructions regarding the protocol, and consent was obtained. Patients were advised that they could withdraw freely from the trial at any time without penalty or prejudice. They underwent the analysis in four separate days and four separate doses • (placebo and three doses of the active medication) with an interval of no less than six days between visits (that is, one visit per week). In this phase, the patients sat in a comfortable chair and an ambulatory tumescence monitor from RIGISCANMR (Dacomed Corp., Minneapolis, Minnesota) was connected to the patient and the computer was adjusted in real-time monitoring mode. The • Blood pressure and heart rate were recorded before dosing with APO or placebo and at the end of the analysis section. Visual analog scales (VAS) were filled by the patient before dosing as well as after dosing (at the end of the test assignment). These scales, at as in phase I, they reflected the feeling of the patient's well-being, the level of sedation, reassurance, anxiety, excitement and any change in yawning behavior.

In a single blind form, a tablet of hydrochloride was administered to the patient, sublingually, during each of the four visits. • of apomorphine (4, 6, or 8 mg) or placebo. Due to the possibility of nausea and the tolerance to this effect that the previous dosage entails, the patient was given increasing doses of apomorphine in each analysis, and the placebo was assigned randomly in one of the visits. They gave instructions to patients not to swallow the • medication, but you had to keep it under your tongue and allow it to be absorbed in that place. The symptoms were commented voluntarily and recorded by the doctor researcher. If the patient complained of nausea or did not feel well in any way, he was asked if he wanted to quit the trial. If the trial was abandoned, the patient was given the choice to take • Gravol 50 mg p.o. (anti-vomit) administered in that time or during adverse events as they arose. In each case, the patient was monitored by the investigating physician until all side effects had been calm. The patient was asked if he wanted to return the next weeks for the next scheduled dose. Patients who did not experience nausea or any other significant adverse effects, within fifteen minutes after the dose with APO or placebo, observed segments of standardized erotic videos, to provide sexual stimulation. The following sequence of videos was observed: an erotic video of ten minutes (Erotic # 1), a neutral video (Neutral) lasting between five and ten minutes, and finally another erotic video of ten minutes (Erotic # 2). The duration of the analysis session for each dose level lasted between 45 and 60 minutes. After determining the most effective dose of apomorphine most effective for the patient, he was then offered APO tablets at the dose for the final phase of the study.

Phase III: to take at home During the phase of home use, of five weeks, subjects had to try intercourse at least once every week after taking a single APO tablet. After each attempt, the subject and his partner filled out a Sexual Function Questionnaire (See Figures 15 and 16) which was subsequently evaluated and used for the final statistical analysis. At the end of this phase a final evaluation was made to the subjects.

Results One objective of this study was to determine the safety and tolerance of APO in the treatment of male erectile dysfunction. Several adverse events associated directly with the administration of OPA in humans were expected: yawning, nausea, • vomiting and cardiovascular effects. Indeed, nausea was the primary adverse event reported in this trial (46% of subjects who received 6 mg of OPA had nausea), but the overall incidence for all doses administered was lower. of 13% of the subjects and only two ^^ 10 cases were considered severe. Figure 12 is a bar graph showing the incidence of nausea as a percentage of administered doses for each level. The incidence of vomiting, as illustrated in Figure 13, was less than 3% for each dose administered. The highest incidence of vomiting, of approximately 2.5%, was also at the 6 mg dose. Hypotension was reported as an adverse event in certain subjects in this study, along with bradycardia, dizziness, syncope and pallor. Only the individual cases of hypotension and pallor were judged to be severe in that study. Increased sweating and fatigue were also reported. One of the cases of increased sweating was considered severe.

The other severe adverse events (edema of the mouth, dysphagia, upper respiratory tract infection) were judged not to be related to the treatment.

Changes in the values of serum chemistry and vital signs were compared with reports of adverse events. There were no clinically significant changes except for a subject who, as judged, had abnormal function of the liver of unknown origin. There were no clinically significant changes in blood values or urinalysis due to the drug. Although fifty (50) patients were enrolled in this study, only thirty-nine (39) patients finished • all phases of this study and were considered valuable. Four additional patients completed treatment with the drug but were not considered valuable because they provided information incomplete or because the forms for reporting the case did not return. Of all, twenty-three (23) patients reported specific adverse effects. Called in the present as adverse events, • associated with apomorphine in one or more phases of tea study. The data were analyzed by an inspection of the adverse events reported, the dose of apomorphine provided and the phase of the study, ie the phases in the patient (escalation of the dose) or the phases to take at home (constant dose). A brief summary of the adverse event data reported by each of the twenty-three patients, as presented in Table XI, clearly demonstrates the effects of dose escalation in reducing the number of reported adverse events (AE ) in the constant dose phase.

Table XI Analysis of the adverse events related to the drug • Internal Patient Taken at Home Anti-vomiting No. of Events At the dose Events At the dose Patient Taken in adverse patient Internal Adverse House 1002 6 6 & 8 0 4 1 0 1003 6 6 & 8 1 6 1 0 1004 10 4, 6, & 8 0 6 0 0 1005 1 8 0 8 0 0 1007 22 4,. 6, & 8 0 6 1 0 1010 11 4,. 6, & 8 0 6 1 0 '1011 1 6 0 4 0 0 2001 2 8 0 4 0 0 2002 4 6 & 8 0 4 1 0 2005 2 8 6 8 0 1 2010 2 6 & 8 0 4 0 0 2012 3 4 0 4 0 0 2013 4 4 & 6 3 4 0 0 2015 10 6 & 8 1 8 0 0 3002 5 4,. 6, & 8 0 6 0 0 3005 1 8 3 6 0 0 3006 2 6 1 6 0 0 • 3008 0 4, 6, & 8 3 6 0 0 3009 3 8 0 6 0 0 4001 7 6 & 8 5 4 1 1 4005 2 6 2 4 & 6 1 0 4006 2 8 0 4 & 6 0 0 4007 3 4 & 6 0 6 1 0 Total 109 25 8 2 Average 4.74 1.09 0.35 0.09 Mode 2 0 0 0 Median 3 0 0 0 Count 23 23 23 23 During the escalation phase of the dose, 109 adverse events related to the drug were reported, or an average of about 4.74 • Adverse Events per patient. The results for 5 the constant dose phase reveal a total of 25 adverse events reported or approximately 1.1 Adverse Effects per patient. A total of 440 tablets were administered to twenty-three patients who exhibited adverse events, ^^ 10 as documented in Table XI, during the two combined phases, ie 157 tablets of four milligrams, 176 tablets of 6 milligrams, and 107 tablets of eight milligrams Sixty-nine of these tablets were administered in the 15-patient internal phase (one tablet of each dosage to each patient). This gives a total of 371 tablets administered during the intake phase at home. The notorious nature of dose escalation data is highlighted when the number of adverse events per tablet is compared between the two phases, as shown in Table XII below.

Table XII Adverse events per tablet 25 Events Tablets Adverse event / Adverse phase taken tablet Internal patient 109 69 1.58 Shot at home 25 371 0.07 The 0.07 adverse events per tablet during the home shot phase represent approximately a 95.6% decrease in the • Adverse events per tablet with respect to the phase of internal patient. This dramatic improvement results from pretreatment with escalation of the dose. Additionally, the review of concomitant medications provided to patients, shows that a patient who is in the escalation phase ^^ 10 or internal patient (Treatment by acclimatization) of the study, required an anti-Vito approximately 35% ' of time (See Table XI). In contrast, during the constant dose phase (External Patient Phase) the percentage of patients that required an anti-vomiting medication decreased to approximately 9% (see Figure 12). This savings in the concomitant medication for vomiting, also verifies the accelerated acclimatization of patients to the side effects of apomorphine, through the methodology of escalation of the dose. A second objective of this study was to further analyze the efficacy of the APO. This objective was achieved during the first two phases of the study, in which the subjects were connected to the RIGISCANMR monitor. Subjects were initially treated with placebo, followed by APO tablets of 6 and 8 mg, randomly mixing a placebo tablet into the treatment.

There were highly significant effects of treatment with APO compared with placebo, placebo 1 was administered during phase I and placebo 2 was randomized during phase II, to suggest an effect of this drug on penile function, both in an environment erotic as in a neutral one, as shown by Table XIII below.

Table XIII RIGISCAN total scores, MR per sequence (Erotic versus Neutral) Significantly greater than placebo 1 * * Significantly greater than placebo 1 and placebo 2 Similarly, referring to Tables XIV and XlVb later, and Figure 14, active doses of APO significantly improved RIGISCANMR scores for penile increases in • each of the four sites, both in the neutral and erotic sequences, the only exception being a slightly lower RIGISCANMR score in erotic # 1, to 4 mg for site # 1 (the results of the analysis for the sequence of the erotic video in the analysis site # 3 are not available because you are • sequences were not shown to the subjects).

• Table XlVa Penile measurements (Maximum increment) Measures by RIGISCAN MR Population attempted to be processed Video sequence EROTIC # 1 Site Treatment Media SEM MEDIA LESS SEM Source value SIGNIFICANT ALL Placebo # 1 36 11.44 1.770 12.22 1.666 Treatment 0.0001 PLACES Placebo # 2 32 13.38 2.051 13.65 1.714 Site 0.0264 4 mg 35 15.31 1.761 15.80 1.674 Treatment per Site 0.0595 6 mg 34 17.09 1.841 17.20 1.695 4mg vs Placebo # 1 0.0120 8 mg 31 19.84 1.610 19.11 1.745 6mg vs Placebo # 1 0.0007 8mg vs Placebo # 1 0.0001 All 11 10.76 2.372 11.04 2.498 4mg vs Placebo # 2 0.1405 treatments Placebo # 1 11 9.73 2.854 9.73 2.931 6mg vs Placebo # 2 0.0166 Placebo # 2 10 9.00 3,300 9.21 2.996 8mg vs Placebo # 2 0.0005 4 mg 11 8.09 2.410 8.09 2.931 Placebo # 1 vs # 2 0.3274 6 mg 11 10.82 3.065 10.82 2.931 8 mg 9 17.89 2.988 17.36 3.070 • • o r r r r r r r r r r r r r r r r r ro r ro r ro r ro r m ro ro ro T ^ < ro ro r r ro r- • r r r r r < > ro r ro r ro ro s > r ~ G ~ CM r ~ ro. r ~ sr LO m CM Table XlVb Penile Measurements (Maximum Increments Measured by Rigiscan) Population that is tried to treat Video Sequence NEUTRAL STATISTICS MEDIA ADJUSTED (LS) DESCRIPTIVE Site Treatment N MEDIA SEM MEDIA (LS) SEM ALL Placebo # 1 48 7.98 1,236 8.34 1,220 SITES Placebo # 2 43 7.49 1,257 7.65 1,272 4 mg 47 11.11 1,295 11.47 1,226 6 mg 45 12.76 1.116 13.10 1,268 8 mg 41 11.98 1.366 12.40 1.331 # 1 All 11 10.56 1.987 10.70 1.789 treatments Placebo # 1 11 8.91 2.470 8.91 2.494 Placebo # 2 10 5.60 2,574 5.68 2,587 4 mg 11 10.45 1.965 10.45 2.494 6 mg 11 12.73 2.832 12.73 2.494 8 mg 9 16.22 3.099 15.73 2.692 # 2 All 16 7,092 1,192 7,242 1,495 treatments Placebo # 1 16 4.44 1,554 4.44 2,068 Placebo # 2 14 5.86 2.099 5.71 2.182 4 mg 15 8.73 2.610 8.70 2.126 6 mg 15 9.60 1.514 .9.56 2.126 8 mg 15 7.73 1.694 7.70 2.126 # 3 All 12 12.22 1.476 12.09 1.706 Treatments Placebo # 1 12 11.33 2.244 11.33 2.388 Placebo # 2 11 10.00 1,902 10.61 2.469 4 mg 12 11.83 2.564 11.83 2.388 6 mg 12 13.58 1.794 13.58 2.388 8 mg 11 12.45 2.458 13.07 2, .469 # 4 All 9 11 .63 2.864 12 .35 2. .023 Treatments Placebo #] 9 8. 67 4.052 8. 67 2. .758 • Placebo # 2 8 9. 25 3,990 8. 58 2.,891 4 mg 9 14 .89 3,071 14 .89 2. .758 6 mg 7 18 .14 2,747 16 .51 3. .046 8 mg 6 15 .33 4.462 13 .11 3., 236 STATISTICS OF; DUC "" TT \ 7? - Source Value p Treatment 0.0002 Site 0.1092 • Treatment per Site 0.7176 4 mg vs. Placebo # 1 0.0230 6 mg vs. Placebo # 1 0.0009 8 mg vs. Placebo # 1 0.0060 4 mg vs. Placebo # 2 0.0074 10 6 mg vs. Placebo # 2 0.0002 8 mg vs Placebo # 2 0.0017 Placebo # 1 vs. # 2 0.6243 The effects were observed especially in 15 measurements carried out at the base of the penis, although all the scores added showed significant effects of the treatment in one or more of the three doses of APO. The tables referenced above and Figure 14 show that the results of the total RIGISCANMR score were from significant to highly significant for a treatment effect of 4, 6 and 8 mg compared to the initial placebo. In addition, the largest part of the treatment effects were from significant to highly significant compared • with the second placebo. Although the first and second placebos did not differ statistically, the results in the second were numerically greater. The results in the erotic phases were higher than those in the neutral phase, and those in the erotic phase one were numerically greater than those in the erotic phase.

«The erotic phase two (see Figure 14). Most significant treatment effects were observed in the neutral phase, but this reflects the largest number of subjects in this phase, since the analysis center # 3 (Columbia) did not show the erotic videos. All doses of APO were effective in causing erections (RIGISCANMR readings greater than or equal to 15) in the presence of erotic stimulation. For the third phase, the subjects talk registered in the baseline, his satisfaction, erection, number of apts, and successful sexual intercourse, on a VAS scale (See Tables Xa-Xc, above). The evaluable subjects first registered a success rate, then filled the scales analogous visuals for the results of erection and satisfaction with the sexual relationship followed by the treatment at home. The success rates, as shown in Tables XVa-XVb, were calculated for doses per milligrams of APO as well as for micrograms per kilogram of the patient's body weight (males). There were four criteria for ww to register a success in the take-home phase. The criteria were: 1) the subjects must have at least one of two successful sexual intercourse apts (based on the subject's responses to the intake questionnaires at home); 2) Subjects must have tested the study medication at home for at least two apts; 3) the subjects must have made the apt # to try a lower or higher dose if the original dose taken at home did not produce optimal results in combination with anti-nausea agents; and 4) the subjects [and their peers] must have filled and returned the take home questionnaires. Several evaluations were made of the data, including the responses of men and women, to the treatments, through the questionnaires (see • Figures 15 and 16). 20 Table XVa Rate of Success in Sexual Relation by Tablet Dose Table XVb Success Rate in the Sexual Relationship by Body Weight • μg / kg The total success rate for the study was • 70% with the APO treatment, as shown in the previous Tables, which is statistically greater than the baseline rate of 28%. The success rate showed numerical increases of four milligrams to six milligrams for male and female participants, but showed a decrease to eight milligrams, for each group. The The highest success rate, as shown in Table IVa, was 73% in both men and women, at six milligrams. However, a dose range of 50 to 74 μg / kg yielded the highest success rate of 82% in women and 73% in males, as shown in table XVb. The success rate per analysis site is presented in Table XVI, below.

Table VI SUMMARY OF THE SUCCESS RATE IN THE TOMAS AT HOME Tables XVIIa-XVIId, below, show the statistical results of phase III with respect to the results of Rigiscan ™ (a and b) and satisfaction in the sexual relation (c and d) based on question 1 and question 3, respectively, of the complete questionnaires (see Figures 15 and 16). These scores for erection rigidity (Question 1) showed a numerical improvement with respect to the baseline and the best results are observed at 4 mg in men and 8 mg in women. The maximum improvement with respect to the baseline was 56% in males and 59% in females. The average improvement was 29% in men and 34% in women. The visual analog scale for satisfaction (question 3) showed similar results with a maximum improvement with respect to the baseline, of 62% in women and 57% in men, both at 8 mg. The average improvements were 34% in women and 45% in men.

Table XVIIa Phase III Percentage Change of Erection Results (Maximum) Regarding the Baseline of the • Effective population Sex: MASCULINE STATISTICS DESCRIPTIVA MEDIA ADJUSTADA (LS) Site Treatment N MEDIA (%) SEM MEDIA LS (%) SEM All 4 mg 55.71 15,055 55.71 14,058 Sites 6 mg 15 42.80 8.777 42.80 9.603 8 mg 7 31.86 15.636 31.86 14.05 # 1 All 9 52.22 12.986 • 4 mg 2 80.50 3.500 6 mg 5 34.20 19.405 8 mg 2 69.00 20,000 # 2 All 4 57.00 19,429 4 mg 1 71.00 6 mg 2 79.00 1,000 8 mg 1 -1.00 # 3 All 9 36.22 11.236 4 mg 2 17.50 34.500 6 mg 4 46.75 14.250 8 mg 3 34.67 22.806 • # 4 All 7 33.00 15.074 4 mg 1 61.50 36.500 6 mg 4 31.50 14,846 8 mg 1 -18.0 DEDUCTIVE STATISTICS Source value p Treatment 0.4950 Table XVIIb Phase III Percentage Change of Erection Results (Maximum) Regarding the Baseline of the effective population w Sex: FEMALE STATISTICAL DESCRIPTIVE MEDIA ADJUSTED (LS) Site Treatment N MEDIA (%) SEM MEDIA LS (%) SEM All 4 mg 7 33.57 14.560 33. .57 13.468 Sites 6 mg 15 45.00 9.103 45., 00 9.201 8 mg 6 59.00 13.466 59,, 00 14,547 • # 1 All 9 52.56 12.586 4 mg 2 78.50 4.500 6 mg 5 36.00 19.396 8 mg 2 68.00 18.000 # 2 All 4 41.25 23.708 4 mg 1 -6.00 6 mg 2 82.00 3.000 8 mg 1 7.00 # 3 All 8 46.50 12.211 4 mg 2 18.00 36,000 • 6 mg 4 42.50 8,302 8 mg 2 83.00 17,000 # 4 All 7 36.29 12,163 4 mg 2 '24.00 0.000 6 mg 4 40.25 21.933 8 mg 1 45.00 DEDUCTIVE STATISTICS-- Source value p 10 Treatment 0.4507 Table XVIIc Phase III Percent Change in Satisfaction, • Respect in the Base Line in the Effective Population Sex: MALE STATISTICS DESCRIPTIVE AVERAGE ADJUSTMENT (LS) Site Treatment N MEDIA (%) SEM MEDIA LS (%) SEM All DS 4 mg 7 49.14 10,276 49., 14 10,617 Sites 6 mg 15 51.47 6.373 51., 47 7.253 8 mg 7 56.57 13.409 56,, 57 10,617 # 1 All 9 58.00 9.876 4 mg 2 67.50 14.500 6 mg 5 40.60 11.374 8 mg 2 92.00 2.000 # 2 All 4 48.50 15.387 4 mg 1 71.00 6 mg 2 59.50 7.500 8 mg 1 4.00 # 3 All 9 49.56 8.026 4 mg 2 34.50 8,500 6 mg 4 54.50 12,017 8 mg 3 53.00 19,035 # 4 All 7 50.00 11.719 4 mg 2 34.50 30.500 6 mg 4 58.00 16.253 8 mg 1 49.00 EST; VDfñTTCA? F.GI? CTTVA Treatment 0.8776 Table XVIId Phase III Change in Satisfaction (Maximum) Respect HP to the Base Line of the Effective Population Sex FEMALE STATISTICS DESCRIPTIVA MEDIA ADJUSTADA (LS) Site Treatment N MEDIA (%) SEM MEDIA LS (%) SEM All 4 mg 7 41.86 14,626 41,, 86 13,535 Sites 6 mg 15 40.60 9.109 40, .60 9,246 • 8 mg 6 62.33 13.723 62,, 33 14.619 # 1 All 9 57.00 16.058 4 mg 2 81.00 9,000 6 mg 5 33.00 24.251 8 mg 2 93.00 3,000 # 2 All 4 57.00 13.988 4 mg 1 72.00 6 mg 2 68.00 16.000 8 mg 1 20.00 # 3 All 8 37.75 9.599 4 mg 2 16.50 20,500 6 mg 4 30.50 7.354 8 mg 2 73.50 0.500 # 4 All 7 33.29 10.794 4 mg 2 13.00 23.000 6 mg 4 46.50 13.426 8 mg 1 21.00 DEDUCTIVE STATISTICS - Source value p 10 Treatment 0.4437 The preceding analysis and the attached examples are presented as illustrative and should not be considered as limiting. Still others are possible • variations within the spirit and scope of this invention and will be readily apparent to those skilled in the art. •

Claims (23)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A method for minimizing the adverse effects of apomorphine in a human patient. , characterized in that it comprises the steps of: (a) administering to the human patient a threshold dose of apomorphine; • (b) administer to the human patient an increasing series of periodic doses, of apomorphine greater than the threshold dose, until the human patient has received a final dose of apomorphine greater than
2. 15 excess of a therapeutic dose; and subsequently (c) administering to the human patient a therapeutic dose of apomorphine. 2. The method according to claim 1, in
3. • where the step of managing a growing series of
4. 20 doses are presented at a rate of one dose per day for at least two days. The method according to claim 1, wherein the therapeutic dose of apomorphine consists of an amount sufficient to induce an erection
5. 25 penile enough for vaginal penetration. The method according to claim 1, wherein the therapeutic dose of apomorphine consists of an amount sufficient to improve sexual dysfunction in a female patient, inducing clitoral erectogenesis and vaginal congestion in the stimulation of the female patient. • The method according to claim 1, wherein the apomorphine is administered as a suppository. 6. The method according to claim 1, wherein the apomorphine is administered transdermally. The method according to claim 1, wherein the apomorphine is administered by subcutaneous injection. 8. A method for minimizing the adverse effects of apomorphine in a male patient, characterized in that it comprises the steps of:
6. 15 (a) administer to the male patient a sublingual threshold dose of apomorphine; (b) administer to the male patient an increasing series of sublingual doses of apomorphine, greater than the threshold dose, until the patient
7. The male has received a final sublingual dose of apomorphine, in excess of that necessary to produce a penile erection sufficient for penetration; and (c) administer to the male patient, prior to sexual activity, a sublingual therapeutic dose.
8. 25 of apomorphine, less than the final dose but sufficient to produce an erection suitable for penetration, without presenting substantial adverse effects.
9. 9. The method according to claim 8, wherein the step of administering an increasing series of doses is presented at a rate of one dose per day

   • for at least three days. The method according to claim 8, further comprising the step of maintaining a concentration of apomorphine in the plasma of the male patient within the range of from about 0.3 to about 5.5 nanograms per milliliter

   , 10 during sexual activity. • The method according to claim 8, further comprising the step of maintaining a concentration of apomorphine in the male patient's plasma preferably within the range of

   15 from about 0.3 to about 4 nanograms per milliliter during sexual activity. 12. The method according to claim 8, further comprising the step of maintaining a

   • concentration of apomorphine in the patient's plasma

   20 male within the range of about 1 to about 2 nanograms per milliliter during sexual activity. The method according to claim 8, wherein the sublingual threshold dose of apomorphine is

   25 in the range of 2 mg to about 8 mg. The method according to claim 8, wherein the therapeutic sublingual dose is in the range of 35 mg to about 74 micrograms per kilogram of the patient's body weight. 15. The method according to claim 8, in

   • where the final sublingual dose of apomorphine is within the range of 8 mg to about 10 mg. The method according to claim 8, wherein the sublingual therapeutic dose is in the range of 50 mg to about 74 micrograms per kilogram of the patient's body weight. 17. A method for improving phobia

   • social of a human patient, comprising the steps of: (a) administering to the human patient a threshold dose of apomorphine; 15 (b) administering to the human patient an increasing series of periodic doses of apomorphine greater than the threshold dose to a final dose of apomorphine in excess of a therapeutic dose of apomorphine that has been received by the human patient,

   20 the therapeutic dose is an amount sufficient to reduce the symptoms of social phobia; and subsequently, (c) administering to the human patient the therapeutic dose of apomorphine. 18. The method according to claim 17, wherein the therapeutic dose is administered to provide the patient with a concentration of plasmic apomorphine, from about 5 to about 8 nanograms per milliliter. 19. A method for minimizing the adverse effects of apomorphine in a human patient comprising the steps of: (a) administering to the human patient a threshold dose of apomorphine, (b) administering to the human patient an increasing series of doses of apomorphine greater than the threshold dose until a final sublingual dose of apomorphine has been received in excess of that needed to improve Parkinson's symptoms by the human patient; and subsequently, (c) administering to the human patient a therapeutic dose of apomorphine less than the final dose but sufficient to improve the symptoms of Parkinson's without presenting substantial adverse effects. The method according to claim 19, wherein the therapeutic dose of apomorphine is administered subcutaneously in the range of about 3 to about 8 milligrams. The method according to claim 19, wherein the therapeutic dose of apomorphine is administered. in a sublingual dosage form containing apomorphine in the range of about 10 to about 60 milligrams. 22. The method according to claim 19, wherein the threshold dose of apomorphine is administered subcutaneously in a dose form containing apomorphine in the range of about 1 to about 5 mg. The method according to claim 19, further comprising the step of maintaining a concentration of apomorphine in the patient's plasma within the range of about 3 to about 20 nanograms per milliliter.