CA2202989C - Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion - Google Patents
Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion Download PDFInfo
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Abstract
This invention is directed to a method of attenuating or preventing the adverse side-effects of a perfluorochemical (PFC) emulsion on the hemostatic system and serum chemistry of an animal. The method includes intravenously administering a corticosteroid to an animal prior to intravenous administration of a PFC emulsion, in an amount sufficient to improve the adverse effects of the PFC upon the hemostatic system and serum triglyceride/enzyme levels of the animal. After administration of the corticosteroid, the PFC emulsion is administered intravenously. Preferably, the corticosteroid is dexamethasone, and the PFC is perfluorodichlorooctane.
Description
USE OF A CORTICOSTEROID TO REDUCE THE ADVERSE t~t~lS OF A PERFLUOROCHEMICAL
EMULSION
Background of the Invention Field of the Invention This invention is directed to the use of corticosteroids, and more particularly, to the use of corticosteroids for reducing or attenuating the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry parameters of an animal.
Description of the Related Art Perfluorochemical (PFC) emulsions are being developed for many different uses. Because PFCs have a high intrinsic solubility for gases, including ~2 and C02, they are especially useful as 02/C02 transport agents, artificial bloods, and red blood cell substitutes. PFC emulsions also are being developed as contrast agents for biological imaging. However, one of the drawbacks in
EMULSION
Background of the Invention Field of the Invention This invention is directed to the use of corticosteroids, and more particularly, to the use of corticosteroids for reducing or attenuating the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry parameters of an animal.
Description of the Related Art Perfluorochemical (PFC) emulsions are being developed for many different uses. Because PFCs have a high intrinsic solubility for gases, including ~2 and C02, they are especially useful as 02/C02 transport agents, artificial bloods, and red blood cell substitutes. PFC emulsions also are being developed as contrast agents for biological imaging. However, one of the drawbacks in
-2-using PFC emulsions in animals is that these emulsions produce certain undesirable side effects.
Side effects from the intravenous infusion of a PFC
emulsion have been reported in both human and animal studies.
Two groups of side effects have been observed in human volunteers receiving a perfluorooctylbromide (PFOB) emulsion. PFOB, also known as Perflubron, is a PFC under development as a component of a blood-pool imaging agent known as Imagent BP. Imagent BP is a phospholipid emulsion containing ninety (90%) percent w/v Perflubron and having a mass median particle size of approximately 0.2 ~. The first group of side effects occurs within the first 2 hours after injection of the PFC emulsion. These acute effects are characterized primarily by skin flushing and back~che. The second group of side effects occurs later than 2 hours post-injection and lasts generally for about a day. These delayed effects, described as a "flu-like syndromen, include fever, dizziness, and occasional nausea. S. F. Flaim, et al., "Characterization and Mechanism of Side Effects of Imagent BP (Highly Concentrated Fluorocarbon Emulsion) In Swinen, Vol. 26, Investigative Radiologv, November Supplement 1991, S122-S124.
PFC emulsions also induce adverse side effects in swine. As with the human volunteers! intravenous administration of a PFOB emulsion produced both an acute and a delayed response in swine. The acute response included a rise in mean pulmonary artery pressure (mPAP) and severe skin flushing, both of which resolved ~ completely by 2 hours post-injection. The delayed side effect was a febrile response characterized by a 1 - 2~C increase in body temperature which peaked at 4 hours post-injection and resolved over the next 2 to 24 hours. The early rise in mPAP is believed to be related to the activation of pulmonary intravascular macrophages, while the skin flushing is attributed to the substantial release of Prostaglandins upon macrophage activation. S. F. Flaim, et al., "Characterization and Mechanism of Side Effects of Imagent BP
(Highly Concentrated Fluorocarbon Emulsion) In Swine", Vol. 26, Investigative Radiologv, November Supplement 1991, S122-S124.
Further research with swine has shown that these particular clinical side effects may be effectively prophylaxed with dexamethasone, ibuprofen, or indomethacin. For example, the acute, transient rise in mPAP and skin flushing both were blocked successfully by prophylaxis with any one of these three compositions. In addition, the delayed febrile response also was blocked successfully by prophylaxis with dexamethasone, ibuprofen, or indomethacin. /d.
Despite the advances made by these animal and human studies, they do not identify other problems or side effects which might be associated with intravenous infusion of PFC emulsions.
Given the increase in clinical use of such emulsions, it would be desirable to identify other potential side effects. Furthermore, once those side effects have been identified, it would be highly beneficial to identify ways in which those side effects might be alleviated or even prevented.
Summarv of the Invention This invention is directed to a method of improving the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry of an animal. The method includes intravenously administering a corticosteroid to an animal prior to intravenous administration of a perfluorochemical emulsion. The corticosteroid is administered in an amount sufficient tO improve the adverse effects of the perfluorochemical upon the hemostatic system and serum triglyceride/enzyme levels of the animal. After administration of the corticosteroid, the perfluorocarbon emulsion is administered intravenously.
Preferably, the corticosteroid is administered at a dose of from about 0.2 mg/kg of body weight to about 6 mg/kg of body weight, and more preferably, at a dose of about 1 mg/kg. The perfluorochemical used in the perfluorochemical emulsion preferably is administered at a dose of from about 0.5 to about 10 ml/kg of body weight.
With respect to the hemostatic system, the method may be conducted for reducing perfluorochemical-induced adverse side effects upon prothrombin time and activated partial thromboplastin time, and for inhibiting perfluorochemical-induced WO 96/13268 . PCT/US95/13714 thrombocytopenia. With respect to serum chemistry, the ",ell,o~
~ may be conducted for reducing perfluorocarbon-induced adverse side effects upon aspartate amino transferase enzyme activity, lactate dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone, while the perfluorochemical preferably is selected from the group consisting of: perfluorodichlorooctane, perfluorodecalin, perfluoromethyldecalin, perfluorodimethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-~
methyl-octahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin, perfluoro-bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated perfluorocarbons, and mixtures thereof. Most preferably, the perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the perfluorochemical in an amount of from about 15 v/v% to about 70 v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps, administration of the perfluorochemical emulsion preferably is begun within several hours after administering the corticosteroid, and can t also be administered immediately following administration of the corticosteroid .
This invention offers several benefits to animals being treated with PFC emulsions. For example, corticosteroid pretreatment attenuates or prevents adverse PFC-induced side effects on the coagulation system. Pretreatment virtually eliminates the PFC-induced adverse effects on prothrombin time and activated partial thromboplastin time, and significantly inhibits PFC-induced thrombocytopenia .
Corticosteroid pretreatment also attenuates or eliminates adverse PFC-induced side effects on several serum chemistry parameters. For example, pretreatment inhibits PFC-induced increases in serum triglycerides and bilirubin, as well as in aspartate amino transferase enzyme activity and lactate dehydrogenase enzyme activity.
Detailed Desc.iulion of the Invention This invention is directed to a method of improving the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry of an animal. The method includes intravenously administering a corticosteroid to an animal prior to intravenous administration of a perfluorochemical emulsion. The corticosteroid is administered in an amount sufficient to improve the adverse effects of the perfluorochemical upon the hemostatic system and serum triglyceride/enzyme levels of the animal. After administration of the corticosteroid, the perfluorocarbon emulsion is administered intravenously.
wo 96/13268 PCT/US95/13714 Preferably, the corticosteroid is administered at a dose of from about 0.2 mg/k~ of body weight to about 6 mg/kg of body weight. At low doses of about 0.1 mg/kg, ptel,eal.,.enl with dexamethasone has li~tle impact on PFC-induced side efreol:.; while doses above about 6.0 mg/kg present safety issues in that such doses may result in undesired changes in the hypothalamic-pituitary-adrenal axis physiology. More preferably, the co~icosleroid is administered at a dose of about 1 mg/kg. The perfluorochemical used in the perfluorochemical emulsion preferably is administered at a dose of from about 0.5 to about 10 ml/kg of body weight.
With respect to the hemostatic system, the method may be conducted for reducing perfluorochemical-induced adverse side effects upon prothrombin time and activated partial thromboplastin time, and for inhibiting perfluorochemical-induced thrombocytopenia. With respect to serum chemistry, the method may be conducted for reducing perfluorocarbon-induced adverse side effects upon aspartate amino transferase enzyme activity, lactate dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone. The perfluorochemical preferably is selected from the group consisting of perfluorodichlorooctane, perfluorodecalin, perfluoro"-~ yldecalin, . perfluorodimethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-~methyl-octahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin, perfluoro-bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated perfluorocarbons, and mixtures thereof. Most preferably, the perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the perfluorochemical in an amount of from about 15 v/v~/0 to about 70 v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps, administration of the perfluorochemical emulsion preferably is begun within several hours after administering the corticosteroid, and can also be administered immediately following administration of the corticosteroid .
Examr~le Study Design and Protocol A study was conducted to assess the responses associated with an acute intravenous exposure of a 40 v/v%
perfluorodichlorooctane ~PFDC0) emulsion in male adult baboons /Papio cynocephalus~ with and without treatment with 1 mg/kg of dexamethasone. Dose levels of the 40 v/v% PFDC0 emulsion were selected to impart minimal, reversible side errecls in the baboon that would be efficacious with respect to intravascular gas transport.
The dexamethasone pretreatment regimen was administered intravenously at a dose level intended to elicit anti-infla",.,~alory effects. The 40 v/v% PFDC0 emulsion included a PFDC0 stem WO 96tl3268 PCT/US95/13714 emulsion, as well as a 23.4% saline annex solution. The specific composition of the stem emulsion, saline annex and final formulation is shown in Table 1.
Table 1 Formulation of the 40 v/v% PFDCO Emulsion Component PFDCO 23.4% Saline Final Formula-Stem Emulsion Annex tion for IV
Administration PFDCO (v/v%) 40 - 39 Lecithin 2 - 1.95 ~w/v%) Safflower Oil 2 - 1.95 (w/v%) Na2CO3 0.01 5 (w/v%) NaCI (w/v%) - 23.4 0.466 Water for q.s q.s q.s Injection Twelve adult male baboons (P~pio cynocephalus~ were selected after being given complete health examinations by veterinary personnel and approved for the study. The animals ranged in age from 8 - 20 years, were either feral or colony born, and were clinically in excellent health.
The twelve animals were divided into four L~eal-~ent groups with three animals in each group. The group I and ll animals each received 1.0 ml/kg PFCDO (2.5 ml/kg stem emulsion annexed with 23.4% sodium chloride), with the Group ll animals also receiving 1 mg/kg dexamethasone intravenously immediately prior to infusion of PFDC0. The Group lll and IV animals each received 2.0 ml/kg PFDC0 (5.0 ml/kg stem emulsion mixed with 23.4% sodium chloride), while the Group IV animals also received 1 mg/kg dexamethasone intravenously immediately prior to infusion.
The baboons were sedated for dexamethasone and PFDC0 infusion with ketamine HCI (IM) supplemented with valium, and additional doses of ketamine HCI were administered when required to maintain sedation. Following sedation and pretreatment blood collection, a 16-20 gauge indwelling angiocatheter was placed and secured into a saphenous vein for infusion of the respective emulsions. The doses of the 40 v/v% PFDC0 emulsion were administered at a rate of approximately 4-6 ml per minute.
Blood samples were drawn and analyzed over a thirty (30) day period following administration of the PFDC0 emulsion.
The baboons were sedated for all blood sampling procedures with ketamine HCI (IM) supplemented with valium, and additional doses of ketamine HCI were administered when required to maintain sedation. Indirect systemic blood pressure was measured using a non-invasive blood pressure unit, and body temperature was monitored using a rectal thermometer. In addition, respiratory rate was measured directly by monitoring the inspiratory excursions of the thoracic or abdominal wall, while heart rate was deterrnined by palpation of a peripheral pulse or chest auscultation. Blood samples were collected percutaneously via a peripheral vein.
W ~ 96113268 PCTAUS95/I3~14 Data Analvsis Methodologv For parameters having multiple baseline and/or pre-infusion measurements, an average baseline value for each animal ~i was calculated. The change in response from the average baseline was statistically evaluated, and between-group comparisons at each dose level of PFC with and without dexamethasone pretreatment were performed at each sample time. A one-factor analysis of variance (ANOVA) was used to test for significance within and between groups over time. The levels of significance were defined as P<.05 and P<.01.
The results presented below were compared to normal values for the adult male baboon as listed in Brenda M. Hainsey, et al., Clinical Parameters of the Normal Baboons (Papio species) and Chimpanzees (Pan troglodytes)", Vol. 43, No. 3, Laboratorv Animal Science, June, 1993. For analysis of Factor Vlll, the results were compared to the normal range for baboons as reported in Hollace M.
Feingold, et al., "Coagulation Assays and Platelet Aggregation Patterns in Human, Baboon, and Canine Blood", Vol. 47, No. 10, American Journal of Veterinary Research, October, 1986.
Imnact of Dexamethasone ~et,aal---ent - on the Hemostatic Svstem Prothrombin time (PTJ is shown for the four treatment groups over the length of the study in Table 2. In the low dose PFC
animals, there was evidence of a rise in the PT at six hours post-infusion, which remained elevated one day after infusion. However, CA 02202989 l997-04-l7 in the low dose animals preL~aaLed with dexamethasone, there were no significant changes in the PT over the course of the study. In the high dose baboons, the PT was significantly elevated at 4 hours, 6 hours, and 1 day post-infusion when compared to the baseline and the high dose animals pretreated with dexamethasone. At 2 days following dosing, the PT of the high dose animals remained significantly prolonged when compared to the baseline. For the pretreated high dose animals, the only significant change in the PT
from baseline occurred at thirty (30) days post-infusion; however, this elevation was not considered to be biologically significant.
The activated partial thromboplastin time (aPTT) results are presented in Table 3. On day 1 post-infusion, the low dose animals showed a significantly higher aPTT when compared with the pretreated low dose animals. In the high dose baboons, the aPTT
was significantly elevated at 4 hours, 6 hours, and 1 day post-infusion when compared to the baseline and the pretreated high dose animals. On day 7, the aPTT of the high dose animals decreased significantly from baseline, although this was not considered to be biologically significant. Meanwhile, in the high dose animals pretreated with dexamethasone, there was no significant change in the aPTT from baseline, and the clotting times were all within normal range for the baboon.
The Factor Vlll (FVIII) results are summarized in Table 4.
FVIII levels of the low dose and pretreated low dose groups showed some scdll~red significant differences from baseline and between ~,edl",ents, however, all of the values were within the normal range for baboons. The FVIII levels of the high dose animals exceeded the upper limit of the normal range on days Z, 4, 7, and 14 post-dosing.
Values for the pretreaLed high dose animals also exceeded the upper limit of the normal range, but only at six hours, 1 day and 2 days post-dosing, coming back into the normal range much sooner than the values for the untreated animals.
The plasma fibrinogen values for the various lrt:al",en groups are shown in Table 5. In the low dose baboons, the fibrinogen concentration exceeded the upper limit of the normal range (214 mg/dl) on days 1 and 2, and was significantly different from baseline on day 2. The fibrinogen concentrations in the pretreated low dose baboons also exceeded the upper limit of the normal range on days 1 and 2, however, these changes were not considered to be biologically significant. The fibrinogen concentration of the high dose group decreased significantly with respect to baseline at six hours post-infusion, and this concentration was below the lower limit of normal (118 mg/dl) for baboons.
Meanwhile, fibrinogen levels in the pre~redLed high dose group increased significantly from baseline on days 1 and 2 and exceeded the upper limit of riormal on days 1, 2, and 4.
Intravenous administration of PFDC0 also induced thrombocytopenia in the u"lrealed study groups. The platelet count data for the four study groups in shown in Table 6. The normal range for a baboon platelet count is 164,000-394,000/mm3, with values below this range indicative of thrombocytopenia. In comparison to the low end of the normal range, the low dose baboons were moderately to mildly thrombocytopenic on days 4 and 7 post-infusion. Meanwhile, the pretreated low dose animals were not considered to be thrombocytopenic since the platelet count values for these animals were within the normal range during the entire study. Meanwhile, both high dosed study groups exhibited signs of thrombocytopenia. However, the untreated high dose animals were thrombocytopenic between days 2 and 14, whereas the thrombocytopenia in the treated high dose group was not visible until day 4.
Imnact of Dexamethasone Pretrealment on Serum Chemistrv Parameters Clinical chemistry parameters were analyzed only for the two high dose study groups.
Serum triglyceride (TG), total bilirubin, and direct bilirubin values are shown in Tables 7 and 8. With respect to serum triglycerides, elevations in the high dose animals exceeded the upper - limit (94 mg/dl) of the normal range for baboons on days 1, 2, and 4, whereas increases in the dexamethasone pretreated group where well within the normal range for the baboon. The TG increases were probably related to the infusion of exogenous triglycerides contained in the corticosteroid and/or PFC emulsion and the number of WO 96/13268 . PCT/US95/13714 chemical sedation procedures required for blood sampling and monitoring of vital signs in the first 4 days post-infusion.
The total bilirubin values exceeded or were at the upper limit (0.40 mg/dl) of normal for baboons at 4 hours, 6 hours, and 1 day in the high dose animals, and were at this upper limit at 4 hours and 6 hours in the pretreated animal group. These rises probably were due to altered hemoglobin metabolism secondary to phagocytosis of the emulsion particles by the hepatic reticuloendothelial (Kupffer) cells. With respect to direct bilirubin, the high dose group exceeded the normal range for baboons (0.20mg/dl) at 6 hours and 1 day post-infusion, whereas all of the values in the pretreatment group were within the normal range.
Aspartate amino transferase (AST) enzyme activity values are shown in Table 9. The AST enzyme activity exceeded the upper limit (62 U/L) of the normal range for baboons in both the high dose and pretreated high dose study groups at 4 hours, 6 hours, 1 day, 2 days and 4 days post-infusion. However, the AST values for the high dose group were significantly greater than the values of the pretreatment high dose group at 6 hours, 1 day and 2 days post-infusion.
The lactate dehydrogenase (LDH) serum enzyme activity values also are shown in Table 9. In the high dose animals, there is a significant elevation of LDH during several measurement times post-infusion, and all of the LDH values between 4 hours and 4 days were above the upper limit ( 438 U/L) of the normal range for baboons. In the pretreated high dose group, LDH values exceeded the upper limit of the normal range only on days 1 and 2.
Furthermore, in this group, there were no significant changes in the LDH level from baseline over the course of the entire study.
This invention offers several benefits to animals being treated with PFC emulsions. For example, corticosteroid pretreatment attenuates or prevents adverse PFC-induced side effects on the coagulation system. Pretreatment virtually eliminates the PFC-induced adverse effects on prothrombin time and activated partial thromboplastin time, and significantly inhibits PFC-induced thrombocytopenia .
Corticosteroid pretreatment also attenuates or eliminates adverse PFC-induced side effects on several serum chemistry parameters. For example, pretreatment inhibits PFC-induced increases in serum triglycerides and bilirubin, as well as in aspartate amino transferase enzyme activity and lactate dehydrogenase enzyme activity.
Wo 96/13268 PCT/US95/13714 Table 2 ..
F~oll.ro...b;n Time (seconds) 1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R ~s - ' .eMean 12.8 12.4 12.8 13.2 Std 0.0 0.5 0.3 0.5 n 3 3 3 3 4 Hour Mean 12.5 12.3 14.3t@ 12.8 Std 0.0 0.3 0.6 0.6 n 3 3 3 3 6 Hour Mean 14.2 13.7 18.0t@ 13.7 Std 1.2 1.5 0.9 0.8 n 3 3 3 3 1 Day Mean 14.4* 13.5 16.0t@ 14.0 Std 1.7 1.3 0.5 0.5 n 3 3 3 3 2 Day Mean 13.2 13.2 14.2t 14.0 Std 0.8 1.0 0.8 0.5 n 3 3 3 3 4 Days Mean 12.5 12.7 12.8 13.8 Std 0.5 0.8 0.3 0.3 n 3 3 3 3 7 Days Mean 13.0 12.5 12.3 13.0 Std 0.5 0.5 0.3 0.5 n 3 3 3 3 14 Days Mean 13.0 12.7 13.0 13.3 Std 0.5 0.6 0.5 0.6 n 3 3 3 3 30 Days Mean 13.0 12.8 13.7 14.2 Std 0.5 0.3 0.3 0.8 n 3 3 3 3 ~Denotes a sig--irica--l dirrerenGe from Lase" ~e (p50.05) Denotes a siy.-irica-.l Jirr_lence within a PFC dose group with and ~;ll-o.Jl t p.t l.eaL---e--l (p50-05) tDenotes a .;yniricanl dirr.,.~nce from ~?S-'- .e (ps0.01) @Denotes a sig.-iricarl dirrerence within a PFC dose group with and without ~,.el-eal---ent (p s 0.01) Table 3 A~ F - ' Parbal Tl' "r 6 ~ Time (arl r) (5~CG. .~ls) 1 ml/kg1 ml/kg PFC 2 ml/kg2 ml/kg PFC Dexam PFC PFC
Dexam P~a~-' .eMean 31.4 29.3 32.9 33.1 Std 0.8 1.6 4.1 1.6 n 3 3 3 3 4 Hour Mean 29.3 28.3 39.5@ 29.2 Std 2.5 1.9 6.1 1.8 n 3 3 3 3 6 Hour Mean 33.3 31.7 44.5t@ 31.5 Std 4.1 2.0 9.0 1.3 n 3 3 3 3 1 Day Mean 36.2 29.7 43.7t@ 32.2 Std 7.7 3.4 6.8 2.0 n 3 3 3 3 2 Day Mean 30.5 28.3 35.2t 29.5 Std 3.0 3.0 5.0 1.3 n 3 3 3 3 4 Days Mean 26.7 29.3 27.2 32.0 Std 1.3 2.6 2.6 2.2 n 3 3 3 3 7 Days Mean 28.3 28.7 26.0* 31.8 Std 2.0 Z.3 2.6 3.5 n 3 3 3 3 14 Days Mean 30.5 31.7 29.8 31.3 Std 1.8 2.5 3.3 3.5 n 3 3 3 3 30 Days Mean 31.7 30.7 31.3 33.5 Std 2.9 2.0 3.3 1.7 n 3 3 3 3 *Denotes a s;g.~;ricanl dirrerence from b~ e (pC0.05) Denotes a ~iy..irica,.l Jirro~e....,G within a PFC dose group with and without .aal~ l (p s 0.05) tDenotes a ;,;g..;ficanl dirt~rGnce from basel;ne (ps0.01) @Denotes a significant .lirrerOnce within a PFC dose group with and without Fi,el-Gal.,.enl (pcO.01) Table 4 Factor Vlll (FVIII) ~%) .
1 ml/kg1 ml/kg PFC2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R~se! )e Mean 64.5 77.0 63.2 61.7 Std 10.7 4.8 5.8 18.9 n 3 3 3 3 4 Hour Mean 77.3 89.3 74.0 87.0 Std 8.6 20.5 16.6 43.6 n 3 3 3 3 6 Hour Me~n 89.3~ 65.7 89.0 105.0*
Std Z.5 21.2 38.0 33.0 n 3 3 3 3 1 Day Mean 58.3 92.0 61.0 100.7 Std 16.5 25.0 8.5 38.6 n 3 3 3 3 2 Day Mean 76.3 87.0 98.7 116.7*
Std 13.4 15.0 8.7 23.4 n 3 3 3 3 4 Days Mean 78.7 70.7 105.0~ 77.0 Std 11.6 3.2 7.5 22.1 n 3 3 3 3 7 Days Mean 67.0 93.3 113.3~ 83.0 Std 8.7 15.5 7.8 29.5 n 3 3 3 3 14 Days Mean 60.7 54.3~ 98.0 87.7 Std 7.1 6.0 17.1 41.0 n 3 3 3 3 30 Days Mean 63.0 82.0 89.3 78.3 Std 6.0 19.1 2.5 25.0 n 3 3 3 3 *Denotes a ,;ynirica-.l dirrerence from ' ~s-' .e (psO.05) _Denotes a siynirica.-l dirrcr~llce within a PFC dose group with and without p.~l,a~ -enl (p50.05) tDenotes a ~iyr.iricanl .lirrorë"ce from Las-'- ~e (psO.01) @Denotes a siyniricsrl dirrere.-ce within a PFC dose group with and -' without p.el.eal,.. ent (psO.01) Table 5 hL ~
Img/dl) 1 mllkg1 mllkg PFC 2 ml/kg 2 ml/kg PFC Dexsm PFC PFC
Dexam B~s~" .eMean 207.8 218.7 187.5 190.0 Std 33.5 23.6 19.8 13.0 n 3 3 3 3 4 Hour Mean 175.3 200.0 159.3 193.3 Std 21.9 Z7.8 37.6 17.6 n 3 3 3 3 6 Hour Mean 170.3 187.7 113.0t@ 200.0 Std 4.0 55.1 51.1 18.0 n 3 3 3 3 1 Day Mean 247.0 248.7 146.7@ 260.0t Std 86.2 59.0 39.5 17.3 n 3 3 3 3 2 Day Mean 276.7~ 238.3 187.7 253.3 Std 58.4 42.5 36.6 30.6 n 3 3 3 3 4 Days Mean 201.7 210.0 210.0 230.0 Std 16.1 27.8 34.6 43.6 n 3 3 3 3 7 Days Mean 156.0 192.7 183.3 195.7 Std 1.7 21.9 10.4 33.9 n 3 3 3 3 14 Days Mean 148.5 173.3 163.3 190.7 Std 17.6 22.5 19.3 20.6 n 3 3 3 3 30 Days Mean 150.0 166.7 152.3 169.0 Std 13.2 14.4 5.9 15.9 n 3 3 3 3 ~Denotes a ~;y..irica..l Jirre~enca from baseline (p50.05) _Denotes a a;y..iricanl dirrerence within a PFC dose group with and without prel,eal...ent (p50.05) tDenotes a siy~irica~l dirrercnce from tase'i )e (pso.ol~
@Denotes a significant .lirrerence within a PFC dose group with and without ~,rel.aal...anl (psO.01) Table 6 ~, Platelet Count (#Imm3) 1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam Baseline Mean 293,667 384,667 256,667 245,000 Std 73,059 87,719 21,808 10,851 n 3 3 3 3 4 Hour Mean 350,000 375,000 249,333 282,667 Std 110,000 72,111 31,770 51,433 n 3 3 3 3 6 Hour Mean 347,333 374,000 228,667 273,000 Std 137,147 82,018 31,134 61,579 n 3 3 3 3 1 Day Mean 313,333 387,000 218,667@ 370,667 Std 119,316 77,660 15,503 170,694 n 3 3 3 3 2 Day Mean 159,000 268,000 108,333t 223,333 Std 54,617 112,468 64,485 75,593 n 3 3 3 3 4 Days Mean71,667~@ 193,333~ 45,333t 86,000t Std 16,803 146,401 14,012 21,703 n 3 3 3 3 7 Days Mean132,667~ 213,333~ 87,000t 65,000t Std 32,578 72,058 23,302 17,346 n 3 3 3 3 14 Days Mean 264,333 311,333 148,000~ 136,000 Std 51,082 72,858 31,225 3,464 n 3 3 3 3 30 Days Mean 337,667 283,333 203,000 242,333 Std 56,518 72,009 98,240 77,526 n 3 3 3 3 ~Denotes a s;y.,iricd.,l Jirr~r~,nce from i ~s ~J ", IpsO.05) - Denotes a s;g"ilicanl .lirrerence within a PFC dose group with and without ~J.el,cdl."a"l (psO.05) tDenotes a ~;g"ilicanl dirr~.cnce from ' -s~ ,e (psO.Ol) @Denotes a ~;g,.;rica"l dirr~rcnce within a PFC dose group with and without ,6,cl-cal",ent (psO.01) Tablo 7 T.;5~1y~.;~s (mg/dl) 2 ml/kg 2 ml/kg PFC PFC
Dexam R? ;~ ~eMean 45-5 33.8 Std 17.7 24.9 n 3 3 4 Hour Mean 47.0 40.7 Std 11.3 16.7 n 3 3 6 Hour Mean 51.0 31.7 Std 16.7 15.1 n 3 3 1 Day Mean 107.7~ Z5.0 Std 51.1 11.3 n 3 3 2 Day Mean 132.7~ 87.3 Std 26.5 15.0 n 3 3 4 Days Mean 115.0~ 89.3 Std 22.6 23.9 n 3 3 7 Days Mean 68.3 45.7 Std 2.5 25.9 n 3 3 14 Days Mean 54.7 54.7 Std 18.9 19.5 n 3 3 30 Days Mean 40.3 40.0 Std 5.0 15.6 n 3 3 ~Denotes a ~;y"iricdnl Jirferel)cc from ~as~' .e (psO.05) _An u "Jersco.2d value denoles a s;g..;rica"l dirrt:,e"ce within a PFC dose group with and without ~Jrelreal~ent (p50.05) tDenotes a s;yniricar,l Jirrer~nce from ~as~' )e (psO.01) @Denotes a s;g";rica"l Jirra~ancc within a PFC dose group with and without ~ e~,l"~enl (pC0.01) Table 8 ~, To~tal '' 1,l' ' Direct r~ ~
(mg/d) (mg/d) 2 ml/kg2 ml/kg PFC2 ml/kg2 ml/kg PFC Dexam PFC PFC
Dexam Baseline Mean 0.2 0.2 0.2 0.2 Std 0.0 0.1 0.0 0.1 n 3 3 3 3 4 HourMean 0.6~ 0.4~ 0.5~ 0.2 Std 0.3 0.1 0.5 0.1 n 3 3 3 3 6 HourMean 0.4~ 0.4* 0.3 0.1 Std 0.1 0.1 0.1 0.0 n 3 3 3 3 1 DayMean 0.4* 0.2 0.4 0.1 Std 0.2 0.0 0.4 0.0 n 3 3 3 3 2 DayMean 0.3 O.Z 0.3 0.1 Std 0.2 0.1 0.2 0.0 n 3 3 3 3 4 DaysMean 0.2 0.2 0.2 0.2 Std 0.1 0.1 0.1 0.1 n 3 3 3 3 7 DaysMean 0.3 0.1 0.1 0.1 Std 0.1 0.1 0.0 0.0 n 3 3 3 3 14 DaysMean 0.3 0.2 0.1 0.1 Std 0.1 0.1 0.0 0.1 n 3 3 3 3 30 DaysMean 0.2 0.1 0.1 0.1 Std 0.1 0.1 0.0 0.0 n 3 3 3 3 *Denotes a s;y"iricanl dirr~.ence from l~aseline (pC0,05J
_An u~duscOrëd value denoles a aiy"iricar,l dirr1renca within a PFC dose group with and without p,el,~al",e.,l (p~0.05) tDenotes a aiy.,iri.,a"l dirr~r~.,ce from La~ e (psO.01) @Denotes a signiricanl dirrelence within a PFC dose group with and without ,~,.el,èal",anl (p~0.01) Table 9 SGOT-AST LDH
(U/L) ~U/L) 2 ml/kg2 ml/kg PFC2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R= ~ .eMean 32.8 27.8 165.2 124.8 Std 12.5 1.8 17.9 58.5 n 3 3 3 3 4 Hour Mean 143.3 89.3 743.3 311.0 Std 28.9 51.7 167.3 127.2 n 3 3 3 3 6 Hour Mean 270.7t 127.0 1289t 492.0 Std 53.0 54.0 448.7 119.7 n 3 3 3 3 1 Day Mean 549.0t 166.7~ 3791.3t 520.0 Std Z40.2 61.8 1604.2 126.1 n 3 3 3 3 2 Day Mean 304.0t 172.3* 1588.3t 558.7 Std 150.7 56.3 1155.5 303.0 n 3 3 3 3 4 Days Mean 73.7 81.3 451.7 299.0 Std 29.7 31.5 112.6 118.9 n 3 3 3 3 7 Days Mean 33.0 40.0 313.7 213.7 Std 7.0 8.5 60.7 62.7 n 3 3 3 3 14 Days Mean 22.3 25.3 228.0 164.3 Std 1.2 5.7 85.5 64.8 n 3 3 3 3 30 Days Mean 22.7 21.7 163.7 122.0 Std 0.6 2.1 36.2 3.2 n 3 3 3 3 ~Denotes a siy.-iric~nl Jirralance from l~asel;ne (ps0.05) An ul-derscGracl value denoles a :.;y..irica-.l dirrarance within a PFC dose group without and without p~ e.-~ enl (ps0.05 tDenotes a significant dirtarence from Laseli.-e Ips0.01) @Denotes a sig..iricanl .lirrt~ nce within a PFC dose group with and without ~rt~ dllll~ (ps0.01) W0 96/13268 rCT/US95/13714 The embodiments presented in the detailed descripLion .;.
i ~ are provided by way of illustration only, and are not intended to limit the scope of the invention. Rather, this invention is defined by the appended claims and any equivalents thereto.
WHAT IS CLAIMED IS:
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Side effects from the intravenous infusion of a PFC
emulsion have been reported in both human and animal studies.
Two groups of side effects have been observed in human volunteers receiving a perfluorooctylbromide (PFOB) emulsion. PFOB, also known as Perflubron, is a PFC under development as a component of a blood-pool imaging agent known as Imagent BP. Imagent BP is a phospholipid emulsion containing ninety (90%) percent w/v Perflubron and having a mass median particle size of approximately 0.2 ~. The first group of side effects occurs within the first 2 hours after injection of the PFC emulsion. These acute effects are characterized primarily by skin flushing and back~che. The second group of side effects occurs later than 2 hours post-injection and lasts generally for about a day. These delayed effects, described as a "flu-like syndromen, include fever, dizziness, and occasional nausea. S. F. Flaim, et al., "Characterization and Mechanism of Side Effects of Imagent BP (Highly Concentrated Fluorocarbon Emulsion) In Swinen, Vol. 26, Investigative Radiologv, November Supplement 1991, S122-S124.
PFC emulsions also induce adverse side effects in swine. As with the human volunteers! intravenous administration of a PFOB emulsion produced both an acute and a delayed response in swine. The acute response included a rise in mean pulmonary artery pressure (mPAP) and severe skin flushing, both of which resolved ~ completely by 2 hours post-injection. The delayed side effect was a febrile response characterized by a 1 - 2~C increase in body temperature which peaked at 4 hours post-injection and resolved over the next 2 to 24 hours. The early rise in mPAP is believed to be related to the activation of pulmonary intravascular macrophages, while the skin flushing is attributed to the substantial release of Prostaglandins upon macrophage activation. S. F. Flaim, et al., "Characterization and Mechanism of Side Effects of Imagent BP
(Highly Concentrated Fluorocarbon Emulsion) In Swine", Vol. 26, Investigative Radiologv, November Supplement 1991, S122-S124.
Further research with swine has shown that these particular clinical side effects may be effectively prophylaxed with dexamethasone, ibuprofen, or indomethacin. For example, the acute, transient rise in mPAP and skin flushing both were blocked successfully by prophylaxis with any one of these three compositions. In addition, the delayed febrile response also was blocked successfully by prophylaxis with dexamethasone, ibuprofen, or indomethacin. /d.
Despite the advances made by these animal and human studies, they do not identify other problems or side effects which might be associated with intravenous infusion of PFC emulsions.
Given the increase in clinical use of such emulsions, it would be desirable to identify other potential side effects. Furthermore, once those side effects have been identified, it would be highly beneficial to identify ways in which those side effects might be alleviated or even prevented.
Summarv of the Invention This invention is directed to a method of improving the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry of an animal. The method includes intravenously administering a corticosteroid to an animal prior to intravenous administration of a perfluorochemical emulsion. The corticosteroid is administered in an amount sufficient tO improve the adverse effects of the perfluorochemical upon the hemostatic system and serum triglyceride/enzyme levels of the animal. After administration of the corticosteroid, the perfluorocarbon emulsion is administered intravenously.
Preferably, the corticosteroid is administered at a dose of from about 0.2 mg/kg of body weight to about 6 mg/kg of body weight, and more preferably, at a dose of about 1 mg/kg. The perfluorochemical used in the perfluorochemical emulsion preferably is administered at a dose of from about 0.5 to about 10 ml/kg of body weight.
With respect to the hemostatic system, the method may be conducted for reducing perfluorochemical-induced adverse side effects upon prothrombin time and activated partial thromboplastin time, and for inhibiting perfluorochemical-induced WO 96/13268 . PCT/US95/13714 thrombocytopenia. With respect to serum chemistry, the ",ell,o~
~ may be conducted for reducing perfluorocarbon-induced adverse side effects upon aspartate amino transferase enzyme activity, lactate dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone, while the perfluorochemical preferably is selected from the group consisting of: perfluorodichlorooctane, perfluorodecalin, perfluoromethyldecalin, perfluorodimethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-~
methyl-octahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin, perfluoro-bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated perfluorocarbons, and mixtures thereof. Most preferably, the perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the perfluorochemical in an amount of from about 15 v/v% to about 70 v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps, administration of the perfluorochemical emulsion preferably is begun within several hours after administering the corticosteroid, and can t also be administered immediately following administration of the corticosteroid .
This invention offers several benefits to animals being treated with PFC emulsions. For example, corticosteroid pretreatment attenuates or prevents adverse PFC-induced side effects on the coagulation system. Pretreatment virtually eliminates the PFC-induced adverse effects on prothrombin time and activated partial thromboplastin time, and significantly inhibits PFC-induced thrombocytopenia .
Corticosteroid pretreatment also attenuates or eliminates adverse PFC-induced side effects on several serum chemistry parameters. For example, pretreatment inhibits PFC-induced increases in serum triglycerides and bilirubin, as well as in aspartate amino transferase enzyme activity and lactate dehydrogenase enzyme activity.
Detailed Desc.iulion of the Invention This invention is directed to a method of improving the adverse effects of a perfluorochemical emulsion on the hemostatic system and serum chemistry of an animal. The method includes intravenously administering a corticosteroid to an animal prior to intravenous administration of a perfluorochemical emulsion. The corticosteroid is administered in an amount sufficient to improve the adverse effects of the perfluorochemical upon the hemostatic system and serum triglyceride/enzyme levels of the animal. After administration of the corticosteroid, the perfluorocarbon emulsion is administered intravenously.
wo 96/13268 PCT/US95/13714 Preferably, the corticosteroid is administered at a dose of from about 0.2 mg/k~ of body weight to about 6 mg/kg of body weight. At low doses of about 0.1 mg/kg, ptel,eal.,.enl with dexamethasone has li~tle impact on PFC-induced side efreol:.; while doses above about 6.0 mg/kg present safety issues in that such doses may result in undesired changes in the hypothalamic-pituitary-adrenal axis physiology. More preferably, the co~icosleroid is administered at a dose of about 1 mg/kg. The perfluorochemical used in the perfluorochemical emulsion preferably is administered at a dose of from about 0.5 to about 10 ml/kg of body weight.
With respect to the hemostatic system, the method may be conducted for reducing perfluorochemical-induced adverse side effects upon prothrombin time and activated partial thromboplastin time, and for inhibiting perfluorochemical-induced thrombocytopenia. With respect to serum chemistry, the method may be conducted for reducing perfluorocarbon-induced adverse side effects upon aspartate amino transferase enzyme activity, lactate dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone. The perfluorochemical preferably is selected from the group consisting of perfluorodichlorooctane, perfluorodecalin, perfluoro"-~ yldecalin, . perfluorodimethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-~methyl-octahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin, perfluoro-bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated perfluorocarbons, and mixtures thereof. Most preferably, the perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the perfluorochemical in an amount of from about 15 v/v~/0 to about 70 v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps, administration of the perfluorochemical emulsion preferably is begun within several hours after administering the corticosteroid, and can also be administered immediately following administration of the corticosteroid .
Examr~le Study Design and Protocol A study was conducted to assess the responses associated with an acute intravenous exposure of a 40 v/v%
perfluorodichlorooctane ~PFDC0) emulsion in male adult baboons /Papio cynocephalus~ with and without treatment with 1 mg/kg of dexamethasone. Dose levels of the 40 v/v% PFDC0 emulsion were selected to impart minimal, reversible side errecls in the baboon that would be efficacious with respect to intravascular gas transport.
The dexamethasone pretreatment regimen was administered intravenously at a dose level intended to elicit anti-infla",.,~alory effects. The 40 v/v% PFDC0 emulsion included a PFDC0 stem WO 96tl3268 PCT/US95/13714 emulsion, as well as a 23.4% saline annex solution. The specific composition of the stem emulsion, saline annex and final formulation is shown in Table 1.
Table 1 Formulation of the 40 v/v% PFDCO Emulsion Component PFDCO 23.4% Saline Final Formula-Stem Emulsion Annex tion for IV
Administration PFDCO (v/v%) 40 - 39 Lecithin 2 - 1.95 ~w/v%) Safflower Oil 2 - 1.95 (w/v%) Na2CO3 0.01 5 (w/v%) NaCI (w/v%) - 23.4 0.466 Water for q.s q.s q.s Injection Twelve adult male baboons (P~pio cynocephalus~ were selected after being given complete health examinations by veterinary personnel and approved for the study. The animals ranged in age from 8 - 20 years, were either feral or colony born, and were clinically in excellent health.
The twelve animals were divided into four L~eal-~ent groups with three animals in each group. The group I and ll animals each received 1.0 ml/kg PFCDO (2.5 ml/kg stem emulsion annexed with 23.4% sodium chloride), with the Group ll animals also receiving 1 mg/kg dexamethasone intravenously immediately prior to infusion of PFDC0. The Group lll and IV animals each received 2.0 ml/kg PFDC0 (5.0 ml/kg stem emulsion mixed with 23.4% sodium chloride), while the Group IV animals also received 1 mg/kg dexamethasone intravenously immediately prior to infusion.
The baboons were sedated for dexamethasone and PFDC0 infusion with ketamine HCI (IM) supplemented with valium, and additional doses of ketamine HCI were administered when required to maintain sedation. Following sedation and pretreatment blood collection, a 16-20 gauge indwelling angiocatheter was placed and secured into a saphenous vein for infusion of the respective emulsions. The doses of the 40 v/v% PFDC0 emulsion were administered at a rate of approximately 4-6 ml per minute.
Blood samples were drawn and analyzed over a thirty (30) day period following administration of the PFDC0 emulsion.
The baboons were sedated for all blood sampling procedures with ketamine HCI (IM) supplemented with valium, and additional doses of ketamine HCI were administered when required to maintain sedation. Indirect systemic blood pressure was measured using a non-invasive blood pressure unit, and body temperature was monitored using a rectal thermometer. In addition, respiratory rate was measured directly by monitoring the inspiratory excursions of the thoracic or abdominal wall, while heart rate was deterrnined by palpation of a peripheral pulse or chest auscultation. Blood samples were collected percutaneously via a peripheral vein.
W ~ 96113268 PCTAUS95/I3~14 Data Analvsis Methodologv For parameters having multiple baseline and/or pre-infusion measurements, an average baseline value for each animal ~i was calculated. The change in response from the average baseline was statistically evaluated, and between-group comparisons at each dose level of PFC with and without dexamethasone pretreatment were performed at each sample time. A one-factor analysis of variance (ANOVA) was used to test for significance within and between groups over time. The levels of significance were defined as P<.05 and P<.01.
The results presented below were compared to normal values for the adult male baboon as listed in Brenda M. Hainsey, et al., Clinical Parameters of the Normal Baboons (Papio species) and Chimpanzees (Pan troglodytes)", Vol. 43, No. 3, Laboratorv Animal Science, June, 1993. For analysis of Factor Vlll, the results were compared to the normal range for baboons as reported in Hollace M.
Feingold, et al., "Coagulation Assays and Platelet Aggregation Patterns in Human, Baboon, and Canine Blood", Vol. 47, No. 10, American Journal of Veterinary Research, October, 1986.
Imnact of Dexamethasone ~et,aal---ent - on the Hemostatic Svstem Prothrombin time (PTJ is shown for the four treatment groups over the length of the study in Table 2. In the low dose PFC
animals, there was evidence of a rise in the PT at six hours post-infusion, which remained elevated one day after infusion. However, CA 02202989 l997-04-l7 in the low dose animals preL~aaLed with dexamethasone, there were no significant changes in the PT over the course of the study. In the high dose baboons, the PT was significantly elevated at 4 hours, 6 hours, and 1 day post-infusion when compared to the baseline and the high dose animals pretreated with dexamethasone. At 2 days following dosing, the PT of the high dose animals remained significantly prolonged when compared to the baseline. For the pretreated high dose animals, the only significant change in the PT
from baseline occurred at thirty (30) days post-infusion; however, this elevation was not considered to be biologically significant.
The activated partial thromboplastin time (aPTT) results are presented in Table 3. On day 1 post-infusion, the low dose animals showed a significantly higher aPTT when compared with the pretreated low dose animals. In the high dose baboons, the aPTT
was significantly elevated at 4 hours, 6 hours, and 1 day post-infusion when compared to the baseline and the pretreated high dose animals. On day 7, the aPTT of the high dose animals decreased significantly from baseline, although this was not considered to be biologically significant. Meanwhile, in the high dose animals pretreated with dexamethasone, there was no significant change in the aPTT from baseline, and the clotting times were all within normal range for the baboon.
The Factor Vlll (FVIII) results are summarized in Table 4.
FVIII levels of the low dose and pretreated low dose groups showed some scdll~red significant differences from baseline and between ~,edl",ents, however, all of the values were within the normal range for baboons. The FVIII levels of the high dose animals exceeded the upper limit of the normal range on days Z, 4, 7, and 14 post-dosing.
Values for the pretreaLed high dose animals also exceeded the upper limit of the normal range, but only at six hours, 1 day and 2 days post-dosing, coming back into the normal range much sooner than the values for the untreated animals.
The plasma fibrinogen values for the various lrt:al",en groups are shown in Table 5. In the low dose baboons, the fibrinogen concentration exceeded the upper limit of the normal range (214 mg/dl) on days 1 and 2, and was significantly different from baseline on day 2. The fibrinogen concentrations in the pretreated low dose baboons also exceeded the upper limit of the normal range on days 1 and 2, however, these changes were not considered to be biologically significant. The fibrinogen concentration of the high dose group decreased significantly with respect to baseline at six hours post-infusion, and this concentration was below the lower limit of normal (118 mg/dl) for baboons.
Meanwhile, fibrinogen levels in the pre~redLed high dose group increased significantly from baseline on days 1 and 2 and exceeded the upper limit of riormal on days 1, 2, and 4.
Intravenous administration of PFDC0 also induced thrombocytopenia in the u"lrealed study groups. The platelet count data for the four study groups in shown in Table 6. The normal range for a baboon platelet count is 164,000-394,000/mm3, with values below this range indicative of thrombocytopenia. In comparison to the low end of the normal range, the low dose baboons were moderately to mildly thrombocytopenic on days 4 and 7 post-infusion. Meanwhile, the pretreated low dose animals were not considered to be thrombocytopenic since the platelet count values for these animals were within the normal range during the entire study. Meanwhile, both high dosed study groups exhibited signs of thrombocytopenia. However, the untreated high dose animals were thrombocytopenic between days 2 and 14, whereas the thrombocytopenia in the treated high dose group was not visible until day 4.
Imnact of Dexamethasone Pretrealment on Serum Chemistrv Parameters Clinical chemistry parameters were analyzed only for the two high dose study groups.
Serum triglyceride (TG), total bilirubin, and direct bilirubin values are shown in Tables 7 and 8. With respect to serum triglycerides, elevations in the high dose animals exceeded the upper - limit (94 mg/dl) of the normal range for baboons on days 1, 2, and 4, whereas increases in the dexamethasone pretreated group where well within the normal range for the baboon. The TG increases were probably related to the infusion of exogenous triglycerides contained in the corticosteroid and/or PFC emulsion and the number of WO 96/13268 . PCT/US95/13714 chemical sedation procedures required for blood sampling and monitoring of vital signs in the first 4 days post-infusion.
The total bilirubin values exceeded or were at the upper limit (0.40 mg/dl) of normal for baboons at 4 hours, 6 hours, and 1 day in the high dose animals, and were at this upper limit at 4 hours and 6 hours in the pretreated animal group. These rises probably were due to altered hemoglobin metabolism secondary to phagocytosis of the emulsion particles by the hepatic reticuloendothelial (Kupffer) cells. With respect to direct bilirubin, the high dose group exceeded the normal range for baboons (0.20mg/dl) at 6 hours and 1 day post-infusion, whereas all of the values in the pretreatment group were within the normal range.
Aspartate amino transferase (AST) enzyme activity values are shown in Table 9. The AST enzyme activity exceeded the upper limit (62 U/L) of the normal range for baboons in both the high dose and pretreated high dose study groups at 4 hours, 6 hours, 1 day, 2 days and 4 days post-infusion. However, the AST values for the high dose group were significantly greater than the values of the pretreatment high dose group at 6 hours, 1 day and 2 days post-infusion.
The lactate dehydrogenase (LDH) serum enzyme activity values also are shown in Table 9. In the high dose animals, there is a significant elevation of LDH during several measurement times post-infusion, and all of the LDH values between 4 hours and 4 days were above the upper limit ( 438 U/L) of the normal range for baboons. In the pretreated high dose group, LDH values exceeded the upper limit of the normal range only on days 1 and 2.
Furthermore, in this group, there were no significant changes in the LDH level from baseline over the course of the entire study.
This invention offers several benefits to animals being treated with PFC emulsions. For example, corticosteroid pretreatment attenuates or prevents adverse PFC-induced side effects on the coagulation system. Pretreatment virtually eliminates the PFC-induced adverse effects on prothrombin time and activated partial thromboplastin time, and significantly inhibits PFC-induced thrombocytopenia .
Corticosteroid pretreatment also attenuates or eliminates adverse PFC-induced side effects on several serum chemistry parameters. For example, pretreatment inhibits PFC-induced increases in serum triglycerides and bilirubin, as well as in aspartate amino transferase enzyme activity and lactate dehydrogenase enzyme activity.
Wo 96/13268 PCT/US95/13714 Table 2 ..
F~oll.ro...b;n Time (seconds) 1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R ~s - ' .eMean 12.8 12.4 12.8 13.2 Std 0.0 0.5 0.3 0.5 n 3 3 3 3 4 Hour Mean 12.5 12.3 14.3t@ 12.8 Std 0.0 0.3 0.6 0.6 n 3 3 3 3 6 Hour Mean 14.2 13.7 18.0t@ 13.7 Std 1.2 1.5 0.9 0.8 n 3 3 3 3 1 Day Mean 14.4* 13.5 16.0t@ 14.0 Std 1.7 1.3 0.5 0.5 n 3 3 3 3 2 Day Mean 13.2 13.2 14.2t 14.0 Std 0.8 1.0 0.8 0.5 n 3 3 3 3 4 Days Mean 12.5 12.7 12.8 13.8 Std 0.5 0.8 0.3 0.3 n 3 3 3 3 7 Days Mean 13.0 12.5 12.3 13.0 Std 0.5 0.5 0.3 0.5 n 3 3 3 3 14 Days Mean 13.0 12.7 13.0 13.3 Std 0.5 0.6 0.5 0.6 n 3 3 3 3 30 Days Mean 13.0 12.8 13.7 14.2 Std 0.5 0.3 0.3 0.8 n 3 3 3 3 ~Denotes a sig--irica--l dirrerenGe from Lase" ~e (p50.05) Denotes a siy.-irica-.l Jirr_lence within a PFC dose group with and ~;ll-o.Jl t p.t l.eaL---e--l (p50-05) tDenotes a .;yniricanl dirr.,.~nce from ~?S-'- .e (ps0.01) @Denotes a sig.-iricarl dirrerence within a PFC dose group with and without ~,.el-eal---ent (p s 0.01) Table 3 A~ F - ' Parbal Tl' "r 6 ~ Time (arl r) (5~CG. .~ls) 1 ml/kg1 ml/kg PFC 2 ml/kg2 ml/kg PFC Dexam PFC PFC
Dexam P~a~-' .eMean 31.4 29.3 32.9 33.1 Std 0.8 1.6 4.1 1.6 n 3 3 3 3 4 Hour Mean 29.3 28.3 39.5@ 29.2 Std 2.5 1.9 6.1 1.8 n 3 3 3 3 6 Hour Mean 33.3 31.7 44.5t@ 31.5 Std 4.1 2.0 9.0 1.3 n 3 3 3 3 1 Day Mean 36.2 29.7 43.7t@ 32.2 Std 7.7 3.4 6.8 2.0 n 3 3 3 3 2 Day Mean 30.5 28.3 35.2t 29.5 Std 3.0 3.0 5.0 1.3 n 3 3 3 3 4 Days Mean 26.7 29.3 27.2 32.0 Std 1.3 2.6 2.6 2.2 n 3 3 3 3 7 Days Mean 28.3 28.7 26.0* 31.8 Std 2.0 Z.3 2.6 3.5 n 3 3 3 3 14 Days Mean 30.5 31.7 29.8 31.3 Std 1.8 2.5 3.3 3.5 n 3 3 3 3 30 Days Mean 31.7 30.7 31.3 33.5 Std 2.9 2.0 3.3 1.7 n 3 3 3 3 *Denotes a s;g.~;ricanl dirrerence from b~ e (pC0.05) Denotes a ~iy..irica,.l Jirro~e....,G within a PFC dose group with and without .aal~ l (p s 0.05) tDenotes a ;,;g..;ficanl dirt~rGnce from basel;ne (ps0.01) @Denotes a significant .lirrerOnce within a PFC dose group with and without Fi,el-Gal.,.enl (pcO.01) Table 4 Factor Vlll (FVIII) ~%) .
1 ml/kg1 ml/kg PFC2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R~se! )e Mean 64.5 77.0 63.2 61.7 Std 10.7 4.8 5.8 18.9 n 3 3 3 3 4 Hour Mean 77.3 89.3 74.0 87.0 Std 8.6 20.5 16.6 43.6 n 3 3 3 3 6 Hour Me~n 89.3~ 65.7 89.0 105.0*
Std Z.5 21.2 38.0 33.0 n 3 3 3 3 1 Day Mean 58.3 92.0 61.0 100.7 Std 16.5 25.0 8.5 38.6 n 3 3 3 3 2 Day Mean 76.3 87.0 98.7 116.7*
Std 13.4 15.0 8.7 23.4 n 3 3 3 3 4 Days Mean 78.7 70.7 105.0~ 77.0 Std 11.6 3.2 7.5 22.1 n 3 3 3 3 7 Days Mean 67.0 93.3 113.3~ 83.0 Std 8.7 15.5 7.8 29.5 n 3 3 3 3 14 Days Mean 60.7 54.3~ 98.0 87.7 Std 7.1 6.0 17.1 41.0 n 3 3 3 3 30 Days Mean 63.0 82.0 89.3 78.3 Std 6.0 19.1 2.5 25.0 n 3 3 3 3 *Denotes a ,;ynirica-.l dirrerence from ' ~s-' .e (psO.05) _Denotes a siynirica.-l dirrcr~llce within a PFC dose group with and without p.~l,a~ -enl (p50.05) tDenotes a ~iyr.iricanl .lirrorë"ce from Las-'- ~e (psO.01) @Denotes a siyniricsrl dirrere.-ce within a PFC dose group with and -' without p.el.eal,.. ent (psO.01) Table 5 hL ~
Img/dl) 1 mllkg1 mllkg PFC 2 ml/kg 2 ml/kg PFC Dexsm PFC PFC
Dexam B~s~" .eMean 207.8 218.7 187.5 190.0 Std 33.5 23.6 19.8 13.0 n 3 3 3 3 4 Hour Mean 175.3 200.0 159.3 193.3 Std 21.9 Z7.8 37.6 17.6 n 3 3 3 3 6 Hour Mean 170.3 187.7 113.0t@ 200.0 Std 4.0 55.1 51.1 18.0 n 3 3 3 3 1 Day Mean 247.0 248.7 146.7@ 260.0t Std 86.2 59.0 39.5 17.3 n 3 3 3 3 2 Day Mean 276.7~ 238.3 187.7 253.3 Std 58.4 42.5 36.6 30.6 n 3 3 3 3 4 Days Mean 201.7 210.0 210.0 230.0 Std 16.1 27.8 34.6 43.6 n 3 3 3 3 7 Days Mean 156.0 192.7 183.3 195.7 Std 1.7 21.9 10.4 33.9 n 3 3 3 3 14 Days Mean 148.5 173.3 163.3 190.7 Std 17.6 22.5 19.3 20.6 n 3 3 3 3 30 Days Mean 150.0 166.7 152.3 169.0 Std 13.2 14.4 5.9 15.9 n 3 3 3 3 ~Denotes a ~;y..irica..l Jirre~enca from baseline (p50.05) _Denotes a a;y..iricanl dirrerence within a PFC dose group with and without prel,eal...ent (p50.05) tDenotes a siy~irica~l dirrercnce from tase'i )e (pso.ol~
@Denotes a significant .lirrerence within a PFC dose group with and without ~,rel.aal...anl (psO.01) Table 6 ~, Platelet Count (#Imm3) 1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam Baseline Mean 293,667 384,667 256,667 245,000 Std 73,059 87,719 21,808 10,851 n 3 3 3 3 4 Hour Mean 350,000 375,000 249,333 282,667 Std 110,000 72,111 31,770 51,433 n 3 3 3 3 6 Hour Mean 347,333 374,000 228,667 273,000 Std 137,147 82,018 31,134 61,579 n 3 3 3 3 1 Day Mean 313,333 387,000 218,667@ 370,667 Std 119,316 77,660 15,503 170,694 n 3 3 3 3 2 Day Mean 159,000 268,000 108,333t 223,333 Std 54,617 112,468 64,485 75,593 n 3 3 3 3 4 Days Mean71,667~@ 193,333~ 45,333t 86,000t Std 16,803 146,401 14,012 21,703 n 3 3 3 3 7 Days Mean132,667~ 213,333~ 87,000t 65,000t Std 32,578 72,058 23,302 17,346 n 3 3 3 3 14 Days Mean 264,333 311,333 148,000~ 136,000 Std 51,082 72,858 31,225 3,464 n 3 3 3 3 30 Days Mean 337,667 283,333 203,000 242,333 Std 56,518 72,009 98,240 77,526 n 3 3 3 3 ~Denotes a s;y.,iricd.,l Jirr~r~,nce from i ~s ~J ", IpsO.05) - Denotes a s;g"ilicanl .lirrerence within a PFC dose group with and without ~J.el,cdl."a"l (psO.05) tDenotes a ~;g"ilicanl dirr~.cnce from ' -s~ ,e (psO.Ol) @Denotes a ~;g,.;rica"l dirr~rcnce within a PFC dose group with and without ,6,cl-cal",ent (psO.01) Tablo 7 T.;5~1y~.;~s (mg/dl) 2 ml/kg 2 ml/kg PFC PFC
Dexam R? ;~ ~eMean 45-5 33.8 Std 17.7 24.9 n 3 3 4 Hour Mean 47.0 40.7 Std 11.3 16.7 n 3 3 6 Hour Mean 51.0 31.7 Std 16.7 15.1 n 3 3 1 Day Mean 107.7~ Z5.0 Std 51.1 11.3 n 3 3 2 Day Mean 132.7~ 87.3 Std 26.5 15.0 n 3 3 4 Days Mean 115.0~ 89.3 Std 22.6 23.9 n 3 3 7 Days Mean 68.3 45.7 Std 2.5 25.9 n 3 3 14 Days Mean 54.7 54.7 Std 18.9 19.5 n 3 3 30 Days Mean 40.3 40.0 Std 5.0 15.6 n 3 3 ~Denotes a ~;y"iricdnl Jirferel)cc from ~as~' .e (psO.05) _An u "Jersco.2d value denoles a s;g..;rica"l dirrt:,e"ce within a PFC dose group with and without ~Jrelreal~ent (p50.05) tDenotes a s;yniricar,l Jirrer~nce from ~as~' )e (psO.01) @Denotes a s;g";rica"l Jirra~ancc within a PFC dose group with and without ~ e~,l"~enl (pC0.01) Table 8 ~, To~tal '' 1,l' ' Direct r~ ~
(mg/d) (mg/d) 2 ml/kg2 ml/kg PFC2 ml/kg2 ml/kg PFC Dexam PFC PFC
Dexam Baseline Mean 0.2 0.2 0.2 0.2 Std 0.0 0.1 0.0 0.1 n 3 3 3 3 4 HourMean 0.6~ 0.4~ 0.5~ 0.2 Std 0.3 0.1 0.5 0.1 n 3 3 3 3 6 HourMean 0.4~ 0.4* 0.3 0.1 Std 0.1 0.1 0.1 0.0 n 3 3 3 3 1 DayMean 0.4* 0.2 0.4 0.1 Std 0.2 0.0 0.4 0.0 n 3 3 3 3 2 DayMean 0.3 O.Z 0.3 0.1 Std 0.2 0.1 0.2 0.0 n 3 3 3 3 4 DaysMean 0.2 0.2 0.2 0.2 Std 0.1 0.1 0.1 0.1 n 3 3 3 3 7 DaysMean 0.3 0.1 0.1 0.1 Std 0.1 0.1 0.0 0.0 n 3 3 3 3 14 DaysMean 0.3 0.2 0.1 0.1 Std 0.1 0.1 0.0 0.1 n 3 3 3 3 30 DaysMean 0.2 0.1 0.1 0.1 Std 0.1 0.1 0.0 0.0 n 3 3 3 3 *Denotes a s;y"iricanl dirr~.ence from l~aseline (pC0,05J
_An u~duscOrëd value denoles a aiy"iricar,l dirr1renca within a PFC dose group with and without p,el,~al",e.,l (p~0.05) tDenotes a aiy.,iri.,a"l dirr~r~.,ce from La~ e (psO.01) @Denotes a signiricanl dirrelence within a PFC dose group with and without ,~,.el,èal",anl (p~0.01) Table 9 SGOT-AST LDH
(U/L) ~U/L) 2 ml/kg2 ml/kg PFC2 ml/kg 2 ml/kg PFC Dexam PFC PFC
Dexam R= ~ .eMean 32.8 27.8 165.2 124.8 Std 12.5 1.8 17.9 58.5 n 3 3 3 3 4 Hour Mean 143.3 89.3 743.3 311.0 Std 28.9 51.7 167.3 127.2 n 3 3 3 3 6 Hour Mean 270.7t 127.0 1289t 492.0 Std 53.0 54.0 448.7 119.7 n 3 3 3 3 1 Day Mean 549.0t 166.7~ 3791.3t 520.0 Std Z40.2 61.8 1604.2 126.1 n 3 3 3 3 2 Day Mean 304.0t 172.3* 1588.3t 558.7 Std 150.7 56.3 1155.5 303.0 n 3 3 3 3 4 Days Mean 73.7 81.3 451.7 299.0 Std 29.7 31.5 112.6 118.9 n 3 3 3 3 7 Days Mean 33.0 40.0 313.7 213.7 Std 7.0 8.5 60.7 62.7 n 3 3 3 3 14 Days Mean 22.3 25.3 228.0 164.3 Std 1.2 5.7 85.5 64.8 n 3 3 3 3 30 Days Mean 22.7 21.7 163.7 122.0 Std 0.6 2.1 36.2 3.2 n 3 3 3 3 ~Denotes a siy.-iric~nl Jirralance from l~asel;ne (ps0.05) An ul-derscGracl value denoles a :.;y..irica-.l dirrarance within a PFC dose group without and without p~ e.-~ enl (ps0.05 tDenotes a significant dirtarence from Laseli.-e Ips0.01) @Denotes a sig..iricanl .lirrt~ nce within a PFC dose group with and without ~rt~ dllll~ (ps0.01) W0 96/13268 rCT/US95/13714 The embodiments presented in the detailed descripLion .;.
i ~ are provided by way of illustration only, and are not intended to limit the scope of the invention. Rather, this invention is defined by the appended claims and any equivalents thereto.
WHAT IS CLAIMED IS:
~ .~
' ' -;
..' ~;
. ~
., ; , = . . r ~ . . ~
, ~ , ~, , . _, .
: ~j .~
~ .~ .
Claims (9)
1 Use of a corticosteroid in the manufacture of medicament for administration to an animal at a dose of from about 0.2 to 6 mg/kg body weight prior to administration of a perfluorochemical to reduce the adverse effects of said perfluorochemical upon the hemostatic system and serum chemistry of said animal.
2 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said corticosteroid is for administration at a dose of about 1 mg/kg.
3 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical is administered at a dose of from about 0.5 to 10 ml/kg of bodyweight of said animal.
4 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 to reduce the adverse effects of said perfluorochemical upon bilirubin, aspartate amino transferase enzyme activity and serum lactate dehydrogenase enzyme activity in the serum.
Use of a corticosteroid in the manufacture of a medicament according to Claim 1 to reduce the adverse effects of said perfluorochemical upon prothrombin time and activated partial thromboplastin time, and for inhibiting perfluorochemical induced thrombocytopenia.
6 Use of a corticosteroid in the manufacture of a medicament according to any preceding claim wherein said corticosteroid is dexamethasone.
7 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical is selected from the group consisting of perfluorodichlorooctane, perfluorodecalin, perfluoromethyldecalin, perfluorodimethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-4-methyl-octahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin, perfluorobicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated perfluorocarbons, and mixtures thereof.
8 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical is perfluorodichlorooctane.
9 Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical emulsion contains said perfluorochemical in an amount of from about 15 v/v% to about 70 v/v%.
Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical emulsion contains said perfluorochemical in an amount 40 v/v%.
Use of a corticosteroid in the manufacture of a medicament according to Claim 1 wherein said perfluorochemical emulsion contains said perfluorochemical in an amount 40 v/v%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002202989A CA2202989C (en) | 1995-10-24 | 1995-10-24 | Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002202989A CA2202989C (en) | 1995-10-24 | 1995-10-24 | Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion |
| PCT/US1995/013714 WO1996013268A2 (en) | 1994-10-28 | 1995-10-24 | Use of a corticosteroid to reduce the adverse effects of a perfluorochemical emulsion |
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| Publication Number | Publication Date |
|---|---|
| CA2202989A1 CA2202989A1 (en) | 1996-05-09 |
| CA2202989C true CA2202989C (en) | 2000-12-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA002202989A Expired - Fee Related CA2202989C (en) | 1995-10-24 | 1995-10-24 | Method of pretreating an animal with a corticosteroid prior to infusion of a perfluorochemical emulsion |
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| Country | Link |
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| CA (1) | CA2202989C (en) |
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1995
- 1995-10-24 CA CA002202989A patent/CA2202989C/en not_active Expired - Fee Related
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