Antihypertensive profile of the angiotensin-converting enzyme inhibitors CI-906 and CI-907

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.     

The action of 5 alpha-dihydrotestosterone and antiandrogens on the activities of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase in the pituitary gland of gonadectomized rats

In gonadectomized rats of either sex s.c. administration of 5 alpha-dihydrotestosterone (DHT) reversed, in a dose dependent manner, effects brought about by gonadectomy: it decreased pituitary wet weight and serum levels of LH and FSH and suppressed microsomal enzyme activities involved in testosterone and progesterone metabolism in the pituitary gland, NADPH-linked 5 alpha-reductase and NADH-linked 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSDH). Concomitantly administered nonsteroidal antiandrogen, flutamide (5 mg/day), antagonized some of the suppressive effects induced by a 14-day treatment of gonadectomized rats with high dose (1 mg/day) of DHT. It completely blocked DHT action on pituitary 5 alpha-reductase activity in the female rat and, in the male, inhibition was found to be 30-35%. In male, but not female rats, it completely blocked DHT suppression of serum FSH level whereas it slightly, but significantly inhibited DHT suppression of serum LH in rats of either sex. However, flutamide did not prevent DHT suppression of pituitary wet weight or NADH-linked 3 alpha-HSDH activity. Concomitantly administered progestational antiandrogen, cyproterone acetate (5 mg/day), inhibited DHT-induced weight increase of seminal vesicles by 50-55% and completely blocked the weight decrease of pituitary gland but did not antagonize DHT suppression of serum gonadotropins or pituitary enzyme activities. The results obtained with flutamide suggest that DHT-induced suppression of pituitary NADPH-linked 5 alpha-reductase, but not NADH-linked 3 alpha-HSDH activity, might involve an androgen receptor mechanism.     

Effects of repeated doses of MDMA ("ecstasy") on cell-mediated immune response in humans.

Cell-mediated immune response after the administration of two repeated doses of 100 mg 3,4-methylenedioxymethamphetamine (MDMA) at 4-hour and 24-hour intervals was evaluated in two randomised, double-blind and cross-over clinical trials conducted in healthy male MDMA consumers. MDMA produced a time-dependent decrease in the CD4/CD8 T-cell ratio due to a decrease in the number of CD4 T-helper cells, a decrease in the functional responsiveness of lymphocytes to mitogenic stimulation, and a simultaneous increase in natural killer cells. In case of two 100 mg MDMA doses given 4 hour apart, immune alterations produced by the first dose were strengthened by the second one. At 24 hours after treatment, statistically significant residual effects were observed for all the altered immune parameters after the administration of two MDMA doses if compared to single dose and placebo. In the second clinical trial, the second 100 mg MDMA dose given 24 hours after the first dose produced immunological changes significantly greater than those induced by the initial drug administration and which seemed to show a delayed onset. Significant residual effects were observed for all the immune parameters as late as 48 hours after the second dose. These results show that repeated administration of MDMA with both a short and a long time interval between doses extends the critical period following MDMA administration, already observed after a single dose, in which immunocompetence is severely compromised.     

3-Nitropropionic Acid Toxicity in the Striatum

Abstract: We examined the effects of chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) in doses ranging from 12 to 16 mg/kg/day for 30 days on striatal cytoarchitecture in rats. Administration of 3-NP at a dose of 16 mg/kg/day resulted in large lesions with a central necrotic core that was depleted of both neurons and glia. Glial fibrillary acidic protein (GFAP) gene expression was decreased in the lesion core, whereas the tissue surrounding this area showed a massive increase in signal intensity. Enkephalin and substance P mRNA expression in the striatum showed dose-dependent decreases following administration of 3-NP. A substantial decrease occurred even in animals treated with 3-NP at a dose of 12 mg/kg/day, in which there was little discernible neuronal loss and no increase in GFAP gene expression. In contrast to the decrease in enkephalin and substance P mRNA expression, somatostatin mRNA-expressing neurons were largely preserved. There was no preferential loss of [³H]naloxone patches in the rat striatum following chronic administration of 3-NP. In animals treated with 12–15 mg/kg/day neither the area nor binding density of the patches was changed. To study the effect of 3-NP on N -methyl- d -aspartate (NMDA)-gated Ca²⁺ channels we used in vivo administration of [³H]MK-801. Three hours after a single injection of 3-NP at a dose of 30 mg/kg there was a three- to fivefold increase in [³H]MK-801 binding in cortex and striatum as compared with saline-treated animals, consistent with an activation of NMDA receptors.     

Interferon-inducing and immunostimulating activity of bonafton in an experiment

It was shown for the first time that the antiviral drug bonafton administered orally to nonlinear albino mice in single doses of 5, 12.5 and 25 mg/kg induced production of interferon in the animal blood serum. The maximum interferon titer of 160-320 IU/ml was observed 18 hours after the drug administration in a dose of 12.5 mg/kg. In low doses of 5 to 12.5 mg/kg bonafton increased the nonspecific resistance of the mice to experimental viral infections when administered orally in single doses not earlier than 2 weeks prior to the contamination. The ability of the drug to stimulate the host protective forces probably plays a certain role in the mechanism of its therapeutic action in severe viral infections of man such as severe recurring ophthalmic herpes, genital herpes, Beh?et's disease, Melkersson-Rosenthal syndrome and others.     

Single intraamniotic injections of prostaglandin F-2-alpha as an abortifacient agent: size of effective dose and effect of parity

This report discusses the authors' experience with intraamniotic administration of single doses of the prostaglandin PGF2alpha as an abortifacient agent. 98 healthy women between the 12th and 26th week of pregnancy admitted to the Clinical Research Unit of the North Carolina Memorial Hospital were given a single intraamniotic dose of PGF2a administered through an indwelling polyethelene catheter inserted either transabdominally or transvaginally. The drug was given as Tham salt with the first 5 mg of any dose being given at the rate of 1 mg/minute for 5 minutes, followed by more rapid administration of the balance of the dose. Abortion which did not occur within 48 hours was considered a failure. Each patient received 1 of the following dosages: 25, 40, 50, and 75. 9 (64%) of 14 patients given 25 mg PGF2a aborted within the 48-hour period. The percentages of abortion in the doses 40, 50, and 75 mg were 88.9% (9 patients), 96.7% (60 patients) and 93.3% (15 patients) respectively. As these figures were almost similar, the 84 patients were combined as a single group (84 patients) relative to the injection-abortion time, effect of parity, and stage of gestation at which the abortion was carried out. Half of the patients in this combined group aborted in approximately 21 hours; more than 90% at the end of 32 hours; and 95% at the end of the 48 hours post-injection. For comparison, the cumulative abortion curve of 552 patients who had intraamniotic saline for abortion showed that 50% of the women aborted within 31 hours, 84% within 48 hours, and 97% within 72 hours. Prostaglandin induced abortions thus are shown to reach the 50% level 10 hours before the saline patients, and the 90% level about 21 hours before the saline patients. Significant side effects (presented elsewhere) were observed in all groups, with the incidence increasing at higher dosages. Mean induction-abortion time for nulliparas at all dosages was 17.4 hours; for multiparas, 20.4 hours. There was no clear relationship between gestational age and parity. The study shows that the effective dose for inducing abortion with PGF2a lies within the 40 to 50 mg dose range.     

Malonate-Induced Degeneration of Basal Forebrain Cholinergic Neurons: Attenuation by Lamotrigine, MK-801, and 7-Nitroindazole

Abstract: Previously, we have reported that intranigral infusions of malonate, an inhibitor of mitochondrial function, lead to the degeneration of the dopaminergic neurons of the nigrostriatal pathway that is mediated, at least in part, through NMDA receptor activation and nitric oxide formation. In the present study, unilateral focal infusions of malonate into the nucleus basalis magnocellularis (nbM) of male Sprague-Dawley rats (weighing 250–300 g) resulted in a dose-related depletion in ipsilateral cortical and amygdaloid choline acetyltransferase (ChAT) activity. Infusion of a 3 µmol dose of malonate into the nbM of vehicle-treated animals resulted in a 41 and 54% decrease in cortical and amygdaloid ChAT activity, respectively. Systemic pretreatment with lamotrigine (16 mg/kg, i.p.) and MK-801 (5 mg/kg, i.p.) attenuated the depletions in cortical and amygdaloid ChAT activity that resulted from an infusion of this dose of malonate into the nbM. Acetylcholinesterase (AChE) histochemistry of the nbM following focal infusion of malonate (3 µmol) showed a marked decrease in the number of AChE-positive neurons that was partially prevented by MK-801 pretreatment. Before examining the role of nitric oxide formation in malonate-induced toxicity, the ability of systemic administration of N^ω-nitro-l -arginine (l -NA) to inhibit nitric oxide synthase (NOS) activity in the nbM and cerebellum was investigated. l -NA (2, 10, and 20 mg/kg, i.p.) produced a dose-related inhibition of nbM and cerebellar NOS activity that was maximal following a dose of 10 mg/kg l -NA. This level of NOS inhibition persisted for at least 13 h following l -NA (10 mg/kg) administration. Subsequently, the effect of l -NA pretreatment on malonate toxicity was evaluated. Following pretreatment with l -NA (2 and 10 mg/kg, i.p.), the toxic action of malonate on cortical and amygdaloid ChAT activity was not altered. In addition, infusion of a lower dose of malonate (2 µmol) into the nbM resulted in decreases in cortical and amygdaloid ChAT activity that were not altered by pretreatment with l -NA (2 and 10 mg/kg, i.p.). In 7-nitroindazole (7-NI; 25 and 50 mg/kg, i.p.)-pretreated animals, malonate (3 µmol) produced decreases in cortical and amygdaloid ChAT activity that were attenuated by both doses of 7-NI. Thus, malonate-induced destruction of the basal forebrain cholinergic neurons was attenuated by systemic pretreatment with lamotrigine, MK-801, and 7-NI but not by l -NA.     

Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys

The pharmacokinetics of subcutaneous (s.c.) administration of a phosphorothioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) with doses of either 1 or 5 mg/kg ISIS 2302. The bioavailability of s.c. injection ranged from 26% to 55% and appeared to be dependent on the concentration of the dosing solution rather than the dose. The bioavailability of a subcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow absorption from the s.c. injection site significantly blunted the maximal concentration (Cmax) compared with i.v. administration. The time to peak plasma concentration (Tmax) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more dependence on absorption than elimination. The half-lives after s.c. administration averaged 3 hours, whereas after i.v. administration, the half-lives were <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administration. In summary, s.c. administration of PS-ODN resulted in prolonged and extensive absorption of the ODN.     

Serum morphine levels in cats during dorsal horn neuron suppression by spinally administered morphine

The degree of serum uptake of morphine following spinal morphine administration was measured in cats. Total serum morphine levels (free plus conjugated) were determined during suppression of noxiously evoked wide dynamic range neuron activity by spinally administered morphine and compared with total serum morphine levels following i.v. administration of similar doses. The serum levels at 30 minutes after spinal application of morphine (a time at which there was significant suppression of noxiously evoked neuronal activity) were low; after 0.1 and 0.25 mg the levels were 6.5 (n=6) and 12.5 (n=5) ng/ml respectively. In contrast, intravenous administration of the same doses (0.1 and 0.25 mg) produced levels at 30 minutes of 24 and 36 ng/ml respectively, while an intravenous dose commonly used in earlier neurophysiologic studies (2 mg/kg) produced serum levels in excess of 400 ng/ml. These results indicate that although there is systemic uptake following spinal administration of morphine, the serum levels achieved are much lower than those following intravenous administration of a comparable dose, and are insufficient to explain the resultant suppression of wide dynamic range neurons.     

Filaricidal efficacy of anthelmintically active cyclodepsipeptides

PF 1022A, a novel anthelmintically active cyclodepsipeptide, and Bay 44-4400, a semisynthetic derivative of PF 1022A were tested for filaricidal efficacy in Mastomys coucha infected with Litomosoides sigmodontis, Acanthocheilonema viteae and Brugia malayi. The parent compound PF 1022A showed limited anti-filarial efficacy in L. sigmodontis and B. malayi infected animals. Oral doses of 5 x 100 mg/kg on consecutive days caused only a temporary decrease of microfilariaemia levels. By contrast, Bay 44-4400 was highly effective against microfilariae of all three species in single oral, subcutaneous and cutaneously applied (spot on) doses. Minimum effective doses (MED, reducing parasitaemia density by > or =95%) determined 3 and 7 days after treatment were 3.125-6.25 and 6.25-12.5mg/kg, respectively. Using the spot on formulation, doses of 6.25mg/kg (L. sigmodontis), 12.5mg/kg (A. viteae) and 25mg/kg (B. malayi) were required to cause reductions of microfilaraemia levels by > or =95% until day 56. Adulticidal effects, determined as minimum curative doses (MCD, eliminating adult parasites within 56 days by >95%) after single dose treatment were limited to A. viteae (MCD, 100mg/kg independent of the route of administration). Repeated oral treatment (100mg/kg on 5 consecutive days) killed all adult L. sigmodontis but did not affect B. malayi. However, single doses of 6.25 and 25mg/kg resulted in severe pathological alterations of intrauterine stages of L. sigmodontis and B. malayi, respectively. These alterations may be responsible for long-lasting reductions of microfilaraemia even when curative effects could not be achieved.     

Supppression of paradoxical sleep by chloramphenicol. Absence of effect by thiamphenicol]

The oral administration of 160-250 mg/kg of chloramphenicol selectively suppresses Paradoxical Sleep in the cat for a duration of 10-20 hours. Larger doses (330 mg/kg) suppress Paradoxical Sleep for 27 hours, but aslso decrease Slow Wave Sleep. At the same dose, Thiamphenicol has no effect.     

Prostacyclin-like activity in rat vascular tissues. Fast, long-lasting inhibition by treatment with lysine acetylsalicylate.

Both arterial and venous tissues obtained from normal rats released prostacyclin (PGI2)-like activity, as marked by its potent inhibitory effect on platelet aggregation. Intraperitoneal or intravenous administration of a single dose of a soluble lysine salt of acetylsalicyclic acid (L-ASA, 1-400 mg/kg) resulted in abolition or substantial reduction of prostacyclin-like activity released from rat vasculature. The inhibitory effect of L-ASA was evident one minute after its i.v. administration to the animals, persisted for at least 24 hours and was still detectable (in venous tissues only) 168 hours later. Venous tissues were inhibited by doses of L-ASA as low as 1 mg/kg, whereas arterial tissues were not inhibited by doses of LA-ASA lower than 10 mg/kg. This difference may possibly be related to the lower prostacyclin-like activity shown by rat venous tissues compared to arterial ones. It is suggested that L-ASA or part of its molecule may bind to and inhibit cyclo-oxygenase in the blood vessel wall in a manner similar to the acetylation of platelt cyclo-oxygenase.     

Antagonism between long acting Monoamine Oxidase Inhibitors (MAOI) and MD780515, a new specific and reversible MAOI

The inhibition of type A and B monoamine oxidase (MAO A and B) in rat brain, liver and heart by MD780515, 3-[4-(3 cyanophenylmethoxy) phenyl]-5-(methoxymethyl)-2-oxazolidinone, has been investigated ex vivo with 5-hydroxytryptamine (5-HT) and β-phenylethylamine (PEA) as substrates. MAO A was strongly inhibited for four hours after oral administration of 10 mg/kg MD780515 (maximum inhibition : 72%, 86% and 83% in brain, liver and heart respectively. In contrast, in heart where PEA is deaminated by type A MAO, the predominant form of MAO in that tissue, the inhibition was 68% 30 minutes after administration of the compound. In all cases, MAO activities reached control values 24 hours after drug administration (10 mg/kg), whereas some inhibitory activity was still present 24 hours after oral administration of higher doses. The strong MAO A inhibition (68 to 83%) remaining in the three tissues 24 hours after oral administration of clorgyline (5 mg/kg) was completely removed by pretreatment with MD780515 (10 mg/kg). In the same conditions, MD780515 protected against the inhibition (53%) by clorgyline of PEA deamination in heart. Oral pretreatment with increasing doses of MD780515 (2.6 to 84 mg/kg) gradually removed brain MAO A inhibition caused by clorgyline (92%, 28.2 mg/kg) or tranylcypromine (88%, 4.8 mg/kg), the complete removal being observed at the dose of 21 mg/kg of MD780515 for clorgyline, and at 42 mg/kg for tranylcypromine. Inhibition of brain MAO B by tranylcypromine (96%) was not modified by pretreatment with the same range of oral doses of MD780515. The results are consistent with a specific and reversible inhibition of MAO A activity by MD780515 which can protect against long acting MAO A inhibitory effects of clorgyline and tranylcypromine. MD780515 enhances the selectivity of tranylcypromine.     

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.     

Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat

Cocaine hydrochloride was administered to pregnant Sprague-Dawley rats as a single intraperitoneal dose or as two doses 1-4 hours apart. A single dose administered on day 16 of gestation was teratogenic in a dose-dependent manner, with 40 mg/kg being a no-effect dose and 50 mg/kg the lowest teratogenic dose; 80 mg/kg was lethal to the dam. Forty-eight hours after exposure to a teratogenic dose on day 16 of pregnancy, the fetuses showed severe hemorrhage and edema in the their extremities, particularly the footplates, tail, genital tubercle, and upper lip/nose. When the fetuses were examined on day 21 of gestation, the main externally visible malformations were reduction deformities of the limbs and tail. When two doses of cocaine were administered 1-4 hours apart, the incidence of affected fetuses increased as the time interval between the two doses decreased. Two doses of cocaine administered 2 hours apart were not teratogenic on day 9, 10, 11, 12, 13, or 14 of gestation but did induce reduction deformities on days 15, 16, 17, 18, or 19. The same dose administered 1 hour apart was teratogenic on days 14-19. In general, cocaine administration on gestational days 14, 15, or 16 induced more severe and more widespread hemorrhage and edema than administration on days 17, 18, or 19. In the latter cases, damage was restricted to the distal parts of the hindlimb digits and the tail. The results show that in the rat cocaine is only teratogenic during the late organogenic or postorganogenic period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biliary excretion of exogenous hematin in rats

Rats with bile fistula were injected intravenously with single doses of hematin (5,10,20,30, and 40 mg/kg body weight). Bile samples were collected every 30 min. for 4 hours, and at longer time intervals thereafter. The concentration of hematin in the bile was measured spectrophotometrically at 590 nm. The maximal hematin concentration in the bile (0.29 mg/ml for 40 mg/kg) observed 1.25 hours (average from 15 rats; range 0.5 – 1.5 hours) after hematin administration occured progressively later for lower doses of hematin, and for 5 mg/kg was observed at 3.14 hours (average for 4 rats; range 2–4 hours). The total hematin excreted within 4 hours was 8.0% of injected dose for 40 mg/kg and is dose dependent.     

Effects of buprenorphine on body temperature, locomotor activity and cardiovascular function when assessed by telemetric monitoring in rats

Buprenorphine is a potent analgesic commonly used clinically in humans and rodents experiencing severe pain. However, effects of therapeutic doses on locomotor activity and the cardiovascular system have not been studied in conscious animals. The effects of buprenorphine were therefore evaluated in this study using telemetric monitoring in conscious animals. Telemetry transmitters were implanted in the peritoneal cavity of Wistar rats with a pressure catheter in the aorta and electrodes for electrocardiogram (ECG) recording subcutaneously. After a single subcutaneous administration of saline, each rat was administered single subcutaneous doses of 0.006, 0.03 or 0.15 mg/kg body weight (bw) of buprenorphine. During a 10 h period after administration, buprenorphine induced a varying dose-dependent increase in body temperature, heart rate, dP/dt and systolic-diastolic blood pressure, as well as a corresponding decrease in QT time. At high dose, however, QT time was still decreased 24 h post-administration, but no arrhythmias or visual changes were observed in the ECG complex. Body temperature and heart rate increased at the high dose of buprenorphine, even at 20-24 h after administration. Moreover, the high dose of buprenorphine induced a biphasic response in diastolic blood pressure, with an early and pronounced increase that, at 14 h after administration, reversed to a decrease, failing to normalize within 24 h post-dosage. The results indicate that buprenorphine induces long-lasting effects (such as body temperature and cardiovascular effects) in the rat after a single subcutaneous dose at 0.15 mg/kg bw.     

Prostacyclin-like activity in rat vascular tissues. fast, long-lasting inhibition by treatment with lysine acetylsalicylate

Both arterial and venous tissues obtained from normal rats released prostacyclin (PGI₂)-like activity, as marked by its potent inhibitory effect on platelet aggregation. Intraperitoneal or intravenous administration of a single dose of a soluble lysine salt of acetylsalicylic acid (L-ASA, 1–400 mg/kg) resulted in abolition or substantial reduction of prostacyclin-like activity released from rat vasculature. The inhibitory effect of L-ASA was evident one minute after its i.v. administration to the animals, persisted for at least 24 hours and was still detectable (in venous tissues only) 168 hours later. Venous tissues were inhibited by doses of L-ASA as low as 1 mg/kg, whereas arterial tissues were not inhibited by doses of L-ASA lower than 10 mg/kg. This difference may possibly be related to the lower prostacyclin-like activity shown by rat venous tissues compared to arterial ones.It is suggested that L-ASA or part of its molecule may bind to and inhibit cyclo-oxygenase in the blood vessel wall in a manner similar to the acetylation of platelet cyclo-oxygenase.     

Hepatoprotective action of abhrak bhasma, an ayurvedic drug in albino rats against hepatitis induced by CCl4

Abhrak bhasma is a commonly used ayurvedic drug against many diseases including hepatitis. It is tested in albino rats using a model of hepatitis induced by a single dose of CCl4 (3 ml/kg body wt). Different doses of abhrak bhasma (10, 20, 30 and 40 mg/kg body wt) were tested to decide the dose related hepatoprotective efficacy. The centrolobular necrosis induced by single dose of CCl4 was reduced significantly by abhrak bhasma (10 mg) and liver histology was also protected by 20 mg dose. Liver acid lipase activity was lowered, while alkaline and lipoprotein lipase activities were elevated due to treatment of single dose of CCl4. Abhrak bhasma counteracted the action of CCl4 on liver lipolytic enzymes. CCl4 did not alter the kidney histologically. Activities of three lipases of rat kidney (acid, alkaline and lipoprotein lipases) were reduced by CCl4 treatment and were reversed by administration of abhrak bhasma. Acid lipase activity of rat adipose tissue was reduced by CCl4 treatment. On the contrary alkaline, lipoprotein and hormone sensitive lipases were enhanced after 24 hr of administration of CCl4. Acid lipase activity was raised by administration of different doses of abhrak bhasma concurrent with CCl4. Abhrak bhasma treatment along with CCl4 enhanced alkaline lipase activity at 10 and 20 mg dose and later it was reduced at 30 and 40 mg doses and came to normal levels. Lipoprotein and hormone sensitive lipases were reduced by the counteraction of increasing doses of abhrak bhasma.     

Effects of thyrotropin-releasing hormone (TRH) and MK-771 on schedule-controlled behavior of squirrel monkeys, rabbits and pigeons

The effects of TRH (0.001-10.0 mg/kg) and a more potent TRH analog, MK-771 (0.001-5.6 mg/kg), were studied on comparable schedule-controlled performances of squirrel monkeys, rabbits and pigeons. Responding was maintained in the presence of different stimuli by a multiple fixed-ratio (FR), fixed-interval (FI) schedule of food presentation (monkeys and pigeons) or 0.25% saccharin solution (rabbits). Generally, TRH and MK-771 produced decreases in responding under both schedules and in all three species. TRH and MK-771 were roughly equipotent in the squirrel monkey, whereas in the pigeon and rabbit MK-771 was approximately 20 times more potent than TRH in decreasing responding to 50 percent of control levels. The duration of action of doses of TRH and MK-771 that reduced responding to 50 percent of control was approximately 3 hr in the squirrel monkey; recovery of performance occurred twice as fast under the FR schedules. With the pigeon, TRH effects that produced 50 percent decreases in responding lasted over 6 hours, whereas behaviorally comparable doses of MK-771 lasted about 4 hours. With few exceptions, TRH and MK-771 appear to produce similar effects of schedule-controlled behavioral performances of the squirrel monkey, rabbit and pigeon. Compared to the effects of other behaviorally-active substances under these procedures, TRH and MK-771 exert a distinctive array of effects.