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Biomedical subjects

A L Misra

Publications and source records attributed to A L Misra.

At least 37 records · Page 2Linked to original sources
PubMed1978

Plasma corticosteroid levels in rats maintained on a long-acting naltrexone delivery system.

A long-acting delivery system for naltrexone has been described, which blocked the antinociceptive action of 10 mg kg-1 s.c. dose of morphine in rats for a period of 2 to 3 months. Male Wistar rats implanted s.c. with such a delivery system showed highly significant depression of plasma corticosteroid levels (40.2% in one week and 22.4 to 27.2% in 3 months) as compared to placebo pellet-implanted animals. Morphine-dependent male rats implanted with 75 mg morphine pellets showed a small (17.5%) but significant increase in plasma corticosteroid levels as compared to the placebo controls 72 hr. after pellet implantation.

Adrenal Cortex Hormones↗
PubMed1977

Severe toxicity and lethality in some monkeys following chronic administration of levo-alpha-acetylmethadol (LAAM).

Recurrent episodes of mild to severe opiate-like toxic effects were observed in 3 of 18 monkeys maintained on 2 mg/kg p.o. dose of LAAM on alternate days 3 times a week for up to one year. Despite antagonist administration and artificial respiration, the final toxic reaction in 3 LAAM sensitive monkeys progressed rapidly to cardio-respiratory arrest and death 3, 6, and 12 months after LAAM treatment. The blood chemistry and hematology were not significantly altered during chronic LAAM administration. Necropsy did not reveal any aberrant gross, histological or neuropathological features other than pulmonary edema. Differential rates of formation and elimination of active metabolites of LAAM may play a significant role in this potentially lethal toxicity. These findings may have important clinical implications for LAAM maintenance treatment programs.

Animals↗
PubMed1977

Evidence for a noncovalent intermolecular interaction of opiates with thiamine.

Opiate agonists and antagonists formed reversible molecular complexes with thiamine. The absorption maxima of these complexes were at wavelengths longer than those of the individual components and their intensities depended on the concentration and nature of the opiate component. The possible implications of such an interaction are discussed.

Chemical Phenomena↗
PubMed1976

[3H]-Noncocaine and [3H]-pseudococaine: effect of N-demethylation and C2-epimerization of cocaine on its pharmacokinetics in the rat.

After i.v. injections of cocaine, norcocaine, pseudococaine to the rat, the T 1/2 in brain were 0.4, 0.6, 0.2 h respectively and in plasma 0.4, 0.5, 0.2 h respectively. Benzoylnorecgonine and norecgonine were the metabolites of norcocaine in brain. Pseudonorcocaine, pseudobenzoylnorecgonine, pseudobenzoylecgonine and pseudoecgonine were the metabolites of pseudococaine in rat brain. Benzolynorecgonine and pseudobenzoylecgonine had potent stimulant activity intracisternally in the rats.

Animals↗
PubMed1976

Disposition and metabolism of [3H]cocaine in acutely and chronically treated dogs.

1. Beagle dogs were chronically treated with cocaine, 5 mg/kg subcutaneously twice daily for 6 weeks, followed by same dose of [3H]cocaine given intravenously. 2. The t1/2 values of cocaine in plasma, liver, spleen and heart, in acutely and chronically treated dogs, were: 1-2, 1-1; 2-2, 1-8; 1-8, 1-3; 2-0, 1-2 h, respectively. In both groups, cocaine disappeared from all areas of the central nervous system 12-24 h after injection but significant amounts of radioactivity due to benzoylnorecgonine and benzoylecgonine persisted in the CNS even 1 week after administration of cocaine. Brain-to-plasma ratios of cocaine were lower in chronically-treated than in acutely-treated dogs 2 and 4 h after injection. 3. Norcocaine, benzoylnorecgonine, benzoylecgonine and ecgonine were metabolites of cocaine in dog brain in both groups. Norcocaine and benzoylnorecgonine were present in higher amounts in brains of chronically treated dogs. Rate of disappearance of norcocaine was similar to cocaine in both groups. 4. The amounts of cocaine excreted in urine and faeces as percentage of dose were 0-9-5-0, 1-1-6 in the acute and 2-2-3-3 and 0-2-0-3 in the chronically treated dogs. Major excretion of radiactivity occurred in urine within 24 h in both groups. Total radioactivity (65% of dose) in urine plus faeces was similar in both groups. 5. Norcocaine, benzoylnorecgonine, benzoylecgonine, ecgonine, norecgonine, ecgonine methyl ester and unidentified compounds were urinary metabolites of cocaine in both groups. Benzoylnorecgonine and ecgonine were excreted in higher amounts and benzoylecgonine and norecgonine in lower amounts in the acute than in the chronically treated dogs. 6. The possible role of persistence of benzoylnorecgonine and benzoylecgonine (which possessed potent stimulant activity intracisternally) in the CNS is discussed.

Animals↗
PubMed1976

Physiological disposition and biotransformation of [allyl-1', 3' - 14C naloxone in the rat and some comparative observations on nalorphine.

A sensitive method is described for the estimation of [14C]naloxone in biological materials. After a 1 mg/kg s.c. dose of [14C]naloxone to male Wistar rats, mean peak levels of drug in brain (506 ng/g) and plasma (119 ng/ml) were attained within 15 minutes. No persistence of drug in brain was observed at this dose. After a 10 mg/kg s.c. dose, the peak levels of naloxone in brain and plasma were 4.31 mug/g and 1.27 mug/ml, respectively, and extensive localization of extractable free drug and its minor metabolite, naloxol, occurred in tissues with high levels in kidney, spleen, lung, heart, skeletal muscle and somewhat lower concentration in the liver. The T1/2 of naloxone and nalorphine in rat brain and plasma with 1 and 10 mg/kg s.c. doses was 0.4 hour. With a 10 mg/kg dose, significant amounts of radioactivity persisted in tissues but not in plasma 96 hours after injection. The brain/plasma ratios and degree of plasma-protein binding were significantly higher for naloxone as compared to nalorphine. The amounts of free naloxone excreted as a percentage of the dose in urine and feces 96 hours after injection of the 10 mg/kg s.c. dose were 4.1 and 3.9 (for nalorphine 4.7 and 8.3); conjugated drug 15.4 and 1.2 (for nalorphine 13 and 0.9); total radioactivity 43.3 and 20.9 (for nalorphine 34.8 and 19.2), respectively. Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. Rapid metabolism of naloxone and rapid elimination are important factors in its short duration of action. Possible relevance of these observations on differential antagonistic properties of these two antagonists are discussed.

Allyl Compounds↗
PubMed1976

Physiological disposition and biotransformation of (3H) cocaine in acutely and chronically treated rats.

A sensitive method was developed for the estimation of [3H] cocaine in biological materials. After an injection of 8 mg/kg i.v. in male Wistar rats, peak levels in brain, tissues and plasma occurred within 15 minutes and cocaine disappeared completely from brain and plasma 6 hours postinjection. The T1/2 of cocaine in brain and plasma was 0.4 and 0.3 hour, respectively. No significant differences were observed in the rates of disappearance of cocaine from the subcutaneous site in acute and chronically treated rats after an injection of 20 mg/kg. After a 20 mg/kg s. c. dose, the peak levels of cocaine were attained gradually in 4 hours in brain, tissues and plasma with the exception of heart (0.5 hour) and fat (2 hours). These peak levels shifted from 4 to 2 hours in the chronically treated group. Consistently higher levels of cocaine were found to be sequestered in fat in the chronically treated animals. The T1/2 of cocaine in brain and plasma of chronically treated rats was approximately 1.8 to 2 hours and that in the acutely treated animals, 0.8 to 1 hour. The brain/plasma ratios were also somewhat higher in chronically treated as compared to the acutely treated animals and were indicative of a high affinity of tissue for cocaine. Although cocaine did not persist in brains of acutely treated animals, measurable amounts were shown to persist in brain and other tissues of chronically treated animals long after the disappearance in plasma. Significantly high concentrations of metabolites of cocaine persisted in brain and plasma of acutely and chronically treated animals. No significant differences were observed in the plasma protein binding of cocaine in control, acutely and chronically treated rats. Unchanged cocaine was excreted in very small amounts in rat bile and approximately 36% of the dose (5 mg/kg i. v.) was excreted as metabolites 3.5 hours after injection. Excretion of free cocaine in urine and feces after a 20 mg/kg s. c. dose in acutely and chronically treated rats was 1.2 and 1.5%, respectively. Significantly higher excretion of total radioactivity occurred in feces in the chronic group (35.9%) as compared to the acute group (22.1%). Benzoylecgonine, benzoyl norecgonine, ecgonine methyl ester and ecgonine were identified as urinary metabolites in both acute and chronic animals. In addition, evidence was obtained for the presence of a phenolic metabolite and two other hydroxylated metabolites (with hydroxylation presumably in positions 6 and 7 of the pyrrolidine ring). Implications of these observations with respect to systemic toxicity, the absence of tolerance and physical dependence liability of cocaine are discussed.

Animals↗
PubMed1976

Disposition of (3H) benzoylnorecgonine (cocaine metabolite) in the rat.

The preparation and disposition of (3H) benzoylnorecgonine, which has potent stimulant activity intracisternally in the rat, has been described. The T1/2 of (3H) benzoylnorecgonine in brain and plasma of rats injected with a 10 mg kg-1 i.v. dose were 3.0, 1.2 h respectively. The ratio of mean peak concentration in brain to that in plasma was 0.03. No metabolites of benzoylnorecgonine were observed in rat brain. The mean percentage of dose excreted in urine and feces in 96 h were 85 and 2.2, respectively, with major excretion (82.5%) occurring within 24 h in urine. Approximately 90% of the radioactivity in urine was due to unmetabolised benzoylnorecgonine and 10% due to an unidentified metabolite. Norecgonine was not detected as a urinary metabolite.

Animals↗