Interactions of cocaine with barbital, pentobarbital and ethanol.

This study deals with the interactions of cocaine with barbital, pentobarbital and ethanol in nontolerant and tolerant male Sprague-Dawley rats. Cocaine hydrochloride (50 mg) pellets implanted s.c. in rats prior to the i.p. injections of sodium barbital (150 mg/kg dose once daily for 4 days) potentiated the hypothermic response 2 hr after the barbital injection, when maximum hypothermia occurred. The s.c. implantation of the same type of pellets prior to the i.p. injections of sodium pentobarbital (75 mg/kg dose once daily for 5 days) potentiated the pentobarbital hypnosis as measured by the duration of loss of the righting reflex in animals. Cocaine pellets (12.5 mg) implanted s.c. in rats potentiated the hypnosis induced by ethanol (3.2 g/kg i.p.) and the implantation of the same type of pellets (12.5, 25 mg) in ethanol-tolerant rats restored the ethanol hypnosis to levels observed in acutely treated animals. The course of tolerance development to barbital-induced hypothermia or pentobarbital hypnosis did not appear to be affected by cocaine. The possible role of central monoamines in the potentiation of barbital hypothermia and pentobarbital and ethanol hypnosis by cocaine is discussed.

Intravenous kinetics and metabolism of [15,16-3H]naltrexonium methiodide in the rat.

After a 4 mg kg-1 bolus intravenous dose of [15,16-3H]naltrexonium methiodide to the rat, brain to plasma concentration ratios of the compound were 0.031 to 0.228 between 0.25 to 6 h after injection and the t 1/2 beta in plasma and brain were 2.92 and 7.61 h, respectively. Ethyl acetate-extracted radioactivity due to metabolites in plasma decayed with t 1/2 beta 1.83 h and the ratios of plasma concentration of metabolites to quaternary compound between 0.25 and 6 h were 0.014-0.026. Only unconjugated 7,8-dihydro-14-hydroxynormorphine, naltrexone and traces of 7,8-dihydro-14-hydroxynormorphinone were the metabolites in plasma. Naltrexone (but not normetabolites) was present only in traces in brain up to 0.5 h after injection and not at later times.

Effect of caffeine on cocaine locomotor stimulant activity in rats.

The effect of caffeine on the locomotor stimulant activity induced by intravenous cocaine in rats was investigated. Low doses of caffeine (20 mg/kg IP) potentiated the locomotor activity induced by 1, 2.5 mg/kg intravenous doses of cocaine and higher doses of caffeine (50, 100 mg/kg IP) had no significant effect. The locomotor stimulant effect of 20 mg/kg IP dose of caffeine per se in vehicle was significantly higher and that with 100 mg/kg dose significantly lower than that of the vehicle control. Thus caffeine produced dose-dependent effects on cocaine-induced locomotor stimulant activity, with low dose potentiating and higher doses having no significant effect on such activity. Pharmacokinetic or dispositional factors did not appear to play a role in potentiation of cocaine locomotor stimulant activity by caffeine.

Disposition in the rat of buprenorphine administered parenterally and as a subcutaneous implant.

Disposition of [15, 16(n)-3H]buprenorphine in the rat has been investigated after a single 0.2 mg/kg i.v. bolus dose and continuous administration via a s.c. implantable long-acting delivery system. After the i.v. injection, the tri-exponential decay of drug from brain occurred with t1/2 values of 0.6, 2.3 and 7.2 h, respectively (plasma t1/2 0.5, 1.4 h, third phase not estimated due to sustained concn.) Decay of drug from another high-affinity binding site in brain occurred with t1/2 values of 1.1 and 68.7 h, respectively. Fat and lung had higher concn. than other tissues and plasma. No metabolites of drug were detected in brain. Unmetabolized drug excreted in urine and faeces one week after i.v. injection were 1.9 and 22.4% of dose, respectively, and 92% of the dose was accounted for in one week. Urinary metabolites (%) were: conjugated buprenorphine 0.9; norbuprenorphine (free 9.4, conjugated 5.2); tentative 6-O-desmethylnorbuprenorphine (free 5.4, conjugated 15.9). Peak plasma concn. of buprenorphine occurred four weeks after s.c. implantation of a long-acting 10 mg 3H-buprenorphine pellet, and apparent dissociation half-lives of drug from low- and high-affinity binding sites in brain were 4.6 and 6.8 weeks, respectively. Fat, spleen and skeletal muscle had higher concn. than other tissues and plasma. No significant difference in brain morphine concn. was observed in placebo and nonlabelled buprenorphine-pelleted animals after a 2 mg/kg i.v. challenge dose of 3H-morphine. This study emphasizes the importance of high-affinity binding of buprenorphine in brain and subsequent slow dissociation as a prime factor in its prolonged agonist/antagonist effects and higher potency than other narcotic agonists.

Potentiation of morphine analgesia by caffeine.

Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation.

Potentiation of morphine analgesia by subanesthetic doses of pentobarbital.

Pentobarbital pretreatment reportedly either inhibits, enhances or has no effect on morphine analgesia. The effect of subanesthetic doses of sodium pentobarbital (8-12 mg kg-1, SC) delivered via a delivery system on analgesia of morphine (5 mg kg-1, SC or 1 mg kg-1, IV) acutely administered 45 min after the sodium pentobarbital pellet implantation was assessed using the warm water (55 degrees C)-induced tail-withdrawal reflex in male Wistar rats. Significant potentiation of morphine analgesia was observed in sodium pentobarbital as compared to the placebo-pelleted animals. Pharmacokinetic or dispositional factors were not involved in this potentiation, which was possibly due to the activation of the descending inhibitory control pathways of nociceptive spinal tail-withdrawal reflex by a combined interaction of two drugs at spinal and supraspinal sites of action, that mediate opiate antinociception.

Effect of diamorphine, delta 9-tetrahydrocannabinol and ethanol on intravenous cocaine disposition.

The disposition of cocaine (1 mg kg-1) was altered by diamorphine (0.1 mg kg-1) and that of morphine (1 mg kg-1) was altered after their concurrent administration as a bolus i.v. injection to rats by cocaine, without any changes in the metabolism of the drugs. delta 9-Tetrahydrocannabinol (10 mg kg-1 i.p.) did not affect the cocaine disposition. Chronic ethanol treatment (2.5 g kg-1 orally twice daily for 16 days) produced a significantly higher brain-to-plasma cocaine concentration ratio than did saline as control, without any changes in cocaine metabolism.

Increased brain uptake of morphine in the presence of the antihistamine tripelennamine.

Disposition of [6 3H (N)]morphine in plasma, brain and liver of rats was studied 15 min after intravenous injection of either a 2 mg kg-1 dose of morphine or a combination of the same dose of morphine with a 6 mg kg-1 dose of tripelennamine. The concentrations of morphine in brain and the brain to plasma morphine ratios in animals receiving the combination of drugs concurrently were significantly higher than those in the control morphine group. No significant differences were seen in the morphine or morphine metabolite concentrations in plasma and liver or liver to plasma morphine concentration ratios in the 2 groups. Data suggest that pharmacokinetic factors play a role in the potentiation of opiate effects by antihistamine on concurrent i.v. administration of the two drugs.

Effect of chronic nicotine pre-treatment on phencyclidine (PCP) disposition in the rat.

Disposition of [3H] phencyclidine (5 mg kg-1 i.p.) in brain, liver and plasma of rats treated chronically with 0.9% saline or nicotine (1 mg kg-1 s.c. twice a day for 11 days) was studied using a method possessing high sensitivity and specificity for PCP. No significant differences were observed in the values of PCP in plasma and tissues and in brain or liver to plasma PCP concentration ratios in the 2 groups 0.5, 1, 2 hr after [3H] PCP injection. With the exception of the value of PCP metabolites in plasma at 0.5 hr, the PCP metabolites concentrations were also not significantly different in the 2 groups. Data suggested that chronic nicotine pretreatment of rats did not affect the disposition of PCP and the potentiation of PCP-induced locomotor stimulant effects by nicotine possibly involves the additive pharmacodynamic interaction of 2 compounds at the level of the central nervous system.

A long-acting buprenorphine delivery system.

A subcutaneously implantable buprenorphine delivery system utilizing cholesterol-glyceryltristearate matrix for prolonged release of drug is described. Implantable cylindrical pellets of buprenorphine (cholesterol 36 mg, glyceryltristearate 4 mg, buprenorphine hydrochloride 10 mg), diameter 3 mm, length 6 mm blocked the antinociceptive action (hot plate, 55 degrees C) of 10 mg kg-1 SC challenge dose of morphine in rats for 12 weeks or more (longer periods not evaluated). The cumulative percent release of buprenorphine from the test devices 2, 4, 6, 10 and 12 weeks after implantation was 27.4, 35.9, 37.6, 39.9 and 43.1, respectively. The release of buprenorphine from 10 mg pellets approximated first-order kinetics with half-lives of 0.85 and 50.24 weeks, for alpha and beta phases, respectively. The test devices possess the desirable characteristics of simplicity, biocompatibility, nontoxicity, ease of sterilization with ethylene oxide, small size for ease of insertion and removal, minimal encapsulation by surrounding tissue and an extended period of drug release unaffected by body metabolism. No side effects were seen in implanted rats which fed well and gained weight during entire treatment. Neither deterioration of implant nor any gross anatomic changes at implant site were apparent 12 weeks after pellet implantation.

Effect of acute and chronic ethanol pre-treatment on the disposition of phencyclidine (PCP) in the rat.

Disposition of [H] Phencyclidine in brain, plasma and adipose tissue of rats acutely and chronically-treated with ethanol was studied using a method possessing high sensitivity and specificity for PCP. In rats acutely-treated with ethanol (5 g/kg PO dose) and PCP (10 mg/kg IP dose), dispositional factors did not play a role in the intensifies pharmacological and behavioral effects of PCP. However in rats chronically-treated with 2.5 g/kg PO dose of ethanol twice a day for 19 days, the disposition of PCP (5 mg/kg IP dose) was significantly altered and the values of PCP in brain, plasma and adipose tissue were significantly higher than those in the control group. Although inhibition of PCP metabolism and a comparatively slower rate of its elimination appear to account for the potentiation of drug effects in animals chronically-treated with ethanol, interaction of drugs at the level of the central nervous system cannot be ruled out.

An improved long-acting delivery system for narcotic antagonists.

The feasibility of using cholesterol-glyceryltristearate matrix for prolonged release of naltrexone was evaluated in rats. Implantable cylindrical pellets (cholesterol 105 mg, glyceryl tristearate 15 mg and naltrexone 30 mg), diameter 4.5 mm, length 9 mm, blocked the antinociceptive action (hot plate 55 degrees C) of 10 mg/kg s.c. challenge dose of morphine in rats for 3 months. The release rate of naltrexone from 10 or 50 mg pellets approximated first-order kinetics with t1/2 alpha of 20-26 days and t1/2 beta 40-60 days. The factors affecting the release of drug from the delivery system were the ratio of cholesterol to naltrexone, drug loading level and surface area to unit volume of dosage form. The minimum release rate of naltrexone to block the effect of 10 mg/kg s.c. dose of morphine in rats was about 4 to 5 microgram/kg/hr. The cumulative urinary excretion of radioactivity from 10 mg [3H] naltrexone pellets implanted s.c. in rats after 30, 60, and 90 days was 17.7, 23.7, and 25.7% of dose respectively and the percent dose released from pellets at these times was 55.8, 68.8, and 78.2 respectively. The devices possess the desirable characteristics of simplicity, nontoxicity, nonirritability, ease of sterilization with ethylene oxide, small size for easy insertion and removal, absence of encapsulation by surrounding tissue, and an extended period of drug release unaffected by body metabolism. Neither deterioration of implant nor gross anatomic or histological changes at the site of implant occurred 6 months to 1 year after implantation and aside from some enhanced sexual activity (e.g., spontaneous penile erections) no side effects were observed in rats, which fed well and gained weight during the entire treatment. The concentrations of free morphine in brains of 30 mg naltrexone pellet-implanted rats were significantly lower (24 and 15%) as compared to the placebo controls 0.5 and 1.0 hr after a 10 mg/kg s.c. dose of [6-3H] morphine. We are currently evaluating these long-acting devices for the duration of effective antagonism to morphine in rhesus monkeys.

Persistence of phencyclidine (PCP) and metabolites in brain and adipose tissue and implications for long-lasting behavioural effects.

PCP and its new metabolites persisted for very prolonged periods in rat brain and adipose tissue after a single 25 mgkg-1 intraperitoneal injection and showed accumulation after multiple dosing. The brain to plasma ratios for PCP between 0.5 h to 48 h after injection ranged between 6 to 8.8 and adipose tissue to plasma ratios between 31 to 113. The concentrations of metabolites of PCP in rat brain (ng-eqt/g. tissue) 1, 2 and 3 weeks after a single 25 mgkg-1 i.p. injection of PCP were approximately 390, 230 and 74 respectively and those of PCP 12, 6 and 5 ng/g. respectively. The long sojourn of PCP in adipose tissue and relatively slow egress therefrom explains cumulative effects upon multiple dosing and raises the possibility of mobilisation or release of large amounts of drug from fat stores in situations involving food deprivation, marked weight loss or stress. The persistence of PCP and its metabolites in brain and high degree of binding with melanin, implying a possible localisation in neuromelanin-rich substantia nigra of midbrain and locus coeruleus of pons may help explain the prolonged duration of clinical effects and persistent neurological and cognitive dysfunction several days after PCP administration.

Metabolism of norcocaine, N-hydroxy norcocaine and cocaine-N-oxide in the rat.

1. The metabolism of [3H]norcocaine, N-hydroxy[3H]norcocaine and cocaine-N-oxide has been investigated in rats after i.v. injection. 2. The biological t 1/2 of norcocaine (dose 2 mg/kg i.v.) in plasma, liver and brain were 0.4, 1.6, 0.5 h, respectively and the compound was not detectable in the central nervous system 6 h after injection. The % dose of norcocaine excreted unchanged in urine and faeces in 96 h were 0.7 and 1.0, respectively. Benzoylnorecgonine, norecgonine, norecgonine methyl ester and an unidentified compound were excreted in urine. 3. The biological t 1/2 of N-hydroxynorcocaine (5 mg/kg i.v.) in brain and plasma were 0.3, 1.6 h respectively and only 1.3 and 1.6% of dose were excreted unchanged in urine and faeces in 96 h. N-Hydroxybenzoylnorecgonine and N-hydroxynorecgonine methyl ester were the major urinary metabolites. N-hydroxynorcocaine was not metabolized to norcocaine in vitro by liver microsomes. Doses of greater than 7.5 mg/kg i.v. resulted in death of rats by cardiorespiratory arrest. 4. Cocaine-N-oxide (50 mg/kg i.v.) yielded ecgonine-N-oxide methyl ester as its major metabolite; other minor metabolites were cocaine (0.5%), norcocaine (1%), benzoylecgonine, ecgonine, ecgonine-N-oxide, along with minor amounts of unmetabolized compound. Lethality of cocaine-N-oxide (100 mg/kg i.v.) was possibly due to metabolism to norcocaine and cocaine.

Cocaine and pseudococaine: comparative effects on electrical after-discharge in the limbic system of cats.

The effects of cocaine and its dextroisomer pseudococaine on electrical after-discharge (AD) evoked by electrical stimulation of the hippocampus or amygdala were studied in cats with electrodes implanted in the brain. Intravenous injection of cocaine (2.0 to 4.0 mg/kg doses) produced a suppressive effect on the AD while producing low-voltage fast waves (LVFWs) in the electrical activities of the brain (EEG) associated with behavioral excitation. In contrast, pseudococaine at the same dose as cocaine failed to show a significant suppressive effect on the AD except at high doses (5.0 mg/kg). Pseudococaine produced high-voltage slow waves (HVSWs) in the EEG associated with behavioral depression. A linear dose-response relationship was observed for the suppressive effect of cocaine on the AD. The results suggested that the limbic system may be involved as a primary site of action of cocaine in the central nervous system (CNS).