Jack E. Wallace

Cocaine and benzoylecgonine excretion in humans

Maximal urinary excretion of unchanged cocaine occurred within 2 h of the intranasal absorption of 1.5 mg/kg body weight of cocaine hydrochloride, and diminished rapidly thereafter. Excretion of benzoylecgonine was maximal 4 to 8 h following administration of the drug and diminished slowly over an interval of several days. Peak cocaine and benzoylecgonine concentrations observed were 24 and 75 microgram/ml, respectively. Benzoylecgonine/cocaine ratios were too varied to allow estimation of cocaine concentrations from benzoylecgonine concentration data or vice versa. Benzoylecgonine concentrations generally exceeded the corresponding cocaine values by a wide margin, but excretion of free cocaine in the absence of benzoylecgonine was observed in one subject. Cocaine was generally detected for only approximately 8 h, and for a maximum of 12 h, whereas benzoylecgonine was generally detected by chromatographic or enzyme immunologic assays for 48 to 72 h. Benzoylecgonine was positively identified in urine by raidoimmunoassay for 96 to 144 h after dosing.

Individualization of phenytoin dosage regimens

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis‐Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady‐state phenytoin serum concentrations resulting from different daily doses: The observed steady‐state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p < 0.02). The average deviation between observed and predicted levels was 0.04 µg/ml (range, ±3.2 µg/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r = 0.360, p < 0.05). The average deviation was −3 µg/ml (range, 3.9 to −11.3 µg/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

12. – ALCOHOL AND OPIATES: A REVIEW OF COMMON NEUROCHEMICAL AND BEHAVIORAL MECHANISMS

Kenneth Blum, Murray G. Hamilton and J.E. Wallace The University of Texas Health Science Center at San Antonio, Departments of Pharmacology and Pathology, San Antonio, Texas, 78284, and The University of Western Ontario, Department of Pharmacology, London, Ontario, Canada. INTRODUCTI ON Among drugs of abuse, none have achieved such wide popularity as ethanol and opiate derivatives. Although these drugs are consumed by a large segment of our population, many consequences of acute and chronic intoxication with alcohol and opiates are not readily understood.

Enkephalinase inhibition: regulation of ethanol intake in genetically predisposed mice.

This is the first report of alteration in alcohol intake in mice with a genetic predisposition to alcohol preference and known to have innate brain enkephalin deficiencies. We have been able to significantly attenuate both volitional and forced ethanol intake respectively by acute and chronic treatment with hydrocinnamic acid and D-phenylalanine, known carboxypeptidase (enkephalinase) inhibitors. Since these agents, through their enkephalinase inhibitory activity, raise brain enkephalin levels, we propose that excessive alcohol intake can be regulated by alteration of endogenous brain opioid peptides.

Morphine suppression of ethanol withdrawal in mice

The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.

Ocular penetration and pharmacokinetics of topical fluconazole.

The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC). Peak corneal levels occurred essentially immediately at 5 min in the corneas [debrided, 8.2 +/- 1.2 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)] and at 15 min after application in the aqueous [debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min. A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.

Suppression of ethanol withdrawal by dopamine.

An ethanol-inhalation technique was used to determine a potential relationship between dopamine and central nervous effects produced by alcohol. Bothl-DOPA and intracranially injected dopamine resulted in attenuation of ethanol-induced withdrawal convulsion scores, whereas, haloperidol, a known dopaminergic blocker was found to significantly increase convulsion scores.

POSSIBLE ROLE OF TETRAHYDROISOQUINOLINE ALKALOIDS IN POSTALCOHOL INTOXICATION STATES

Because norepinephrine (NE) and dopamine (DA) constitute the major catecholamines in the body, it IS possible that their tetrahydroisoquinoline (TIQ) derivatives (condensation products of biogenic amines and acetaldehyde), if formed in vivo after alcohol consumption, could contribute to some pharmacologic responses to ethanol by interfering with catecholaminergic (adrenergic and dopaminergic) mechanisms in the brain and in the periphery.’-3 The speculation that TIQ alkaloids may form in vivo during alcohol intoxication has been recently supported by the work of Collins and Bigdeli.4 These authors were able to identify TIQ in the brain of rats pretreated with L-Dopa, ethanol, ,and pyrogallol, a known catecholamine methyltransferase inhibitor.5 Sandler et a1.h also reported that administration of ethanol to Parkinson’s disease patients who were being treated with large doses of L-Dopa provoked urinary excretion of the TIQ condensation product of DA with acetaldehyde. Furthermore, the suggestion that TIQ alkaloids possess peripheral pharmacologic activity has now been documented in a report by Mytilineou e! al.7 These investigators showed that irides of mice or rats depleted of endogenous NE by treatment with a-methyl-p-tyrosine (a-M PT) again showed fluorescence after subsequent intravenous injections of 6,7-dihydroxytetrahydroisoquinoline (6,7-DTIQ). They also reported that during stimulated release of 6,7-DTIQ, there was marked retraction of the eyelid, protrusion of the eyeball, and dilation of the pupil. These responses were similar to those seen in normal (NE-containing) animals. The results suggested that the dopamine-derived TIQ possesses the properties of a false transmitter. The results of another study by Cohen et d7 also demonstrate CNS activity for 6,7-DTIQ due to its catecholamine-releasing properties. The results of a study from our laboratory that show that 6,7-DTIQ produced hyperexcitability, as measured by convulsions elicited by handling in mice, further demonstrate the central action of this TIQ alkaloid. The fact that the slopes of the first derivatives of dose-response curves are similar for N E and 6,7-DTIQ and are dissimilar for both

Enhancement of Alcohol Withdrawal Convulsions in Mice by Haloperidol

Based on the data presented here and the clinical observations cited it would appear that although haloperidol has been used with a certain degree of success for the treatment of acute alcohol abstinence the authors would like to caution the clinician against widespread use of heloperidol for treatment of alcohol withdrawal. In experimentally induced ethanol withdrawal, chlordiazepoxide appears to be a more effective and safer agent for ameliorating symptoms associated with excitation such as tremor, insomnia, anxiety, and hyperexcitability. A double blind comparative clinical investigation between chlordiazepoxide and haloperidol for treatment of alcohol withdrawal is warranted.

Thin-layer chromatographic analysis of cocaine and benzoylecgonine in urine

The sensitivity achieved by the described thin-layer chromatographic (TLC) method greatly exceeds that of previously published TLC methods for the determination of cocaine and its principal metabolite, benzoylecgonine, in urine. Sensitivity for cocaine and benzoylecgonine approaches 0.1 and 0.25 mug/ml, respectively, for a 5.0-ml specimen. A simple extraction with a mixed organic solvent provides the basic mechanism for isolating the drugs from biologic specimens. Cocaine and its metabolites are stable in sulfuric acid solutions but labile in aqueous media containing certain other inorganic and organic acids; therefore, an emphasis on the utilization of sulfuric acid solutions is employed throughout the procedure. An evaluation of sensitivities achieved for cocaine and benzoylecgonine by various detection reagents is presented. The technique is applicable to drug screening programs.