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Biomedical subjects

J A Dougherty

Publications and source records attributed to J A Dougherty.

8 recordsLinked to original sources
PubMed2001

Gabapentin: a unique anti-epileptic agent.

Gabapentin is an anti-epileptic drug (AED) that was approved in 1993 for the adjunct treatment of complex partial seizures (CPS) with and without generalization. Although the mechanism of action of gabapentin has not been fully elucidated, it has been shown to be effective not only as an adjunct AED in patients with CPS, but also in children with epilepsy, many pain syndromes (most notably neuropathic pain), and several other neurological diseases. The efficacy of the drug as an AED In both adults and children has been mostly seen when used as an adjunct with other AEDs. When used as monotherapy, it has been most effective for CPS in adults at higher doses. Gabapentin as monotherapy in children has not been shown to be as beneficial as in adults. Also, the dosing of the drug in children has been complicated by negative behavioral adverse effects. Overall, gabapentin has a low incidence of adverse effects, a pharmacokinetic profile that limits its drug interactions, and limited effects on cognition when compared to traditional AEDs. The dosing of the drug is dependent on the disease state targeted, the number of specific therapeutic drugs used, and the renal function of the patient.

Acetates↗
PubMed1988

Neurobehavioral toxicity and tolerance to the herbicide 2,4-dichlorophenoxyacetic acid-n-butyl ester (2,4-D ester).

2,4-Dichlorophenoxyacetic acid (2,4-D) is a commonly used herbicide and one component of Agent Orange. The subchronic neurobehavioral toxicity of 2,4-D-n-butyl ester (2,4-D ester) was assessed in rats by monitoring performance in a battery of behavioral tests. 2,4-D ester was injected daily (150-250 mg/kg sc) in four successive 14-day periods. Five- to eight-day exposure-free periods separated dosing escalations. All doses produced a significant decrease in schedule-controlled lever pressing and photocell locomotor activity while increasing landing foot splay. Peak effects occurred by the 3rd injection, while tolerance developed by the 10th injection. Neurobehavioral effects associated with 2,4-D ester exposure were rapidly reversible and disappeared within 24-48 hr. Brain and blood 2,4-D kinetics revealed that the compound accumulated in brain with repeated dosing. This observation indicates a cellular mechanism for tolerance development. Other neurobehavioral measures, rota rod and grip strength, were not consistently affected by 2,4-D ester. These studies confirm that 2,4-D ester produces behavioral toxicity, that tolerance develops to the 2,4-D ester-induced behavioral deficits with repeated exposures, and that a cellular mechanism appears to be responsible for the developed tolerance to 2,4-D ester.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1985

The metabolic fate of 2,4-dichlorophenoxyacetic acid-n-butyl ester in the Wistar rat.

The metabolic fate of 2,4-dichlorophenoxyacetic acid (2,4-D)-n-butyl ester in rats has not been extensively studied. Upon subcutaneous administration of a 100 mg/kg dose of 2,4-D butyl ester to four male Wistar rats, urine samples were analyzed by three analytical techniques for the presence of the butyl ester and metabolites. Thin layer chromatography (TLC), gas chromatography using an electron capture detector (GC-ECD), and gas chromatography-mass spectroscopy (GC-MS) were the techniques employed. 2,4-D butyl ester was rapidly hydrolyzed in the body to form 2,4-D acid. Ninety-five percent of the administered dose was excreted into the urine as the free acid within 48 h of injection, while only a small fraction (5%) was excreted over an additional 48 h. No amino acid conjugates or the parent 2,4-D butyl ester could be detected in the urine of treated rats. A minor metabolite (less than or equal to 2% of dose) was detected by GC-MS analysis of urine samples. This compound appears to be a side chain metabolite of the 2,4-D butyl ester. Some chemical properties of the metabolite were characterized, and a 2,4-D hydroxyethyl ester structure proposed. The mechanism of this minor metabolic formation remains unknown.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Interoceptive conditioning through repeated suppression of morphine-abstinence. II. Relapse-testing.

The reinforcing properties of etonitazene, both conditioned and unconditioned, were measured in rats that had received saline only by continuous intravenous infusion ("saline" group) and in two groups of rats that had been physically dependent on morphine to equal degrees (and presumably had developed equal degrees of tolerance to morphine): one by once daily passive intravenous injection of morphine ("injection" group) and the other by passive continuous intravenous morphine infusion at the same daily doses for approximately the same number of days ("infusion" group). Prior to passive saline and morphine administration, all rats were trained to press right- and left-sided levers for water reinforcement from 1600 to 0800 hrs to a not more than 60-40 split, and these and other measures ("baselines") were repeated after recovery from the early (acute) morphine-abstinence syndromes. Then etonitazene, 5 micrograms/ml, was substituted for water on the nonpreferred side and all measures were repeated from 1600 to 0800 hrs once every two weeks for 20 weeks (10 "relapse" tests). It was postulated that the daily cycles of morphine-abstinence and suppression of abstinence in the injection group only would generate latent interoceptively conditioned reinforcing properties of morphine because of conditioning of suppression of abstinence to the concomitant internal sensorial effects of morphine, which would persist after morphine withdrawal and be transferred to the internal effects of another opioid, etonitazene. It was found that across the first nine relapse tests, the injection group consumed significantly more etonitazene than the infusion group, while there were no significant differences in water consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Neurobehavioral toxicity of 2,4-D-n-butyl ester (2,4-D ester): tolerance and lack of cross-tolerance.

Daily administration of 2,4-dichlorophenoxyacetic acid-n-butyl ester to rats (2,4-D ester, 150 mg/kg/day SC) initially produced depressions in photocell locomotor activity and increases in landing foot splay. Maximal tolerance developed to these effects following ten days of repeated exposure. By themselves, physostigmine sulfate (0.01-0.10 mg/kg) and (0.3-10.0 mg/kg) n-butanol produced locomotor activity depression in a dose-related manner. n-Butanol produced increases in landing foot splay while physostigmine had no effect at the doses employed. No cross-tolerance was observed between 2,4-D ester and physostigmine sulfate or n-butanol when locomotor activity was the dependent variable. Similarly, a lack of cross-tolerance was observed between 2,4-D ester and n-butanol when landing foot splay was measured. Unlike physostigmine, prior exposure to n-butanol tended to enhance its toxicity upon subsequent exposures, an effect which was blocked when 2,4-D ester was administered between n-butanol exposures.

1-Butanol↗
PubMedDate not supplied

Interoceptive conditioning through repeated suppression of morphine-abstinence. I. Basis for conditioning: once-daily vs. continuous intravenous morphine infusion.

Experimental evaluation of Wikler's interoceptive conditioning hypothesis of relapse to opioid use in ex-addicts requires a preliminary study of the degree of physical dependence produced by two methods of drug administration. Wistar rats were made physically dependent on morphine by single daily intravenous injections or by a continuous i.v. infusion. Rats received the same total daily dose regardless of administration schedule. The initial daily morphine dose was 20 mg/kg, and was increased every fourth day by 20 mg/kg, until a dose of 200 mg/kg per day was reached. The rats were maintained at the highest dose level for 18 days, at which time morphine was discontinued. Body weight and water intake were the primary variables measured during addiction, maintenance, and abstinence phases of the study. Equivalent and parallel changes in mean weight and water intake in injection and infusion rats indicate equivalent degrees of physical dependence were developed. This finding allows separation of the contribution of conditioning factors and of protracted abstinence in facilitating opioid self-administration in formerly-dependent organisms.

Animals↗