Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Behavioral effects and blood or plasma levels of d-amphetamine, ethanol, cocaine, and diazepam were examined in rhesus monkeys treated chronically with alpha-l-acetylmethadol (LAAM), methadone, or vehicle. Chronic treatment with the opiates failed to alter blood or plasma levels and behavioral effects of d-amphetamine or ethanol. LAAM-maintained monkeys were somewhat less sensitive to rate-decreasing effects of cocaine on schedule-controlled responding, but cocaine plasma levels and half-lives generally did not differ across the chronic treatment conditions. Behavioral depression after diazepam was prolonged substantially in LAAM- and methadone-maintained monkeys, but blood levels of diazepam and metabolites were not increased prolonged in those animals. Naloxone partially antagonized the residual depression LAAM- and methadone-maintained monkeys 24 hr after diazepam, but had no effect on the weaker sesidual depression in vehicle-maintained aniamals. Thus, diazepam appeared to interfere with the metabolic inactivation of the opiates. One LAAM-maintained monkey showed recurrent episodes of LAAM overdose and eventually died during the course of the study.
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PMID:Interactions of acetylmethadol or methadone with other drugs in rhesus monkeys. 10 65

LAAM was administered intravenously to conscious dogs at doses of either 0.1, 0.3 or 1.0 mg/kg. Cardiopulmonary responses were measured prior to drug administration, 0.5 hr post-drug and hourly thereafter. All doses produced a sleep-like state which was dose-related in duration (3-14 hr). Cardiac output, heart rate, respiratory rate and minute volume were decreased below mean pre-drug control values after drug administration in the two higher dosage groups; cardiac output in both groups failed to return to pre-drug control levels. Additionally, total peripheral resistance was elevated in these dosage groups although mean arterial pressure remained stable. Arterial pCO2 increased and arterial pH decreased as respiratory rate and minute volume decreased. Depression of rectal temperature occurred only in response to the highest dose.
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PMID:Effect of 1-alpha-acetylmethadol (LAAM) on various physiological parameters in the conscious dog. 63 19

The effects of 1-alphacetylmethadol (LAAM) on heart rate and force of contraction of isolated guinea-pig hearts and on release of tritium from sympathetic nerves were investigated. In vitro perfusion with LAAM depressed resting heart rate and right ventricular pressure. Nerve stimulation-induced tritium overflow was inhibited in a concentration related manner by LAAM. Increasing the calcium concentration in the perfusate partially inhibited the negative chronotropy and completely prevented the negative inotropic effect. One micromolar atropine prevented the negative chronotropy, partially inhibited the negative inotropic effect of LAAM and the depression of tritium release. Ten micromolar naltrexone failed to antagonize the effects of LAAM. Our results suggest that LAAM: 1) has a direct myocardial depressant effect which may be due to an inhibition of calcium influx; 2) produces a negative chronotropy through stimulation of atrial muscarinic receptors; and 3) interacts with presynaptic muscarinic receptors which modulate nerve stimulation-induced release of noradrenaline.
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PMID:Cardiac and autonomic nervous system effects of L-alphacetylmethadol (LAAM). 718 82

Stimulant dependence has become a major public health problem in the world over the last 15 years, and pharmacotherapies have been evolved based on our understanding of the neurobiological alterations induced by these drugs. Among the stimulants cocaine and amphetamine are the most common dependencies, and they share several common pathophysiologies in producing disease and in guiding medication approaches to treatment--neurotransmitter re-normalization, reversal of cerebral perfusion abnormalities and peripheral cocaine blockers. First is neurotransmitter re-normalization. A relative catecholamine deficiency occurs following prolonged abuse of cocaine and amphetamine due to transporter upregulation and receptor downregulation. This abnormality in dopamine and serotonin neurotransmission appears to be associated with depression and has supported antidepressant treatments to re-normalize neurotransmission. Dopaminergic and serotonergic agonists have also been given to re-normalize neurotransmission, but in contrast to substitution therapies such as methadone, LAAM or buprenorphine for opioids, these approaches have had limited success in unselected cocaine dependent patients. As a correlary approach to substitution, however, aspects of dopamine function can be augmented by dopamine beta hydroxylase inhibitors such as disulfiram to increase the aversive properties of stimulants and decrease their abuse. The second medication approach relates to cerebral perfusion defects and associated cognitive deficits due to vasoconstriction and abnormalities in platelets, which can respond to antiplatelet therapies as well as excitatory amino acid (EAA) antagonists. These EAA antagonists can prevent neuronal damage that is due to the release of EAA during cerebral ischemia induced by stimulant use. Finally, peripheral blockade treatment for cocaine may be possible using a newly developed active vaccine that blocks the uptake of cocaine from the bloodstream into the brain. Its potential efficacy has been shown in rodents that decrease their self-administration of cocaine when immunized with this vaccine, and preliminary human studies support its safety and immunogenicity. In summary, stimulant pharmacotherapy has made great progress in developing treatments based on understanding the neurobiology of these abused drugs, but these pharmacotherapies must be delivered in the context of appropriate behavioral and cognitive psychotherapies, which are also rapidly evolving.
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PMID:Pharmacotherapy of stimulant dependence: one of Japan's greatest public health challenges. 1063 24

The National Institute on Drug Abuse has funded a medications program that has concentrated on the development of medications for opiate and cocaine dependence. Levomethadyl acetate (LAAM) and buprenorphine and buprenorphine/naloxone sublingual tablets were developed in conjunction with pharmaceutical partners and approved by the Food and Drug Administration. The remaining challenges for medications development for opiate dependence involves Phase IV studies in special populations, for example, pregnant opiate-dependent patients, and to translate neuroscience-based findings into treatments. Several marketed medications have shown initial efficacy to reduce cocaine use in well-controlled clinical trials. Disulfiram has been shown to reduce cocaine use in several clinical trials, while baclofen, modafinil, naltrexone, ondansetron, tiagabine, and topiramate have shown preliminary efficacy in initial clinical studies. Confirmatory studies of many of these medications is underway. More recently, the NIDA medications program has evaluated medications for their ability to reduce methamphetamine use. To date, no medications tested have shown efficacy to reduce methamphetamine use. Both marketed medications and investigational agents will be tested. Finally, NIDA has begun to test medications for efficacy to reduce cannabis use. Initial studies are underway. Both agonist and antagonist approaches will be evaluated. Additionally, medications will be tested in cannabis-dependent patients for the management of insomnia, withdrawal, and concurrent depression.
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PMID:Medications development: successes and challenges. 1608 66