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)

Four hundred and thirty-four patients suffering from mild to moderate depression were recruited into a double-blind multicentre general practice study and randomly received either Limbitrol (25 mg amitriptyline and 10 mg chlordiazepoxide) or amitriptyline 25 mg in matching white capsules given as a single night-time dose. The dose was titrated to a maximum of four capsules per night. Patients were assessed on entry and at 7-day intervals for depressive state (Hamilton Rating Scale for Depression), cardiovascular effect and side-effects for 28 days. Self-assessments of depression and anxiety using the Leeds Scale were made in the form of a patient questionnaire. Both groups showed significant improvement at each visit and significantly more patients improved after 7 days in the Limbitrol group. There was no significant difference in treatment over all between groups, in the incidence of side-effects, or in the effects on the heart.
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PMID:Comparison of limbitrol (chlordiazepoxide/amitriptyline) and amitriptyline alone as a single night-time dose for the treatment of depression with anxiety. 388 30

Both cimetidine therapy and cirrhosis individually interfere with normal elimination of various drugs. Cimetidine is often prescribed in patients with cirrhosis but there is incomplete data on its effect on drug elimination in cirrhotics. The purpose of this study was to address this issue. Eight stable cirrhotics were studied prior to and following 7 days of cimetidine administration, (300 mg orally q.i.d.). Chlordiazepoxide (Librium), which is eliminated by the liver after demethylation, and indocyanine green, which is removed by the liver without biotransformation, were used as probes. Consistent with the concept that cimetidine interferes with drug metabolism by inhibiting microsomal oxidation, chlordiazepoxide clearance in the cirrhotics was inhibited by cimetidine (p less than 0.05), but indocyanine green clearance was unaffected. As shown by us previously (Roberts, R. K. et al., Gastroenterology 1978; 75:479-485), untreated cirrhotics had substantially lower chlordiazepoxide clearance than did controls. The inhibitory effect of cimetidine on chlordiazepoxide clearance was less in cirrhotics than in controls (p less than 0.05). In all subjects, there was excellent correlation between initial clearance and magnitude of depression in clearance after cimetidine, i.e., the larger the initial clearance, the larger the change (r = 0.97, p less than 0.0001). Forty-eight hours after stopping cimetidine, chlordiazepoxide clearance returned to baseline in cirrhotics and controls. Our data demonstrate that cimetidine and cirrhosis may act additively to impair drug metabolism. This effect of cimetidine on chlordiazepoxide clearance is smaller in cirrhotics than in controls, but, because of impaired initial drug elimination in cirrhosis, it may result in adverse clinical effects.
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PMID:The effect of cimetidine on hepatic drug elimination in cirrhosis. 397 62

The rat olfactory cortex slice has been used to investigate the effects of chlordiazepoxide on evoked field potentials and the release of endogenous amino acid neurotransmitters (aspartate, glutamate, GABA and possibly taurine) which accompany electrical stimulation of the lateral olfactory tract. When single, low frequency stimuli were employed, chlordiazepoxide (2 microM-1 mM) depressed the amplitude of the field potential correlate of the depolarizing actions of the lateral olfactory tract excitatory transmitter (aspartate?) although aspartate release was unaffected. The field potential correlate of GABA-mediated presynaptic inhibition (late N-wave) was also depressed in amplitude but low drug concentrations (between approximately 2 and 50 microM) increased its peak duration . Effects of chlordiazepoxide on evoked inhibition were analyzed by giving paired stimuli such that the second stimulus occurred during the field potentials evoked by the first stimulus. Chlordiazepoxide (1-20 microM) increased the depression in amplitudes of the presynaptic massed action potential and late N-wave evoked by the second of a pair of stimuli compared with those evoked by the first stimulus suggesting that presynaptic inhibition was potentiated. These effects of chlordiazepoxide were accompanied by a significant reduction in aspartate release from the lateral olfactory tract terminals. Moreover, the drug effects on presynaptic inhibition and aspartate release were antagonized by picrotoxin (5 microM). On the other hand, chlordiazepoxide (1-50 microM) had no significant effect on postsynaptic inhibition. The results are discussed in terms of both the sites (presynaptic or postsynaptic) and mechanisms of action of chlordiazepoxide.
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PMID:The effects of chlordiazepoxide on synaptic transmission and amino acid neurotransmitter release in slices of rat olfactory cortex. 611 29

Chlordiazepoxide (CDP) and amphetamine (AMPH) were tested, alone or in combination, in BALB/c mice pretreated with alpha-methyl-p-tyrosine (AMT) and subjected to shuttle-box avoidance training. CDP and AMPH, given alone, partly reversed avoidance depression induced by 50 mg/kg of AMT, but were ineffective in mice pretreated with 100 mg/kg of AMT. Stronger effects were produced by CDP-AMPH combinations, which also improved avoidance performance in mice pretreated with the higher dose of AMT. The results suggest that catecholamines may play a role in the facilitation of avoidance induced by CDP, especially when given in combination with AMPH.
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PMID:Avoidance facilitation by chlordiazepoxide-amphetamine combinations in mice: effect of alpha-methyl-p-tyrosine. 611 20

In gross-behavioral observations, chlordiazepoxide, diazepam, meprobamate, and pentobarbital-Na produced excitatory behavior at 5 and 10, 1 and 2, 100 and 200, and 10 and 20 mg/kg p.o., respectively whereas afloqualone produced no excitatory behavior at doses up to 20 mg/kg p.o., these doses induce muscle relaxation and motor depression. Afloqualone depressed DRL response at 10 and 20 mg/kg p.o. Similar effects were seen with chlorpromazine (5, 10, 20 mg/kg p.o.). Chlordiazepoxide, meprobamate, and pentobarbital-Na facilitated DRL response at doses producing excitatory behavior. Methamphetamine (0.5, 1, 2 mg/kg p.o.) facilitated the response, dose-dependently. In CER, chlordiazepoxide (5, 10, 20 mg/kg p.o.), diazepam (1, 2, 5 mg/kg p.o.), and meprobamate (50, 100, 200 mg/kg p.o.) dose-dependently increased the response during the alarm period, regardless of the response during the safe period. Pentobarbital-Na (5, 10, 20 mg/kg p.o.) had much the same effect. Afloqualone slightly increased the response during the alarm period in one out of 3 rats at 5, 10, and 20 mg/kg p.o., respectively. Chlorpromazine and methamphetamine had no influence on the response during the alarm period at doses up to 20 and 2 mg/kg p.o., respectively. These results suggest that the pharmacological properties of afloqualone, as related to behavior differ from those of anti-anxiety drugs, hypnotics, and stimulants.
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PMID:[Effects of afloqualone, a new centrally acting muscle relaxant, on DRL response and CER in rats (author's transl)]. 612 Jan 27

The effect of pentobarbital (PB) and related compounds on frog motoneurons was examined with sucrose gap recording from the ventral roots. PB was found to: (1) depress the action of glutamate, (2) selectively enhance the action of GABA, (3) reverse the non-competitive picrotoxin antagonism of GABA and the competitive strychnine antagonism of beta-alanine, but not the competitive bicuculline methiodide antagonism of GABA, and (4) elicit a GABAmimetic hyperpolarization. The first three actions had a threshold concentration of 10 microM, while the GABAmimetic action required a 10-fold higher concentration. The reversal of picrotoxin's action by PB suggests that PB might modify GABA mechanisms by combining to the picrotoxin recognition site. Phenobarbital shared all of the properties of PB but was approximately one-fifth as potent. The only property that phenytoin shared with PB was a weak depression of glutamate responses. Chlordiazepoxide selectively enhanced GABA responses but was devoid of the other actions of PB. These results suggest that the GABAmimetic effect of PB may be an important feature in the depressant and anesthetic properties of PB. The anesthetic chloralose, which is structurally unrelated to PB, nevertheless shared all of the actions of PB. This finding suggests that the properties described for PB may also be found in other general anesthetics.
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PMID:The effects of pentobarbital and related compounds on frog motoneurons. 624 12

The effects of combined administration of ethanol (4 g/kg) and chlordiazepoxide (CDP, 12.5 mg/kg) on mouse brain c-AMP and c-GMP levels were investigated in order to test the hypothesis that the supra-additive effect of CDP on ethanol sleep time may be related to a supra-additive alteration in brain cyclic nucleotide levels induced by the combined drugs. Ethanol alone or CDP by itself did not cause any change in brain c-AMP levels, except for a transient decrease in the cerebral cortex and midbrain at 0.5 hr after ethanol injection, as well as a transient increase in the cerebellum at 0.5 hr after CDP injection. The combined drug treatment did not result in a supra-additive effect on c-AMP levels. On the other hand, c-GMP levels were depressed significantly for 4 hr after ethanol injection especially in the cerebellum. The mice regained the righting reflex when the c-GMP levels were still about 30 per cent of control values. Ethanol and CDP together induced a supra-additive decrease of c-GMP concentrations in the cerebellum at 2 and 4 hr. This resulted in a lengthened period (about 2.5 hr) during which the cerebellar c-GMP levels were below 30 per cent of control values, and this interval coincided with the increase in sleep time, suggesting a possible relationship between these two factors. Injection of ethanol and N-demethyl-chlordiazepoxide (NDCDP) simultaneously (the latter being a metabolite of CDP) also elicited a more than additive depression of cerebellar c-GMP levels at 4 hr. These data suggest that NDCDP or its metabolite could be responsible for the supra-additive effect of CDP on the ethanol-induced decrease in cerebellar c-GMP levels.
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PMID:Relationship of brain cyclic nucleotide levels and the interaction of ethanol with chlordiazepoxide. 627 37

To initiate studies of benzodiazepine tolerance and physical dependence, a reproducible animal model has been developed utilizing chlordiazepoxide in rats. Based on the "chronically equivalent" dosing principle, a regimen has been devised to maintain rats in a state of quantifiable intoxication for 5 weeks. Chlordiazepoxide was delivered intragastrically on a b.i.d. basis in doses individually adjusted day-to-day and animal-to-animal to produce an equivalent impairment of motor function evaluated by a gross neurological screen. Quantitative analysis of central nervous system depression ratings during the time of peak effect (4 hr postdose) confirmed that the criterion of chronic equivalence was indeed met. Over the 5-week period of repeated dosing, tolerance was reflected in a 5-fold increase in maintenance dose, from 163.3 mg/kg on day 2 to 839.3 mg/kg on day 35. Tolerance developed more rapidly during the first 9 to 10 days, but continued to develop thereafter more slowly without apparent ceiling. Upon abrupt withdrawal, a syndrome of hyperexcitation developed. Signs included twitches, tremors, muscle hypertonus, arched back, piloerection, myoclonic jerks, augmented struggle and vocalization upon handling, increased startle response, tail erection, teeth chatter, blanched ears and weight loss. No spontaneous convulsions occurred. Latency to onset of withdrawal ranged from 2 to 5 days, and signs peaked in intensity in 8 days and disappeared by 14 days posttreatment. This animal model appears to provide a useful tool for the study of specific mechanisms underlying benzodiazepine tolerance and physical dependence.
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PMID:Experimental induction of benzodiazepine tolerance and physical dependence. 668 12

Alcohol withdrawal syndrome (AWS) may result in nausea, vomiting, diarrhea, weakness, sweating, tremors, tachycardia, hypertension, agitation, delirium, hallucinations, seizures, and death beginning 6 hours after alcohol cessation in alcoholics. Benzodiazepines are cross-tolerant with ethanol and are considered first-line therapy for treating AWS. Chlordiazepoxide and diazepam are first metabolized by hepatic oxidation, then glucuronidation. Lorazepam and oxazepam undergo only hepatic glucuronidation. Benzodiazepine oxidation is decreased in persons with liver disease and the elderly. Accumulation with resultant excessive sedation and respiratory depression may be significant when administering chlordiazepoxide or diazepam to patients with impaired oxidative metabolism. Lorazepam and oxazepam metabolism is minimally affected by age and liver disease. Chlordiazepoxide and diazepam are erratically absorbed by the intramuscular route. Lorazepam is predictably absorbed by the intramuscular route. Oxazepam is not available in parenteral form. Lorazepam appears to be the safest empiric choice among the various benzodiazepines for treating AWS in the elderly and in patients with liver disease, or those who require therapy by the intramuscular route.
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PMID:Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. 870 Jul 92

This study investigates the influence of possible stress due to housing in Bolman cages on antinociception and on respiratory depression following opioid administration. To evaluate the functional role of this stressor and to modulate it, rats were subcutaneously pretreated with the anxiolytic chlordiazepoxide (CDP; 10 mg/kg) or saline (SAL) before the immobilization in the Bolman cages and before the intravenous administration of small doses of morphine (MOR), sufentanil (SUF), or vehicle (VEH). Antinociception, respiratory impairment and stress were evaluated by means of the tail-flick latency, blood gas analysis, and serum corticosterone (CS), adrenocorticotropic hormone (ACTH), and prolactin (PRL) determinations. The results demonstrated that 10 mg/kg CDP did not alter the antinociceptive effects of low doses of morphine and sufentanil. CDP pretreatment differentially affected the various blood gas parameters. Compared to vehicle pretreatment, there was a larger decrease in PaO2 following MOR and SUF in the CDP-pretreated rats. The effects were most pronounced at the lowest doses of both opioids. A CDP potentiation was also observed for the short-lasting raises in PaCO2 with the lowest concentrations of the opioids. At higher concentrations of the opioids, CDP was without any effect. With regard to the stress hormones, immobilization and an intravenous injection resulted in increases in CS and PRL in both CDP- and VEH-pretreated rats. ACTH did not change in these controls. SUF prevented the CS raises independent of a CDP pretreatment, while ACTH only increased in the SUF plus CDP groups, pointing to a stress-reducing effect of SUF. Also, MOR without CDP prevented the increases in CS, but the opioid intrinsically increased ACTH. These results indicate that restraint in Bolman cages in the present setup, with animals recovering for several hours in these cages after being equipped with an arterial catheter, is stressful but without any significant effect on the opioid-induced antinociception. Pretreatment with an anxiolytic benzodiazepine only minimally affected the outcome of the opioids on respiratory depression and pointed to a stress-reducing effect of low doses of the opioids, especially sufentanil.
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PMID:Effects of chlordiazepoxide on opioid-induced antinociception and respiratory depression in restrained rats. 951 69


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