Study Chlordiazepoxide

Diazepam and its nordiazepam, oxazepam, and temazepam metabolites are well retained by the MIP, while they are much less retained on NIP, also exhibiting large RSD. Other benzodiazepines of similar structures (Figure 1.50) were well retained on the MIP, showing that this template can be used for the general class of benzodiazepines. Two benzodiazepines studied, chlordiazepoxide and flunitrazepam, were poorly retained, indicating poor fit of these structures into the templated MIP. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

It was conclusively shown that deoxychlordiazepoxide (393) had none of the phototoxic properties of the parent drug, at least in the rat [225]. Chlordiazepoxide, demethylchlordiazepoxide, demoxepam and diazepam-4-oxide were all phototoxic to a bacterial cell preparation. There was a close relationship between the phototoxicities of the A-oxides and the toxicity in the dark of their oxaziridines. The reduced forms of the four compounds were not phototoxic [ 228 ]. Kinetic studies demonstrated that the oxaziridine (390) covalently bonds to plasma proteins. The half-life of the oxaziridine in the presence of high concentrations of protein was about 30 min. It therefore has time not only to bind to biomolecules in the skin surface, but also to attack internal organs. This was put forward as the explanation of previously observed kidney and liver damage in the rat [229]. 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

According to Sternbach s account of the discovery of chlordiazepoxide, chance was also at work in the laboratories of Hoffmann-1 a Roche, although in a different way of the series of substances that Stembach had synthesized, why should it have been chlordiazepoxide, of all others, that had been left behind untested in the chemist s laboratory Rather than stressing this chance occurrence, the well-conducted clinical trial of the experimental preparation should be emphasized instead. This study was not restricted to a single indication or dosage range, but was extended in the face of initial unfavorable results into those indications within which the then standard preparation meprobamate achieved its best results (Cohen, 1970). 

Kellner R, Wilson RM, Muldawer MD, et al. Anxiety in schizophrenia the responses to chlordiazepoxide in an intensive design study. Arch Gen Psychiatry 1975 32 1246-1254. 

Smith ME. A clinical study of chlorpromazine and chlordiazepoxide. Conn Med 1961 25 153-157. 

Hekimian LJ, Friedhoff AJ. A controlled study of placebo, chlordiazepoxide and chlorpromazine with thirty male schizophrenic patients. Dis Nerv Syst 1967 28 675-678. 

Topiramate, another antiepileptic drug, may also be helpful in a dose of 400 mg daily, built up gradually. Small quantities of alcohol may suppress essential tremor but only for a short time. Alprazolam (in doses up to 3 mg daily) or gabapentin (100-2400 mg/d) is helpful in some patients. Others are helped by intramuscular injections of botulinum toxin. Thalamic stimulation by an implanted electrode and stimulator is often worthwhile in advanced cases refractory to pharmacotherapy. Diazepam, chlordiazepoxide, mephenesin, and antiparkinsonism agents have been advocated in the past but are generally worthless. Anecdotal reports of benefit from mirtazapine were not confirmed in a double-blind study, which found no effect on the tremor in most patients. 

The pulse polarographic determination of chlordiazepoxide and its metabolites in plasma has also been described [191]. Chlordiazepoxide and its metabolites are extracted from serum buffered to pH 9.0 followed by a TLC separation, elution, and final quantitation in 0.5 M H2S04. The detection limit of the assay of 0.05-0.1 ng of each compound per milliliter of serum using a 2-mL sample is sufficiently useful for pharmacokinetic studies. 

Smith and Sanagi reported the packed-column SFC of benzodiazepines (diazepam, lorazepam, lormetazepam, nordazepam, temazepam, es-trazolam, chlordiazepoxide, triazolam, cloxazolam, ketazolam, and lopra-zolam) with methanol-modified carbon dioxide as the mobile phase [29]. The effect of methanol concentration on separation was studied on three columns polystyrene-divinylbenzene, octadecylsilane, and cyanopropyl-bonded silica columns. They concluded that proportion of methanol has marked effect on the selectivity of compounds containing different functional groups. 

Only a few behavioral studies have so far been reported with these modulated RF fields. Chicks exposed to 450 MHz, 1 or 5 mW/cm2 fields sinusoidally modulated at 3 or 16 Hz during performance of a fixed-time 30 sec schedule of water reinforcement showed trends towards longer latency of response (44). In Soviet studies, rabbits and rats chronically exposed for 120 days to extremely low levels of 50 or 2500 MHz continuous fields or 10 GHz fields pulsed at 1000 or 20 Hz showed statistically significant alterations in conditioned reflexes with field intensities between 1.9 and 2.0 yW/cm2. A 2450 MHz, 1 mW/cm2 microwave field pulsed at 1000/sec had a synergic effect on the action of Valium (chlordiazepoxide) on fixed-interval behavior in rats (46). 

Salzman et al. (1974), in a placebo-controlled study, showed that volunteers taking chlordiazepoxide became more hostile when confronted... 

Czeizel AE, Rockenbauer M, Sorenson, Olsen J. A population-based case-control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities. Neurotoxicol Teratol 2004 26(4) 593-8. 

Disulfiram inhibits hepatic drug metabolism and can prolong the effects of substances that are normally metabolized in the liver. This has been studied for various benzodiazepines. The clearances of chlordiazepoxide and diazepam were significantly reduced and their half-lives prolonged by disulfiram (43). 

Cornellissen PJ, Beijersbergen van Henegouwen G, Gerritsma KW. Photochemical decomposition of 1,4-benzodiazepines. Chlordiazepoxide. Int J Pharm 1979 3 205-220. Vargas F, Rivas C, Canudas N. Formation of a perbenzoic acid derivative in the photodegradation of fenofibrate phototoxicity studies on etrythrocytes. J Pharm Sci 1993 87(6) 590-591. 

Recently a hyperactivity model induced by a combination of D-amphetamine and chlordiazepoxide was studied. Lamotrig-ine, valproate, and carbamazepine, all used to treat bipolar disorder, were all found to decrease this hyperactivity (Arban et al., 2005). Interestingly, while most mania models assume an increase in dopamine, an early model used dopamine depletion with in tracerebr oven trie ular injection of 6-hydroxydopa-mine, which induces hyper-reactivity to environmental stimuli, but not hyperactivity per se (Petty and Sherman, 1981). This model was responsive to chronic lithium and to chronic electroconvulsive shock, and also to acute chloiq romazine, while imipramine w orsened the behavior. 

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