Chlorpromazine effects

Tecce, J., Cole, J., 6c Savignano-Bowman, J. (1975). Chlorpromazine effects on brain activity (contingent negative variation) and reaction time in normal women. Psychophar-... 

Herling S, Woods IH (1980) Chlorpromazine effects on cocaine-reinforced responding in rhesus monkeys reciprocal modification of rate-altering effects of the drugs. Pharmacol Exp Therap 214 354-361. 

Fig. 6 shows that BC-PL are able to affect in men prolactin secretion and spinal lumbar HVA suggesting an effect on dopaminergic system also in humans. Phospholipids induce a decrease of serum prolactim and an increase of HVA in the lumbar spinal fluid. Serum prolactin is believed to be under the inhibitory control of DA along the hypothalamic pituitary axis (Me Leod Lehmeyrer, 1974), while lumbar HVA may be indicative of DA turnover (Curzon, 1975). Furthermore, BC-PL reverse the chlorpromazine effect on serum prolactim. The effect of phenothiazines on prolactin secretion seems to depend on a block of dopamine receptors and it is counteracted by the administration of L-dopa and of dopamine agonists (Frantz et al., 1972). 

Increasing the gastric pH, which causes a decrease in absorption of weakly acidic drugs and results in a decreased drug effect (eg, digoxin, phenytoin, chlorpromazine, and isoniazid)... 

The following drugp have a decreased pharmacologic effect when administered with an antacid corticosteroids, digoxin, chlorpromazine, oral iron products, isoniazid, phenothiazines, ranitidine, phenytoin, valproic acid, and the tetracyclines. 

The multidrug resistance (mdr) reversing effect of the new phenothiazine complexes were tested on mouse T cell lymphoma cell lines. Trifluoperazine (TFP) was much more effective at the same concentration than verapamil. The efficacy of some metal coordination complexes [TFP-Cu(ll) and TFP-V(IV)] exceeded the action of TFP alone. Chlorpromazine (CPZ) or CPZ-Pt(ll) complex had the same or less effect than verapamil or promethazine (Pz) used as a control. 

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Certainly clozapine can avoid EPSs by only blocking a fraction of D2 receptors but that seems insufficient on its own to make clozapine so effective in schizophrenia. That is probably achieved by a unique combination of other blocking actions, at Di, D4, 5-HT2, o 2 and possibly other receptors (see Fig. 17.8). It may simply be that clozapine is so effective because it is so dirty , a view held for many years about the first neuroleptic chlorpromazine. Indeed it is unlikely that the varied symptoms of such a complicated disorder could be rectified by manipulating just one NT. 

Geller, I, Kulak, JT and Seifter, J (1962) The effects of chlordiazepoxide and chlorpromazine on a punished discrimination. Psychopharmacologia 3 374—385. 

Set against this background is the finding that the inhibition of [ H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. This serves as a testimony... 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Powell. D.A. Walters, K. Duncan, S. and Holley, J.R. The effects of chlorpromazine and ( -amphetamine upon shock-elicited aggression. Psychopharmacologia 30 303-314, 1973. 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

Gl. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., and Ghezzi, P., Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J. Exp. Med. 173, 1305-1310 (1991). 

Figure 6.12 Correction of the apparent solubility pH profile (solid curves) for the effect of DMSO and/or aggregation (a) chlorpromazine (b) terfenadine (c) piroxicam (d) phen-azopyridine. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

The most dramatic effects are with the bases. The first seven bases in Table 7.19 are the most lipophilic. Cosolvent causes their %R to decrease, consistent with effect (2) listed above. For the three least-lipophilic bases, %R increases with cosolvent, consistent with effect (1). Chlorpromazine and verapamil experience... 

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