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The release from the depot, hydrolysis and distribution in the organsim as well as the metabolism and elimination of intramuscularly injected clopenthixol decanoate in Viscoleo have been studied in dogs and rats with radioactive as well as non-labelled drug after single as well as repeated administration. The studies clearly demonstrate the depot effect of clopenthixol decanoate given intramuscularly in oil compared to orally administered clopenthixol. The amounts of drug remaining at the site of injection in dogs suggest monoexponential release of drug from the depot and a half-life of 4-5 days. Rapid hydrolysis to clopenthixol in the organism was indicated by in vitro experiments and in vivo findings. Clopenthixol was found to be the main compound in the organism after single as well as repeated doses. The clopenthixol formed by hydrolysis appeared to be metabolized in the same way as clopenthixol given orally i.e. by dealkylation of the side chain and by S-oxide and N-oxide formation. The elimination pattern with predominant fecal excretion also appeared to be the same after clopenthixol and its esterified derivative apart from the reflection in the latter case of the slow release from depot. A rapid exchange in the organism between tritium from the drugs and hydrogen from the body water was demonstrated. This has to be considered in studies with tritium labelled drugs, where estimation of total radioactivity gives the sum of tritium in drug, metabolites and water.
The clinical effect of cis(Z)-clopenthixol has been compared with that of clopenthixol, which is a mixture of the pharmacologically active cis(Z)-isomer and the inactive trans(E)-isomer. In the 2-month double-blind trial were included 57 psychotic patients, mainly schizophrenics. Ratings evaluating severity of illness, therapeutic effect, possible interference of side effects with the patient's functioning, as well as any individual side effects were done at months 0, 1, and 2. The antipsychotic effect of cis(Z)-clopenthixol was found equal to that of clopenthixol whereas the cis(Z)-isomer on a mg/mg basis was twice as active as clopenthixol. Apart from the finding that the unspecific sedative effect appeared to be less marked with cis(Z)-clopenthixol, the type, degree, and frequency of side effects were the same in the two groups of patients. More than half of the patients experienced no side effects.
The antibacterial effect of the stereo-isomeric compounds cis(Z)- and trans(E)-clopenthixol and the two main metabolites of clopenthixol in man, N-dealkyl-clopenthixol and clopenthixol sulfoxide, was examined in 24 Gram-positive and 37 Gram-negative bacterial strains in vitro. The antibacterial potency of the drugs towards the Gram-positive strains, measured as IC50, was: N-dealkyl-clopenthixol, 6.2 microM (3.7 micrograms/ml), trans(E)-clopenthixol, 16 microM (7.6 micrograms/ml) and cis(Z)-clopenthixol, 37 microM (17.5 micrograms/ml), and clopenthixol sulfoxide was inactive in the investigated area. Against the Gram-negative strains the drugs are less potent. A therapeutic application of these results, especially in the case of trans(E)-clopenthixol, which possesses no neuroleptic activity, requires in vivo testing in an animal model. However, the in vitro model employed might also be useful in the study of such agents and other membrane-active compounds with regard to their interaction with biological membranes.
The duration and intensity of the neuroleptic effect of cis(Z)-clopenthixol decanoate in Viscoleo have been compared with those of cis(Z)-clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)-clopenthixol, 2 HCl had a strong, but short-lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)-clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)-clopenthixol decanoate whereas cis(Z)-clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)-clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.
New antimalaria drugs are needed on the background of increasing resistance to chloroquine. This study was undertaken to elucidate whether other membrane stabilizers than chloroquine have anti-malarial activity in vitro. We here report the anti-plasmodial activity of chlorpromazine (CPZ) and the stereo-isomeric compounds cis(Z)- and trans(E)-clopenthixol. As a screening method we used a modified Desjardins' 3H-hypoxanthine assay. The IC50 = 50% inhibition of 3H-hypoxanthine uptake was found at 1.028 ng/ml = 3.2 microM CPZ, 758 ng/ml = 1.6 microM trans(E)-clopenthixol and 436 ng/ml = 0.9 microM cis(Z)-clopenthixol. The inhibitory effect of trans(E)-clopenthixol in these low concentrations on Plasmodium falciparum in vitro seems particularly promising, since it is known that trans(E)-clopenthixol has no neuroleptic effect.
Phenothiazines have been shown to depress several functions of neutrophils, including chemotaxis. A biphasic effect of chlorpromazine (CPZ) and other phenothiazines on human neutrophil chemotaxis has recently been described. We investigated the effect of the stereo-isomers of clopenthizol, a thioxanthene, and of CPZ on human neutrophil chemotaxis. CPZ, at a concentration of 157 microM, and cis(Z)- or trans(E)-clopenthixol, at 105 microM, decreased cell viability. Cis(Z)- and trans(E)-clopenthixol as well as CPZ exerted a biphasic effect on neutrophil chemotaxis with a maximal enhancement of 57%, 92%, and 119%, respectively, and inhibition at higher concentrations. Enhancement of human neutrophil chemotaxis and possibly of the antibacterial activity of these cells by CPZ and the stereo-isomeric compounds of clopenthixol may have clinical implications especially in immunocompromised hosts. The enhancing effect of trans(E)-clopenthixol is of particular importance as this stereo-isomer of clopenthixol exhibits both antimicrobial and antiplasmodial activity but has no antipsychotic or antihypersecretory effect.
Previous in vitro studies have shown suppression of the growth of Plasmodium falciparum by the neuroleptic agents chlorpromazine and zuclopenthixol (formerly known as cis(Z)-clopenthixol) as well as by the neuroleptic inactive steroisomer trans(E)-clopenthixol. These compounds are chemically related to riboflavin and may act as inhibitors of riboflavin metabolism. As trans(E)-clopenthixol has been found active against chloroquine-resistant strains of P. falciparum in vitro and has been approved for human use, though inactive as a neuroleptic, this drug was selected for the present in vivo study. The dosage of trans(E)-clopenthixol was optimized through a pharmacokinetic study, and the suppression of the growth of Plasmodium berghei in vivo was tested in mice, with chloroquine acting as the positive and saline as the negative control. Trans(E)-clopenthixol did not inhibit the growth of P. berghei, whereas chloroquine almost eradicated the infection. The use of in vitro screening for anti-malarial activity in drugs approved for human use for other indications is discussed in the light of the results. It is concluded that the selection of drugs for further studies in vivo cannot solely be based on positive results in vitro.
Measurement of the IC50 of cis(Z)-clopenthixol and trans(E)-clopenthixol on 188 bacterial strains from human clinical specimens shows that the antibacterial activity of clopenthixol is exerted by both isomerical components and trans(E)-clopenthixol is the most active antibiotic of the two drugs against the sensitive strains. It is known that the trans(E)-clopenthixol isomere is without neuroleptic effect. The possibility of creating new antibiotics by e.g. steric alteration of neuroleptical agents is stressed. These drugs have different antibiotic patterns from those of classical antibiotics. It seems particularly promising that Pseudomonas aeruginosa is sensitive to these drugs.
Forty-five patients were entered into a 24-week double-blind trial of clopenthixol decanoate and fluphenazine decanoate. The 24-week double-blind period was preceded by a 12-week open period. Of the 45 patients entered, 6 failed to attend the second interview and 1 left the country before the final assessment. Doses administered were in the range 100 mg 4-weekly to 400 mg 2-weekly for clopenthixol decanoate and 12.5 mg 4-weekly to 37.5 mg 3-weekly for fluphenazine decanoate. Both depot neuroleptics appeared to have an equivalent duration of action, with 200 mg clopenthixol decanoate approximately equivalent to 25 mg fluphenazine decanoate. Patients' mental state was assessed on the Brief Psychiatric Rating Scale, Clinical Global Impression, Krawiecka, Goldberg and Vaughan Rating Scale, and unwanted effects were recorded on a checklist. No differences were detected between the two drugs with regard to therapeutic activity or side-effects. It is concluded that clopenthixol decanoate is as effective and as well-tolerated a depot neuroleptic as fluphenazine decanoate.
Twenty-three chronic schizophrenic patients were followed-up over periods up to 5 years (1978-1983) while receiving treatment with depot injections of clopenthixol decanoate in doses ranging from 100 to 600 mg every 2 to 4 weeks. The highest single dose given was 1600 mg. Improvement in psychotic symptoms occurred progressively over the 5 years, with reduction in mean overall symptom score for schizophrenia from 7.43 to 0.88. Mean side-effects scores decreased over the same period from 2.0 to 0.5. After 5 years, 10 patients were still maintained on clopenthixol decanoate. Although during the first 2 months there was little improvement in 'negative' or 'loss' symptoms, improvement was similar in 'positive' and 'negative' symptoms after 5 years. Clopenthixol decanoate appeared to have a better calming effect than that encountered with flupenthixol decanoate. At higher doses, it caused drowsiness and subdued hostility and aggression.
Whole blood and plasma concentrations of active neuroleptic drugs were measured in eight schizophrenic outpatients who had received cis(Z)-clopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil by intramuscular injection. Whole blood and plasma concentrations were very similar, though there was a slight tendency for blood concentrations to be higher than plasma concentrations. Maximum concentrations appeared at 1 week after administration of cis(Z)-clopenthixol decanoate, whereas the highest concentrations after fluphenazine decanoate were seen at the end of the 3-week dosage interval. Some between-individual variation and a limited within-individual variation was seen.
The three-dimensional structures and molecular electrostatic potentials of the cis(Z) and trans(E)-isomers of flupenthixol and clopenthixol were examined by computer graphics and molecular mechanical and quantum mechanical calculations, and their internal molecular motions were studied by molecular dynamics simulations in vacuo and in aqueous solution. The simulations demonstrated that both the side chains and the tricyclic ring systems of clopenthixol and flupenthixol are highly flexible. The angle between the two phenyl ring planes varied between 105 and 171 degrees during the simulations in solution. The electrostatic potentials around the 2-substituent were significantly more negative in the trans(E)-isomers than in the cis(Z)-isomers. The stronger negative potentials may weaken electrostatic receptor interactions and, thereby, cause the trans(E)-isomers to be less active than cis(Z)-isomers. Differences both in three-dimensional structure and in electronic structure may cause the difference in pharmacological activity between cis(Z)- and trans(E)-thioxanthenes.
The authors report the results of an open clinical trial with Cis(Z)-Clopenthixol (Cisordinol), the isolated Cis-isomer of the Clopenthixol racemate (Sordinol). The drug was applied to 18 patients with severe forms of manic or schizophrenic disease, diagnosed according to ICD 9. The compound was applied intravenously or orally, daily doses ranging from 10-160 mg. For the duration of the study (6 weeks) the patients were repeatedly rated with the CGI, BPRS or IMPS (abbreviated version), and several hematological and enzyme patterns, cardiac, renal function and electrolytes were monitored, as was the FFA. Due to the relatively small number of patients in relatively heterogeneous diagnostic composition, a number of items rated failed to reach statistical significance. The CGI showed a good therapeutic effect with a minimal incidence or severity of side effects. BPRS and IMPS documented an impressive decline in formal thought-disorders, agitation, logorrhea and tenseness. The sedative effects of the drug were slight and of short duration, anti-Parkinson medication was necessary in more than 50% of the patients studied. The results of the study show a good efficacy of the drug in manic and schizophrenic disorders, Cisordinol being well tolerated intravenously. The range of doses administered is approximately 50% of the dose-range of the parent-drug (Sordinol).
Combined liquid chromatography and mass spectrometry (LC/MS) with a moving belt interface can be used as a rapid method for the determination of bromazepam, clopenthixol, and reserpine in serum samples obtained from cases of acute overdoses with combinations of these drugs. Low resolution detection limits are about 100 pg for the three drugs, while in high resolution mode the detection limit for bromazepam is shown to be at least 35 pg. Accurate masses were obtained in a serum sample within 5 ppm using high voltage scanning over a narrow mass range for about 10 ng of bromazepam and clopenthixol, respectively. Chemical deactivation of the belt was shown to effectively reduce memory effects and to improve the desorption characteristics of the belt leading to higher yields of evaporated intact molecules.
The clinical effect of clopenthixol decanoate has been assessed in a 5-month controlled including 21 hospitalized chronic schizophrenic patients. The ratings were done with BPRS, NOSIE 30, the two psychological tests of WAIS and Grübaum, and the rating scale of Simpson & Angus to assess extrapyramidal side effects. Clopenthixol decanoate was found an effective and long-acting antipsychotic compound with few autonomic and neurological side effects. Compared with previous maintenance treatment it also showed a positive influence on depression and facilitation of the social adaptation of the patients.
In the reversed-phase chromatography of nitrogen-containing bases on chemically bonded ODS-silica, peak tailing and prolonged retention are often considerable problems. These effects are due to residual silanols on the surface of the column material and may be remedied by adding suitable amines or quaternary ammonium ions to the eluent as anti-tailing agents. However, further addition of an anionic compound is often needed to achieve a suitable retention. The retention mechanism in such systems is complex as interaction takes place between the anionic compound and the solute molecules, anti-tailing agent and column packing material. The influence of the nature of the anti-tailing agent and anionic counter-ion on the retention of cis- and trans-clopenthixol and of other basic drug substances was investigated and it was found that both the retention and the selectivity were greatly affected.