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At least 19 recordsLinked to original sources
PubMed1978

Differential effects of benzamides and thioxanthenes on dopamine-elicited accumulation of cyclic AMP in isolated rabbit retina.

Benzamides or thioxanthenes were tested as potential antagonists of the cyclic AMP accumulation induced by 10(-4) M dopamine in intact rabbit retinae in vitro in the presence of 5 to 7 mM theophylline. The neuroleptic sulpiride (10(-4) M) was found to be totally inactive whereas a substituted benzamide (clebopride) had small but significant antagonist effect at the same concentration. Among thioxanthenes, isomers of cisconfiguration, which are potent neuroleptics, completely inhibit the cyclic AMP accumulation induced by dopamine, in contrast to trans-isomers which had no inhibitory effects. These data would confirm that retina in vitro is another suitable model for screening antipsychotic activity of classical neuroleptics and that the mechanism of action of sulpiride still needs further investigation.

Animals↗
PubMed1979

The evaluation of a radioimmunoassay for phenothiazines and thioxanthenes using an iodinated tracer.

Antisera have been raised in rabbits to the immogen 2-trifluoromethylphenothiazine-10-beta-propionate bovine serum albumin. An [125I]-labelled tyrosine methyl ester derivative of the immunogen precursor has been synthesised and used with the antisera to develop a simple, precise and sensitive radioimmunoassay for phenothiazines and thioxanthenes bearing 2-trifluoromethyl substituents. The assay can detect 0.4 ng/ml of fluphenazine, trifluorperazine or (Z)-flupenthixol in 100 microliter of human serum without interference from their sulphoxide or 7-hydroxylated metabolites. An acceptable correlation between this assay and an established fluphenazine radioimmunoassay using commercial [3H]fluphenazine has been obtained for plasma samples.

Animals↗
PubMed1976

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 7. Bisalkamine esters of 9-oxoxanthene-2,7-dicarboxylic acid, 3,6-bis-basic ethers of xanthen-9-one, and 2,7-bis(aminoacyl)xanthen-9-ones-xanthenes, and -thioxanthenes.

3,6-Bis[2-(dimethylamino)ethoxy]-9H-xanthen-9-one dihydrochloride (4, RMI 10874DA) and 1,1'-(9H-xanthene 2,7-diyl)bis[2-(dimethylamino)ethanone] dihydrochloride (16, RMI 11513DA) were found to prolong survival of mice infected with lethal challenges of encephalomyocarditis (EMC) virus. They were effective by oral as well as subcutaneous administration and showed broad-spectrum antiviral activity. They were selected for preclinical evaluation from the five series of compounds named in the title that were synthesized in analogy to tilorone and related fluorenone derivatives, described earlier. In addition to 4 and 16, compounds 11, 12, 17, and 18 showed high antiviral activity on oral as well as subcutaneous administration. High antiviral activity on subcutaneous admistration was found in the bisalkamine esters 1,2, and 14, the bis(aminoacyl)xanthenes 23 and 26, the bis(aminoalkylene)xanthene 31, the bis(aminoacyl)thioxanthenes 34-40, and the bis-basic ethers of 9-benzylide-nexanthenes 41 and 42. Structure-activity relationships showed a decrease of oral activity with increased length of side chains and increased molecular weight of dialkylamino substituents of 3,6-bis-basic ethers of xanthen-9-one and of 2,7-bis(aminoacyl)xanthenes and-xanthen-9-ones. At least one carbonyl or alkenyl function in conjugation to the xanthene nucleus either at the 9 position of the nucleus or in the side chains is required for high antiviral activity.

Administration, Oral↗
PubMed1978

Maintenance treatment of chronic schizophrenic patients. A study with the long-acting thioxanthene derivative, cis(Z)-clopenthixol decanoate-sordinol depot.

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.

Adult↗
PubMed1978

[Induction of hepatic tyrosine transaminase in rats by phenothiazine derivatives and analogs].

We have showed induction of tyrosine-alpha-ketoglutarate transaminase in hepatic cytosol of Rats (Wistar strain) five hours after intraperitoneal administration of tricyclic compounds (phenothiazine, iminodibenzyl, thioxanthene, thiophenylpyridylamin, dibenzocycloheptadiene, dibenzoxepin derivatives). Chemical structure of these molecules is very important: sulfur atom (phenothiazine, thioxanthene), some substituants like chlorine (chlorpromazine, chlorprothixene) and 2'-dimethylaminopropyl chain (promethazine) increase this inductive effect.

Animals↗
PubMed1977

Ocular accumulation and toxicity of certain systemically administered drugs.

Certain polycyclic compounds with a coplanar ring structure (phenothiazines, thioxanthenes, 4-aminoquinolines, and amitriptyline), monocyclic sympathomimetic amines, and other drugs become concentrated in the eyes of animals following acute or chronic systemic administration. Some are known to cross the placental barrier and accumulate in the fetal eye. Following drug withdrawal, these substances disappear relatively slowly from ocular tissues compared with other tissues. The main reason for the accumulation of these compounds seem to be their affinity for the melanin of the uveal tract and pigment epithelium and they therefore do not accumulate in the eyes of albino animals. The mechanism of uptake by melanin probably involves a "charge transfer" reaction involving the transfer of an electron from drug to melanin, which acts as an "electron trap" and in consequence binds the donor compound firmly. The accumulation of a nontoxic drug in the eye is not necessarily of clinical significance, but ocular damage can occur in patients on long-term tricyclic agents when the amount, duration, and frequency of dosage are sufficiently high. The most serious form of ocular damage is pigmentary retinopathy, which, if caused by chloroquine, is irreversible. In contrast, phenothiazine retinopathy is reversible. Lesions may also be produced in anterior structures of the eye, usually the cornea and lens, by both chloroquine and the phenothiazines, but they are of a relatively minor nature. Possible mechanisms for the oculotoxicity of the phenothiazines and antimalarials are discussed, particularly in relation to melanin.

Amitriptyline↗
PubMed1979

A high performance liquid chromatographic assay of cis- and trans- isomers of tricyclic neuroleptic drugs.

Tricyclic neuroleptics based upon the thioxanthene nucleus exhibit geometrical isomerism and the major pharmacological activity resides in the Z-component. An h.p.l.c. procedure which enables the separation detection and quantification of these isomers is described. The method is applicable to the analysis of flupenthixol, clopenthixol, chlorprothixene, doxepin and dothiepin. Measurement of the isomer-ratios in various samples of flupenthixol has shown that small batch to batch variations are apparent. The determination of the isomer-ratio in formulations has been shown to rely upon the complete extraction of the medicament. This is due to the differential release of the components from the tablet matrix with the cis-isomer being favoured. There is little difference observed between the adsorption isotherms of the two components (onto charcoal) but in competition experiments differential adsorption may be demonstrated. This has clear implications for the pharmacokinetics of these drugs.

Antipsychotic Agents↗
PubMedDate not supplied

[Preliminary note on the antiautistic, antidelusional and hallucinolytic effect of teflutixol (author's transl)].

The first thioxanthene derivative without the double bind up to now considered mandatory for the antipsychotic effect, teflutixol, was administered in a phase II pilot efficacy trial to acute or subacute psychotic inpatients (mean age 36,1) during at least 5 weeks at a dosage of 3 to 20 mg p.d. once a day. The patients were abruptly switched from a haloperidol baseline therapy, which was administered on an average for 3 weeks at 15 mg p.d. Preliminary results are reported for the first 11 patients on a purely clinical basis. Despite the limitations of a small sample and of a qualitative analysis of data, it is hypothesized that teflutixol is a potent and original neuroleptic drug combining at 6 mg p.d. or less potent antidelusional, hallucinolytic and antiautistic effects. Latency and duration of action approximate 2 days. At 6 mg and above appear side-effects of the desinhibiting type (anxious and/or aggressive mood, withdrawal, flaring up of delusions, insomnia, agitation) and extrapyramidal side-effects of the akathisia type. No adrenolytic, anticholinergic or toxic effects were prominent. The patient followed up for the longest period (6 months on 3 mg p.d.) has not relapsed and has normal liver functions.

Adult↗
PubMed1979

Induction of hepatic neoplastic lesions in mice with a single dose of hycanthone methanesulfonate after partial hepatectomy.

Experiments were designed to determine whether hycanthone methanesulfonate (1-([2-(diethylamino)ethyl]amino)-4-(hydroxymethyl)thioxanthen-9-one monomethanesulfonate), an antischistosomal drug, and its analog, IA-4-N-oxide (8-chloro-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazole 5-methanol monomethanesulfonate), will induce neoplastic lesions in the livers of mice not infected with Schistosoma mansoni. All the mice received a single i.m. injection of hycanthone methanesulfonate (76 mg/kg), IA-4-N-oxide (80 mg/kg), or an equivalent volume of the solvent, 0.9% NaCl solution, 42 hr after partial hepatectomy. Of the mice receiving hycanthone methanesulfonate and living 200 days or longer, hepatocellular carcinoma was seen in 11.5% and liver sarcoma was seen in 4.2%. This type of malignant neoplasm was not seen in the animals receiving either IA-4-N-oxide or 0.9% NaCl solution. In addition, mice receiving hycanthone methanesulfonate showed a significantly higher incidence of both type 1 (43% compared to 21% in controls) and type 2 (21% compared to 12% in controls) hepatocyte neoplasms. Mice receiving IA-4-N-oxide showed no increased incidence of neoplasms.

Animals↗
PubMed1975

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

The antischizophrenic activity of phenothiazine drugs and their tendency to elicit extrapyramidal symptoms are thought to involve blockade of synaptic dopamine receptors in the brain. Space filling molecular models show how favorable Van der Waal's interactions between the side chain amino of phenothiazines and the 2-substituent on ring A can promote a conformation mimicking dopamine. These Van der Waal's attractive forces can expain (i) the greater potency of drugs with trifluoromethyl rather than chlorine as a 2-substituent; (ii) the enhanced activity of phenothiazines with piperazine instead of alkylamino side chains; (iii) the increased potency associated with hydroxyethylpiperazines as contrasted to piperazine side chains; (iv) the greater potency of cis rather than trans thioxanthenes; and (v) the crucial location of the ring A substituent at carbon no. 2. Potential energy calculations support the observations with molecular models and suggest an active conformation for the phenothiazines.

Antipsychotic Agents↗
PubMed1978

Neuroleptic blockade of the effect of various neurotransmitter substances.

The antagonistic effect of neuroleptics to acetylcholine, histamine, 5-HT, and noradrenaline was examined in various in vivo and in vitro models. Piflutixol, a new potent thioxanthene neuroleptic, markedly antagonizes the effect of dopamine, noradrenaline, 5-HT and to some extent histamine, whereas the affinity for muscarinic receptors was rather weak. Clozapine and chlorprothixene on the other hand, have high affinity for muscarinic receptors and also antagonize the effect of histamine and 5-HT, whereas clozapine was a weak antagonist of noradrenaline and dopamine when compared to the effect of piflutixol. Chlorprothixene, however, also exhibits a rather good antagonism of noradrenaline and dopamine. Haloperidol proved to be weak in all models when compared with the other neuroleptics examined. Flupenthixol specifically antagonizes dopamine and noradrenaline, whereas fluphenazine was a more potent antagonist of dopamine than of the other transmitters. The data show, that neuroleptic compounds possess very different profiles with regard to interaction with various neurotransmitter substances. It is suggested, that the rather potent anti 5-HT and antihistamine effects observed for certain substances may contribute to the central effect of these drugs.

Animals↗
PubMed1978

Drug therapy in the treatment of minimal brain dysfunction.

The pharmacotherapy of minimal brain dysfunction (MBD) is reviewed. Studies using central nervous system (CNS) stimulants (amphetamines and methylphenidate, deanol, pemoline, caffeine), antidepressants (imipramine and desipramine), anticonvulsants (phenytoin and primidone), antianxiety agents (chlordiazepoxide, hydroxyzine, meprobamate), antipsychotic agents (phenothiazines, thioxanthenes, butyrophenones) and miscellaneous agents (benztropine, thyrotropin-releasing hormone, megavitamins) are discussed. When drugs are indicated, the CNS stimulants are the agents of choice in the treatment of MBD. The use of tricyclic antidepressants in MBD is regarded as investigational and warrants careful monitoring to minimize toxicities. Anticonvulsants have been ineffective in controlling behavior problems; however, phenytoin may be helpful in auditory perception problems. Anti-anxiety and antipsychotic agents are not as desirable as the CNS stimulants for treatment since they do not decrease distractibility or increase attention spans.

Anti-Anxiety Agents↗
PubMed1976

[Neuroleptics with prolonged action].

In the last twenty years, the study of long-acting neuroleptic drugs has been active and promising progress in maintenance of psychotic patients. At present, there are several long-acting derivatives of phenothiazines, e.g. thioridazine, or drugs that allow the esterification of phenothiazine, e.g. perphenazine, fluphenazine and pipothiazine. Other esterifiable product is flupenthizol, which is a thioxanthene, and other long-acting drug is chlofluperol, which is a butyrophenone derivative. There is also a new series of neuroleptics, diphenilbultilpiperidine derivatives, such as fluspirilene, pimocide and penfluridol. Our clinical studies with these drugs allows us to state that there is a new revolution in pharmacological psychiatry, with important perspectives in the ways of helping patients.

Antipsychotic Agents↗
PubMed1979

Techniques for quantitative organic analysis in microdroplets.

Techniques are described for the chemical analysis of urea by means of X-ray microanalysis. A selective labelling reagent, thioxanthen-9-ol, is used to precipitate urea together with a sulfur label. Reagents are added to and removed from microdroplets of 50 picoliter volume by means of oil-water partition. The sensitivity of the method is less than 1 picomole. The possibility of extension of these techniques to other analyses is discussed.

Chemical Phenomena↗
PubMed1977

Phenothiazine phototoxicity: an experimental study on chlorpromazine and related tricyclic drugs.

A large number of phenothiazines and chemically related tricyclic drugs have been studied with respect to their phototoxic potency. Two methods were used, an in vivo technique based on the inflammatory response of the mouse tail after systemic administration of the drug plus UVA irradiation, and an in vitro method based on growth inhibition of Candida albicans. Of 27 commercial tricyclic drugs tested in vivo, the most potent were chlorpromazine and two other chlorinated compounds, prochlorperazine and perphenazine. Tricyclic drugs lacking nitrogen, sulphur, or both in their ring system showed no activity. All compounds phototoxic in the mouse were so in the yeast test as well. Here, however, the thioxanthenes (lacking nitrogen) were also highly active.

Animals↗
PubMed1976

[The influence of neuroleptic drugs on urinary excretion of non-protein nitrogen (author's transl)].

During treatment with thioxanthenes or phenothiazines of schizophrenic patients non-protein nitrogen in urine was measured. The values were calculated in relation to the excretion of creatinine. a) Flupentixol or fluphenazine applied in optimal dosage, increased the excretion of urea and the amino acids asp, glu + gln, and gly. b) Moreover, if the drug induced a parkinsonoid (thioridazine) the excretion of ser and thr was increased, too. The usual desalting procedure by ion-exchanging resins before chromatography increases the contents of several amino acids, e.g. asp, asn, ala, gly, cys, ser, thr, indicating a breakdown of some instable products.

Amino Acids↗