In vitro chloroquine resistance modulation study on fresh isolates of Brazilian Plasmodium falciparum: intrinsic antimalarial activity of phenothiazine drugs

Phenothiazine drugs - fluphenazine, chlorpromazine, methotrimeprazine and trifluoperazine - were evaluated as modulating agents against Brazilian chloroquine-resistant fresh isolates of Plasmodium falciparum. Aiming to simulate therapeutic schedules, chloroquine was employed at the concentration used for sensitive falciparum malaria treatment and anti-psychotic therapeutic concentrations of the phenothiazine drugs were adopted in two-fold serial dilutions. The in vitro microtechnique for drug susceptibility was employed. Unlike earlier reported data, the phenothiazine modulating effect was not observed. However, all the drugs demonstrated intrinsic antiplasmodial activity in concentrations lower than those described in the literature. In addition, IC50 estimates have been shown to be inferior to the usual anti-psychotic therapeutic concentrations. Statistical analysis also suggested an increase in the parasitaemia rate or, even, a predominant antiparasitic effect of phenothiazine over chloroquine when used in combination.     

THIORIDAZINE (MELLARIL?) IN PSYCHIATRIC PATIENTS

Thioridazine (Mellaril®) was given to 104 psychiatric patients with a variety of illnesses, chiefly schizophrenic reactions. Of 14 patients treated in a double-blind study with successive one-month courses of drug or placebo, nine improved most on the drug and only one on placebo. These results, although limited, confirm a definite therapeutic action for this compound.Nine of 24 patients were significantly improved after treatment with thioridazine for an average of four months following previous treatwith other phenothiazine tranquilizers. Of ten patients treated intensively with thioridazine after they had not responded to other phenothiazine drugs, two were definitely improved and three were slightly improved. Twenty-eight of 56 patients treated from the outset with thioridazine were significantly improved after an average of six months. Most patients received from 100 to 400 mg. daily. These results were comparable to those obtained from other potent phenothiazine tranquilizers. The drug is particularly advantageous for a group of schizophrenic patients who are sometimes made worse by other phenothiazine derivatives or rauwolfia alkaloids. It should also be suitable for treating patients with psychoneuroses and chronic brain syndromes.Only minimal side reactions were observed, chiefly drowsiness, dizziness and nasal stuffiness. Weight gain occurred frequently during treatment.     

Effect of transdermally administered hyoscine methobromide on nocturnal acid secretion in patients with duodenal ulcer.

Use of anticholinergic drugs in treatment of duodenal ulcers is limited by the side effects of widespread parasympathetic blockade evoked by usual therapeutic doses. A study was conducted into the effectiveness of transdermal delivery of hyoscine methobromide using a new system which releases the drug into the circulation at a controlled rate. In six patients whose duodenal ulcer had healed secretion of acid was measured over two nights, the first on placebo and the second on hyoscine methobromide. All patients responded to the active drug and showed a significant inhibition of acid secretion. Four subjects complained of a dry mouth after overnight treatment with hyoscine methobromide; no other side effects were reported. Transdermal delivery of anticholinergic drugs may be useful in maintenance treatment of duodenal ulcers and further clinical tests are indicated.     

Prostaglandin biosynthesis inhibitors and endometriosis

Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebo controlled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylic acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PG-synthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis.     

Outpatient Maintenance of Chronic Schizophrenic Patients with Long-acting Fluphenazine: Double-blind Placebo

A double-blind placebo trial of fluphenazine decanoate, a long-acting phenothiazine, was carried out to determine its value in maintenance therapy of chronic schizophrenic outpatients already established on the drug for a minimum period of eight weeks. In low doses it was significantly more effective than placebo in preventing relapse and admission to hospital. Relapse was accompanied by a resurgence of specifically schizophrenic symptoms and by an increase in abnormalities described by the relatives. There was no difference between the experimental and control groups in the treatment required for depression. The group on active medication required more treatment for Parkinsonism, but this difference did not reach statistical significance.In the context of a well-run special clinic for outpatient follow-up of chronic schizophrenic patients these results confirm the usefulness of long-acting fluphenazine. By inference, the benefit of this treatment highlights the need for adequate community services to deal with the residual chronic disabilities which are characteristic of these patients.     

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.     

“Anticonvulsant Action” of Vitamin D in Epileptic Patients? A Controlled Pilot Study

The frequency of epileptic seizures was observed in a controlled therapeutic trial on 23 epileptic inpatients before and after treatment with vitamin D₂ or placebo in addition to anticonvulsant drugs. The number of seizures was reduced during treatment with vitamin D₂ but not with placebo. The effect was unrelated to changes in serum calcium or magnesium. The results may support the concept that epileptics should be treated prophylactically with vitamin D.     

L-Dopa in Parkinsonism and the Influence of Previous Thalamotomy

A double-blind cross-over trial over 24 weeks (10 weeks on the active remedy, 4 weeks off treatment, and 10 weeks on placebo) of the effect of L-dopa on idiopathic Parkinsonism (paralysis agitans) has shown no difference in the response obtained in patients who had undergone previous stereotaxic ventrolateral thalamotomy and in those who had not. Of the 34 patients (18 men and 16 women) in the trial 18 had been operated on (nine unilateral, nine bilateral operations) and 16 had not. All patients entering the trial were taking anticholinergic drugs in stable dosage and these were continued throughout. The only factor which seemed to limit the response to treatment was pre-existing hypertension. Of 31 patients who completed the 10-week treatment period, 12 showed marked improvement, 15 moderate improvement, and 4 and mild or negligible change. It seems that previous ventrolateral thalamotomy affords some protection against the development of L-dopa-induced involuntary limb movements on the side contralateral to the operation. As found by others, maximum benefit was seen in bradykinesia and rigidity and related features but a significant reduction in tremor was also noted during treatment. Side effects (nausea, hypotension, and involuntary movements) were common but rarely limited the therapeutic response.     

Action of etmozin and ethacizin on dopaminergic adenylate cyclase of the striate system of the brain

The authors studied the effect of phenothiazine and butyrophenone neuroleptics and that of the antiarrhythmic drugs etmozine and etacizine on the dopamine--activated adenylate cyclase of the rabbit brain striatum. It was shown that all the neuroleptics under study prevented the development of the activating effect of dopamine, whereas the antiarrhythmic drugs administered at the same concentrations did not influence adenylate cyclase stimulation with dopamine. The affinity of etmozine and etacizine for dopamine receptors was 15-20 times less than the affinity of the typical neuroleptic trifluoroperazine. It is concluded that application of etmozine and etacizine to the treatment of arrhythmias is not complicated by neuroleptic or other dopaminergic effects of these drugs.     

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE--To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN--Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING--The medical wards of University and City Hospitals, Nottingham. SUBJECTS--1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES--Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS--Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS--Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.     

Thiopropazate Hydrochloride in Persistent Dyskinesia

Thiopropazate (Dartalan) was found to be significantly more effective than a placebo in relieving dyskinesia in 23 patients with functional psychosis and persistent dyskinesia associated with prolonged phenothiazine therapy. Each patient whose dyskinesia had persisted unchanged for at least one month after phenothiazine withdrawal received thiopropazate by mouth for three weeks and the placebo for a similar period. Patients were evaluated before the trial, at three weeks, and at six weeks.The drug also improved psychotic behaviour. Possible side effects, which were generally mild, were noted in eight patients, of whom six had Parkinsonism and four drowsiness. None had side effects while on the placebo.The findings indicate that thiopropazate is of value in persistent dyskinesia associated with prolonged phenothiazine intake—a condition hitherto unresponsive to other treatment. Further research is required to determine the long-term effectiveness of the drug.     

Dietary amino acid taurine ameliorates liver injury in chronic hepatitis patients

The effect of dietary amino acid taurine on the liver function of chronic hepatitis patients was investigated. The 24 chronic hepatitis patients with 2-5 times over normal activities of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were selected and equally divided into taurine treatment and control groups. In taurine treatment group, each patient took 2 g taurine 3 times a day for three months, and then stopped treatment for 1 month. Patients taking placebo without taurine for 4 months served as a control group. ALT and AST activities and levels of cholesterol, triglyceride and thiobarbituric acid relative substances of serum plasma in the taurine group were all decreased at the end of three month treatment. The study suggested that dietary amino acid taurine may ameliorate liver injury for chronic hepatitis patients.     

Growth and metabolism of Penicillium lilacinum Thom. with reference to the effects of riboflavin and nicotinic acid

Summary Growth and metabolism of Penicillium lilacinum were followed over a period of incubation of 18 days on a high sugar-salts medium favourable for fat formation with or without the addition of riboflavin or nicotinic acid to the growth medium. The high sugar content in the culture media helped rapid uptake and vigorous growth. Nicotinic acid and to a less extent riboflavin, enhanced sugar and nitrogen absorption and the rate of building up of cellular material in consequence. Nitrogenous compounds have been released from the mycelial cells into the external media before growth started to decline; the release being earlier and more rapid in the presence of nicotinic acid. It is suggested that the release of nitrogenous compounds in this case is not purely due to autolysis, and that nicotinic acid affected this process by increasing cell permeability. Both riboflavin and nicotinic acid accelerated the accumulation of carbohydrates and fat in the mycelium. Fat formation became active only when the nitrogen content of the culture media dropped to a very low value and the building of nitrogenous compounds almost stopped. The inverse relationship between synthesis of fat and of complicated nitrogenous compounds was quite clear under the present experimental conditions and was not affected by either riboflavin or nicotinic acid.     

Unconventional ligands and modulators of nicotinic receptors

Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and beta-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.     

Choreoathetotic Movement Disorder in Alcoholism

A syndrome of choreoathetosis in association with alcoholism has been found in 12 patients. It appeared to occur more often in women, was transient, and may have been associated with alcohol withdrawal. It was not associated with gross liver disease, phenothiazine administration, or familial chorea, and no consistent abnormalities in whole blood thiamine or nicotinic acid, in serum magnesium, or in serum vitamin B₁₂ levels were present.     

Double blind placebo controlled trial of pulse treatment with methylprednisolone combined with disease modifying drugs in rheumatoid arthritis.

OBJECTIVE--To assess whether monthly treatment with intravenous methylprednisolone enhances or accelerates the effect of disease modifying drugs in patients with rheumatoid arthritis. DESIGN--A 12 month double blind, placebo controlled, multicentre trial in which patients with active rheumatoid arthritis were randomly allocated to receive pulses of either methylprednisolone or saline every four weeks for six months. At the start of the pulse treatment all patients were started on penicillamine or azathioprine. SETTING--Four rheumatology departments in Denmark. PATIENTS--97 Patients (71 women, 26 men) aged 23-84 (mean 60) who had active rheumatoid arthritis of at least four weeks'' duration despite treatment with non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES--Monthly clinical recording of morning stiffness, number of tender and swollen joints, blinded observers'' evaluation of therapeutic effect, and patients'' self assessed condition. Concomitant laboratory measurements of erythrocyte sedimentation rate and concentrations of C reactive protein and haemoglobin. Radiography to determine the number of erosions at the start of treatment and after 12 months. RESULTS--57 Patients completed the trial, taking the same disease modifying drug throughout. Evaluation four weeks after each pulse treatment and at 12 month follow up showed no significant differences between the methylprednisolone and placebo groups in any of the clinical or laboratory variables. Radiography showed the same degree of progression of erosions in both groups. Evaluation of the total data on 97 patients and on the 57 who completed the trial showed the same lack of significance between the treatment groups. CONCLUSIONS--Intravenous pulse treatment with steroids can be recommended only for rapid temporary relief of flares of disease in patients with rheumatoid arthritis. The response is short lived. Repeated pulses of methylprednisolone at four week intervals do not improve the results of treatment with drugs that induce remission such as penicillamine and azathioprine.     

Formation of vitamins by pure cultures of tempe moulds and bacteria during the tempe solid substrate fermentation

The formation of water soluble vitamins (vitamin B₁₂, vitamin B₆, riboflavin, thiamine, nicotinic acid and nicotinamide) during the tempe solid substrate fermentation was investigated. The role of several strains of Rhizopus oligosporus, R. arrhizus , and R. stolonifer and the role of several bacteria in the vitamin formation process were checked. All fungal and bacterial strains were isolated from Indonesian tempe and soaking water samples. The Rhizopus strains formed riboflavin, nicotinic acid, nicotinamide and vitamin B₆. The final concentrations of these substances depended on the different strains involved and on the fermentation time. Isolates of R. oligosporus were generally the best vitamin formers. The moulds did not produce physiologically active vitamin B₁₂. The thiamine content decreased during fermentation. The addition of bacteria, which had been selected in a screening for vitamin B₁₂ production, resulted in an increase of physiologically active vitamin B₁₂. Citrobacter freundii and Klebsiella pneumoniae showed the best formation capabilities. Furthermore, the bacteria produced riboflavin and vitamin B₆ in addition to the moulds. The influence of Rhizopus on the vitamin B₁₂ formation of Cit. freundii was also investigated. The vitamin content of tempe that was fermented with the mould and the bacterium was three times as high as a control fermentation with Cit. freundii only.     

Varenicline Effects on Smoking,Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial

Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer.Trial Registration: ClinicalTrials.gov 00802919     

Correlations between activated charcoal, Fe-EDTA and other organic media ingredients in cultured anthers of Anemone canadensis

The effects of activated charcoal and organic substances on embryogenesis in anther cultures of Anemone canadensis L. were studied. Embryogenesis was independent of the presence in the culture medium of glycine, nicotinic acid, pyridoxine, thiamine, folic acid, d -biotin or myoinositol. Absence of Fe-EDTA totally inhibited embryogenesis. Activated charcoal (AC) adsorbed Fe-EDTA, pyridoxine, folic acid and nicotinic acid in a double-layer medium almost completely within 24 h. If petri dishes according to the souble-layer method were stored overnight or more, embryogenesis was totally inhibited, probably due to adsorbtion of Fe-EDTA by AC. It was shown that AC itself released some yet unidentified substance(s) that stimulated embryogenesis. The addition of polyvinylpolypyrrolidone (PVPP) to the culture medium stimulated embryogenesis, but PVPP was not as efficient as AC. Embryogenesis was totally inhibited when AC and PVPP were applied together. Minor additions of ethanol to the culture medium stimulated embryogenesis when AC was present, but no such effect was obtained when AC was absent.     

Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients.

Sulphasalazine has been reported to be effective in ankylosing spondylitis with peripheral arthritis, but its efficacy in spondylitis is unknown. Thus 60 patients with active ankylosing spondylitis without peripheral arthritis or gastrointestinal symptoms were randomly allocated to one of two therapeutic groups. One group received 2 g sulphasalazine daily for six months and the other a placebo. Thirteen patients (six given placebo and seven given sulphasalazine) dropped out of the trial and were considered to be treatment failures. After six months'' follow up efficacy was rated as good or very good by 15 of the 30 patients given sulphasalazine and by only six of the 30 given placebo (p less than 0.02). Furthermore, in the patients given sulphasalazine the daily consumption of non-steroidal anti-inflammatory drugs, functional index, and plasma IgG concentrations had fallen significantly. These data suggest that sulphasalazine may be a safe and effective treatment for spondylitis in ankylosing spondylitis.