Effectiveness of alpha,beta-arteether in acute falciparum malaria.

With the emergence of widespread chloroquine resistance and a world-wide scarcity of quinine, a search for newer antimalarial drugs has become imperative. Different derivatives of qinghaosu have been successfully tried. alpha,beta-Arteether, an ethyl derivative of qinghaosu, was administered to 51 patients with Plasmodium falciparum malaria, in a dose of 150 mg intramuscularly once a day on 3 consecutive days. Complete parasite clearance from the peripheral blood was observed in 80% of the patients at 48 h and in 98% at 72 h. The median parasite clearance time was 2 d (range 1-4 d). 65% of the patients became afebrile within 48 h and 81% by 72 h. The mean fever clearance time was 52.04 h (standard deviation 27.09). No side effect was seen. Patients were followed-up for 4 weeks; 7 were readmitted with P. falciparum infection but it could not be ascertained definitely whether these cases were reinfections or recrudescences. alpha-beta Arteether was a safe, effective and convenient drug for treating P. falciparum malaria. This is the first clinical study with arteether in falciparum malaria.

Pharmacokinetics of centchroman in healthy female subjects after oral administration.

The pharmacokinetics of centchroman, a non-steroidal antifertility agent, were assessed in serum of eleven healthy female subjects after a single 30 mg oral dose. Maximum serum concentration (Cmax) of 55.53 (s.d., 15.45) microgram/L was attained at 5.18 (s.d., 1.78) h after oral administration. The concentration-time profile was best described by a two-compartment open model with bi-exponential disposition functions. The mean terminal elimination half-life (t1/2) was 165 (s.d., 49) h with a clearance of 6.17 (s.d., 1.67) L/h and volume of distribution of 1420 (s.d., 478) L. Comparison of the pharmacokinetic parameters of this study with those obtained after a single 60 mg oral dose did not show statistically significant differences in the rate of absorption, distribution and elimination. The Cmax and AUC0-infinity were dose-dependent. Thus, the absorption and disposition of centchroman are of first-order, reproducible and dose-dependent.

Centchroman: a new non-steroidal oral contraceptive in human milk.

Centchroman, a non-steroidal oral contraceptive drug, was given to 13 nursing mothers comprising two groups. Each participant in group I (n = 8) received a single 30 mg dose, and in group II (n = 5) each participant received a 30 mg twice a week dose for twelve weeks. Simultaneous blood and milk samples were collected and analyzed for the parent drug by high performance liquid chromatography. In the single dose study (group I), the mean +/- peak centchroman concentrations in milk and serum were 78.7 +/- 28.4 and 63.6 +/- 23.6 ng/ml with milk-to-serum (M/S) ratio of 1.4 +/- 0.9. There was no significant increase in centchroman concentrations in milk after multiple dosing (group II). However, serum concentrations reached up to 112.5 ng/ml at 6 h after the 13th dose. Average M/S ratios were insignificantly different at trough (prior to next dose) and at peak (4-6 h after dose) centchroman levels. Additionally, the breast milk and serum centchroman concentrations showed a significant correlation (r = 0.64, P < 0.01), indicating that the amount of centchroman excreted into breast milk is dependent on serum concentrations. The weekly dose (% of the maternal dose) of centchroman ingested by the breast-fed infant at peak maternal serum and milk levels was in the range of 0.4 to 11.5%, assuming a weekly milk uptake of 1.05 l/kg. There was no significant difference in the dose ingested by the infants between the two dosing groups. These levels of centchroman passing into breast milk and subsequent exposure to the infants are unlikely to be of any physiological consequence.

Optimization of contraceptive dosage regimen of Centchroman.

Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of centchroman and its active metabolite, 7-desmethyl centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception.

Clinical pharmacological studies on centpropazine--a new antidepressant compound.

Single oral doses of 10 to 160 mg centpropazine, a new antidepressant (synthesized by CDRI, Lucknow, India) were administered to groups of 4-5 male volunteers, each dose being interspersed with placebo in a double blind, non-crossover study by random distribution. The drug was well tolerated. Drowsiness, heaviness, weakness and/or headache were reported only at doses of 120 mg and above. No adverse effect was noted in various laboratory tests, ECG or vital parameters. In a multiple dose study, volunteers received 40 or 80 mg centpropazine daily for 4 wk. Mild restlessness and insomnia were observed in some subjects receiving 80 mg dose. In this study also no effect was observed in various laboratory tests, ECG or vital parameters.

Efficacy of alpha,beta-arteether in acute uncomplicated P. falciparum malaria.

A phase-III clinical trial was conducted in 50 patients (42M + 8F) with acute uncomplicated falciparum malaria from Delhi during the period of September to November 1995. Their mean age was 27.2 years, and the mean parasitaemia on day 0 was 0.65%. Patients were hospitalized and treated with a new ethyl derivative of artemisinin developed at CDRI called alpha, beta-arteether, at the dosage of 150 mg l/M for three consecutive days. Peripheral smears were examined every day for 4 days and then weekly up to 28 days. The results of the study showed that the mean parasite and fever clearance times were respectively 19.94 +/- 6.87 and 37.81 +/- 21.67 hours. Within 48 h, 70% of the cases became afebrile and the peripheral smear was negative in 100% of the cases. The drug was well tolerated. Three cases (6%) had recrudescence within 28 days. It is concluded that alpha, beta-arteether is a safe, effective and rapidly acting antimalarial.

Effectiveness of alpha-beta arteether in clearing Plasmodium falciparum parasitemia in central India (Madhya Pradesh).

Forty-six patients (25 Females + 21 Males) of uncomplicated Plasmodium falciparum in districts Jabalpur and Mandla of central India (Madhya Pradesh) were administered alpha-beta arteether (an ethyl derivative of qinghaosu), intramuscularly for 3 consecutive days (150 mg once a day). The results revealed that there was rapid control of fever in all the patients without administration of any antipyretic drug. The mean parasite clearance time was 30.78 +/- 10.92 hours and recrudescence/reinfection rate was 6.7% within 28 days. Study indicates that arteether, besides being a potent and fast acting schizontocidal drug, also exhibited gametocytocidal action on P. falciparum.

Clinical trials with gugulipid. A new hypolipidaemic agent.

Multicentric clinical trials of the efficacy of gugulipid conducted at Bombay, Bangalore, Delhi, Jaipur, Lucknow, Nagpur and Varanasi have been reported. Two hundred and five patients completed 12 week open trial with gugulipid in a dose of 500 mg tds after 8 week diet and placebo therapy. One patient showed gastrointestinal symptoms which did not necessitate withdrawal of the drug. A significant lowering of serum cholesterol (av. 23.6%) and serum triglycerides (av. 22.6%) was observed in 70-80% patients Double-blind, crossover study was completed in 125 patients with gugulipid therapy and in 108 patients with clofibrate therapy. Two patients had flu-like syndrome with clofibrate and opted out from the study. With gugulipid the average fall in serum cholesterol and triglycerides was 11 and 16.8% respectively and with clofibrate 10 and 21.6% respectively. The lipid lowering effect of both drugs became evident 3-4 week after starting the drug and had no relationship with age, sex, and concomitant drug intake. Hypercholesterolaemic patients responded better to gugulipid therapy than hypertriglyceridaemic patients who responded better to clofibrate therapy. In mixed hyperlipidaemic patients response to both drugs was comparable. HDL-cholesterol was increased in 60% cases who responded to gugulipid therapy. Clofibrate had no effect on HDL-cholesterol. A significant decrease in LDL-cholesterol was observed in the responder group to both drugs.

Post-marketing surveillance of arteether in malaria.

OBJECTIVE: To undertake post-marketing surveillance (PMS) of arteether (E-Mal) with the aim of obtaining feedback from clinicians regarding its safety, tolerability, efficacy and adverse event profile in patients of P. falciparum malaria. METHOD: Post-marketing surveillance proforma to collect data from clinicians using arteether (E-Mal) was provided to institutions/nursing homes and hospitals where Arteether (E-Mal) was available for use in treatment of P. falciparum malaria. These clinicians were informed about the need and relevance of providing this feedback regarding their reexperience on E-Mal therapy on predesigned proforma. Duly filled proformas were received by Central Drug Research Institute, Lucknow for data analysis, documentation and conclusions regarding E-Mal therapy. RESULT: A total of 300 reports were received for analysis from states of Bihar, Gujarat, Madhya Pradesh, Maharashtra, Rajasthan and Uttar Pradesh. The results show that 294 cases (98%) were cured, five cases improved and one patient did not show any change in the clinical status. The side effects (headache, nausea, vomiting and giddiness) reported in the proforma of 14 cases were mild in nature and no causal relationship with arteether could be ascertained. CONCLUSION: An indepth analysis of these 300 reports confirmed the safety, highlighted excellent tolerability and further proved the efficacy of three-day schedule of arteether (IMI) for treatment of malaria. Arteether should not be used in P. Vivax malaria (E-Mal) except when smear is positive for both (P. falciparum and P. vivax). In such a situation risk-benefit should be carefully evaluated before advocating the use of E-Mal therapy. The post-marketing surveillance is continuing and it is hoped that with more feedback from the clinicians from various parts of the country PMS data on this novel antimalarial drug (E-Mal) would further be documented.

A multicentric study with arteether in patients of uncomplicated falciparum malaria.

Two hundred and sixty seven patients of uncomplicated P. falciparum malaria completed study in a multicentric phase III clinical trial of Arteether. Arteether was given intramuscularly in a dose of 150 mg daily for three consecutive days. Each patient was followed upto 28 days of alpha, beta arteether therapy. The cure rate was 97% with fever clearance time between 1-7 days (24-168 hours) and parasite clearance time between 1-3 days (24-72 hours). Parasite reappearance rate was found to be 3% and reported at only three of the centres. Following the treatment no adverse effect was observed on haematological, biochemical and vital clinical parameters.

Multicentric clinical trials for safety and efficacy evaluation of alpha;beta arteether in complicated P. falciparum malaria.

OBJECTIVE: To evaluate efficacy of alpha;beta arteether in patients of P. falciparum malaria presenting with complications was undertaken in a multicentric clinical trial. METHOD: Each patient who consented to undergo clinical trial with parenteral Arteether was treated with a fixed dose schedule of Arteether given intramuscularly in a dose of 150 mg once a day on three consecutive days. Every patient was followed upto 28 days with clinical, haematological and parasitological monitoring every day upto one week and thereafter at 14, 21 and 28 days. The response was assessed in terms of fever clearance time, parasite clearance time, cure rate and parasite reappearance rate. RESULTS: A total of 211 patients of P. falciparum malaria were included in the study from four centres (Bhilai, Guwahati, Jamshedpur and Rourkela). Results of this study showed that fever clearance time ranged between 24-168 hours, parasite clearance time ranged between 24-120 hours and overall mortality ranged between 4-8.5%. Out of 211, only 14 patients expired during the study, of these, 10 patients expired within first two days i.e. before completing the three day schedule of arteether therapy. Tolerability to arteether injection was good in all these patients and no untoward effects were experienced or reported during the study. Overall cure rate observed in these studies was 93%. CONCLUSION: This study shows a rapid parasite and fever clearance in patients of complicated P. falciparum malaria.

Detection of anti-PPD IgG antibody and PPD-induced delayed type hypersensitivity in anterior uveitis patients.

Present study relates to the results of anti-PPD IgG, anti-A60 and antinuclear antibodies and PPD-induced delayed type hypersensitivity (DTH) in 17 anterior uveitis, (AU) patients. Results of anti-PPD IgG assay revealed detection of higher mean antibody level (O.D. 0.11 +/- 0.06) compared to healthy controls (O.D. 0.04 +/- 0.03), other eye disease controls (O.D. 0.05 +/- 0.003) and leprosy controls (O.D. 0.03 +/- 0.03). Anti-A60 IgM antibody assay revealed insignificant differences in mean antibody levels between various groups. Four of 17(23.5%) AU patients and 1(5.8%) subject each, belonging to other eye disease and healthy control groups had raised anti-nuclear antibody index. Findings of PPD skin test revealed detection of moderate to strong (2 to 4+) reactivity in 14 (82%). AU patients. Conversely, 13(76%) healthy controls and 8(47%) other eye disease controls gave mild (1+) reactivity. Results of this study suggested possible role of hypersensitivity to mycobacterial antigens in pathogenesis of anterior uveitis.

Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment.

BACKGROUND: Brahmi (Bacopa monniera) is a traditional Indian medicinal plant which causes multiple effects on the central nervous system. The standardized extract of this plant has shown enhanced behavioural learning in preclinical studies and enhanced information processing in healthy volunteers. AIM: To study the efficacy of standardized Bacopa monniera extract (SBME) in subjects with age-associated memory impairment (AAMI) without any evidence of dementia or psychiatric disorder. METHODS: A double-blind, placebo-controlled randomized study design was employed. The subjects received either 125 mg of SBME or placebo twice a day for a period of 12 weeks followed by a placebo period of another 4 weeks (total duration of the trial 16 weeks). Each subject was evaluated for cognition on a battery of tests comprising mental control, logical memory, digit forward, digit backward, visual reproduction and paired associate learning. RESULTS: SBME produced significant improvement on mental control, logical memory and paired associated learning during the 12-week drug therapy. CONCLUSION: SBME is efficacious in subjects with age-associated memory impairment.

Role of curcumin in idiopathic inflammatory orbital pseudotumours.

The present report, describes for the first time the clinical efficacy of curcumin, the active constituent of rhizomes of Curcuma longa, in the treatment of patients suffering from idiopathic inflammatory orbital pseudotumours. Curcumin was administered orally at a dose of 375 mg/3 times/day orally for a period of 6-22 months in eight patients. They were followed up for a period of 2 years at 3 monthly intervals. Five patients completed the study, out of which four recovered completely and in one patient the swelling regressed completely but some limitation of movement persisted. No side effect was noted in any patient and there was no recurrence. It is suggested that curcumin could be used as a safe and effective drug in the treatment of idiopathic inflammatory orbital pseudotumours.

A comparative efficacy study of centbutindole and haloperidol in schizophrenia.

A double blind study was undertaken to compare the efficacy between centbutindole and haloperidol. A total of 44 patients suffering from schizophrenia diagnosed in accordance to ICD-10 criteria were included. They were randomly assigned into two groups receiving centbutindole (4.5 mg) or haloperidol (15 mg) in two divided doses per day for six weeks. Each patient was evaluated on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale (CGI-S) and UKU side effect scale every week. Five patients (1 patient in centbutindole group, 4 patients in haloperidol group) dropped out due to various reasons. A total of 39 patients (21 patients in centbutindole group and 18 patients in haloperidol group) completed the study. The results revealed an early onset of therapeutic effect with centbutindole for both positive and negative symptoms. However, the efficacy was comparable between centibutindole and haloperidol from 3rd week onwards.

Simultaneous determination of centbutindole and its hydroxy metabolite in serum by high-performance liquid chromatography.

A high-performance liquid chromatographic assay has been developed and validated for the determination of centbutindole and its hydroxy metabolite in serum. The method involves extraction of serum samples with diethyl ether at pH greater than 8, back-extraction into 0.5 M hydrochloric acid and finally again with diethyl ether after addition of 2 M potassium hydroxide. Separation was accomplished by reversed-phase high-performance liquid chromatography on a cyano column with an acetonitrile-phosphate buffer system. The recovery of centbutindole and its metabolite was always greater than 80%. Calibration curves were linear over the concentration range 0.25-5 ng/ml for centbutindole and 0.05-1 ng/ml for the hydroxy metabolite. Although the lower limit of detection was 0.1 ng/ml for centbuntindole and 0.02 ng/ml for the hydroxy metabolite, the reliable limits of quantitation were 0.25 and 0.05 ng/ml, respectively, using 4 ml of serum.

Comparative efficacy of centbutindole & risperidone in schizophrenia.

Centbutindole is a new antipsychotic agent related to butyrophenone group. The drug is dopamine antagonist but it also blocks 5HT(2) receptors. Clinically the drug has passed through phase I, II & III clinical trials successfully and it has shown effective antipsychotic activity in schizophrenic patients. In the present study the drug was compared with risperidone in a double blind manner for a period of 8 weeks to assess the efficacy in schizophrenic patients. Patients of schizophrenia evaluated on PANSS, CGI & UKU side effect rating scale weekly Out of 44 patients included in study, 38 completed the trial. The intergroup comparison of two drugs showed that centbudindole and risperidone have similar onset of antipsychotic action as both the drugs showed significant decrease in the total PANSS score as well as positive syndrome score, negative syndrome score and general psychopathology score from 2nd week onwards. The scores in both the groups showed a steady and significant decline from 2nd week to 8th week of study. The present study showed that centbutindole has similar improvement on clinical global impression with risperidone. The side effect profile was similar in the two drugs except dystonia (5 patients in centbutindole vs 1 patient in risperidone group). The findings of present study shows that Centbutindole could be used as a promising new drug for treatment of schizophrenia in place of a typical antipsychotics as it has shown improvement on negative symptoms similar to risperidone.