Efficacy of Olyset long-lasting bednets to control transmission of cutaneous leishmaniasis in Iran.

A large-scale intervention field trial of the effect of Olyset long-lasting insecticide-treated bednets on transmission of cutaneous leishmaniasis was carried out in 2 cities in the Islamic Republic of Iran from October 2003 to July 2005. We enrolled 8620 individuals in 3000 households in 6 pairs of sectors in each city. Epidemiological and entomological surveys were carried out pre- and post-intervention. In both cities a statistically significant reduction was found in the incidence of new cases in intervention sectors who received bednets compared with control areas. Entomological surveys showed a reduction in numbers of female Phlebotomus sergenti captured indoors in intervention sectors.

Preliminary field testing of a long-lasting insecticide-treated hammock against Anopheles gambiae and Mansonia spp. (Diptera: Culicidae) in West Africa.

The efficacy of an experimental long-lasting insecticide-treated hammock (LLIH) with a long-lasting treated net used as a blanket and made of the same fabric (polyethylene) was tested in a concrete block experimental hut, against the malaria vector Anopheles gambiae s.l. and the arbovirus vectors and nuisance mosquitoes Mansonia africana (Theobald) and Mansonia uniformis (Theobald). The LLIH was treated with the pyrethroid insecticide permethrin. It was evaluated concurrently with ignited mosquito coils over 20 successive weeks. In total, 2,227 mosquitoes (130 An. gambiae and 2,097 Mansonia spp.) corresponding to 27.8 mosquitoes per trap-night were collected in the untreated hut (control). The repellent effect of both coils and LLIH significantly reduced the number of mosquitoes entering the huts (35- 60%). There was no significant difference between LLIH and mosquito coils in blood-feeding inhibition (93-97%) or in mortality (88-98%). The LLIH is more cost-effective and user-friendly than mosquito coils, which need to be replaced nightly to protect people sleeping indoors from mosquito bites. The effects of LLIH on exophagic vectors also need to be investigated because most people that sleep in hammocks are outdoors.

Dyeing process may alter the efficacy of insecticide-treated nets.

The biological efficacy as judged by mortality against Anopheles gambiae s.s. of three net samples, one white and two colored, treated with deltamethrin by conventional dipping was compared. Efficacy as well as chemical analysis results showed that uptake of insecticide by white net material was much higher than by colored nets. After a single wash, efficacy of colored nets was reduced significantly below 80% mortality, which is the minimum acceptable level for a field application. This unexpected result could be because of either low uptake of insecticide by colored fibers or high alkalinity on the fibers, resulting from the dyeing process (reduction clearing). alpha-Cyanopyrethroids, such as deltamethrin, have a low stability in alkaline conditions and rapidly degrade. Practical implications of this finding are of primary importance because the majority of nets currently purchased by institutional buyers for malaria prevention are colored.

Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: We report the results of the Subcutaneous Administration Propeukin Program (SCAPP) II trial of an outpatient treatment in renal cell carcinoma using interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) administered subcutaneously in combination with fluorouracil (5-FU). The objective of this multicenter trial was to confirm that the combination of IL-2, IFN-alpha, and 5-FU leads to a response rate greater than 20%. PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma were included in this study. During the induction phase of the treatment, which lasted 10 weeks, IL-2 and IFN-alpha were administered subcutaneously three times a week for 8 weeks at doses of 18 MIU and 9 MIU, respectively. During these 8 weeks, every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. After evaluation, responding patients or patients with stable disease (SD) were given maintenance treatment, until disease progression (PD) or the appearance of unacceptable toxicity. Each maintenance cycle consisted of a 2-week treatment followed by a three-week rest period. During treatment, IL-2 and IFN-alpha were administered subcutaneously three times a week at doses of 18 MIU and 9 MIU, respectively. Every Monday, 5-FU was administered at a dose of 750 mg by intravenous infusion over 30 minutes. RESULTS: This trial was closed when the sixth sequential analysis showed the lack of benefit from this combination. At the end of the induction period, of 62 patients, 12 (19%; 95% confidence interval [CI], 10% to 31%) reached an objective response, including one complete response (CR), 16 presented with SD, and 27 showed PD. Twenty-seven patients (43%) developed severe toxicity that required reduction of the planned doses (13 patients), delayed treatment (eight patients), or treatment termination (six patients). Seventeen patients were given maintenance treatment. One- and 2-year survival rates were estimated at 55% and 33%, respectively. The 2-year survival rate was 15% in 11 patients who presented with three poor-prognosis factors and 41% in 51 patients who initially presented with no, one, or two poor-prognosis factors (P = .04). CONCLUSION: As in other recently published studies that used 5-FU, IL-2, and IFN-alpha, the multicenter SCAPP II trial in patients with metastatic renal cell carcinoma generated severe toxicity. This sequential trial failed to confirm the favorable results previously obtained by Atzpodien and Sella with this combination of three drugs. Its efficacy, assessed on the response and survival rates, is near to the results observed in programs that used IL-2 alone given subcutaneously.

A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II.

ALS is a progressive motor neuron disease with no effective treatment. The anti-excitotoxic drug riluzole (100 mg/day) has been shown to decrease mortality and muscular deterioration in ALS patients. To confirm and extend the therapeutic effect of riluzole, we performed a double-blind, placebo-controlled, multicenter, international, dose-ranging (50, 100, 200 mg/day), stratified study in 959 ALS outpatients treated for up to 18 months. Primary efficacy criterion was survival and the effect of treatment was analyzed before (Wilcoxon and log rank tests) and after adjustment on prognostic factors (Cox model). Secondary efficacy criterion was disease progression assessed through change in functional measures. Tracheostomy-free survival rates were: 50.4% (placebo), 55.3% (50 mg riluzole) (p = 0.23, Wilcoxon test; p = 0.25, log-rank test), 56.8% (100 mg riluzole) (p = 0.05, Wilcoxon test; p = 0.076, log-rank test), and 57.8% (200 mg riluzole) (p = 0.061, Wilcoxon test; p = 0.075, log-rank test). At the end of the 18-month study, there was a significant dose-related decrease in risk of death or tracheostomy (p = 0.04). Adjustment for baseline prognostic factors showed a 35% decreased risk of death with the 100-mg dose compared with placebo (p = 0.002). No significant treatment effects were detected for the functional assessments. The most frequent dose-related adverse events included nausea, asthenia, and elevated liver enzyme levels. This study confirms the therapeutic effect of riluzole in a large representative ALS sample, over an 18-month period. Riluzole is well tolerated and decreases the risk of death or tracheostomy in ALS patients.

Left atrial myxoma in the elderly: diagnosis by M-mode and bidimensional echocardiography.

Two cases are reported of left atrial myxoma in elderly patients, diagnosed by combined M-mode and bidimensional echocardiography. One patient was an 80-year-old man presenting with typical signs of mitral obstruction by an atrial tumor. His symptoms were erroneously attributed to chronic bronchitis until an echocardiogram was obtained. The other patient was a 70-year-old woman with atrial fibrillation of one year's duration. Left atrial myxoma, although rarely observed in the elderly, may be diagnosed easily by means of echocardiography. Some cases may prove amenable to surgical treatment.

Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic.

The combined use of a hypnotic and a neuroleptic is a rather frequent situation, encountered especially in the psychiatric sphere. We therefore tested zolpidem and chlorpromazine in six healthy subjects by using a double-blind latin square design. All of them received single doses of 20 mg zolpidem (ZOL), 50 mg chlorpromazine (CPZ) and the combination of ZOL + CPZ. The medication was given as a single dose in the morning and each treatment being separated by a 1-week interval. Zolpidem produced moderate to severe sedation varying according to the subjects. Psychometric performances (manual dexterity, Stroop test), alertness and psychomotricity (visual analogue scales) were reduced up to 3 h after drug intake. Chlorpromazine alone did not have much effect. Combined administration of ZOL and CPZ was rather more effective than ZOL alone. The pharmacokinetics of ZOL or CPZ remained unchanged except for the elimination half-life of CPZ, which increased significantly when administered along with ZOL. No other pharmacodynamic or pharmacokinetic interaction between ZOL and CPZ was evident. The fact that the ZOL and CPZ combination accentuated the pharmacodynamical effects can be explained to result from the summation of each of their own pharmacological effect.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma.

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10(-3) M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016 +/- 143 mumol/l. The mean dose delivered was 13.2 +/- 2 g/m2. The clearance was 49.1 +/- 11.7 ml min-1 m-2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with a t1/2 alpha of 2.66 +/- 0.82 h and a t1/2 beta of 15.69 +/- 8.63 h. The volume of distribution was 0.32 +/- 0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%-21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. The t1/2 alpha and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P < 0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significant different from those of the group of nonsensitive patients.

A Bayesian dosing method for carboplatin given by continuous infusion for 120 h.

Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1 h). We therefore propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were 0.99 +/- 0.10, 1.41 +/- 0.13, and 1.72 +/- 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice, and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a median dose that was 20% higher than the usual dose (484 +/- 190 mg/m2 as compared with 400 mg/m2). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol.

Pharmacokinetic and pharmacodynamic study of suriclone imipramine interaction in man.

Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Caucasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 x 4 Latin-square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine-suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high-performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.

The pharmacokinetics of suriclone after single- and multiple-dose administration in healthy elderly volunteers.

Healthy elderly people aged 70 or more should receive a starting dosage of the anxiolytic drug suriclone half that recommended for younger people; frail or ill elderly people may require further dosage reduction. These conclusions were based on a study of the pharmacokinetics and tolerability of orally administered suriclone after a single dose of 0.2mg and after multiple doses of 0.2mg 3-times daily in 8 male and 8 female healthy elderly volunteers. Informal comparisons of the pharmacokinetic data from this study with studies in younger volunteers showed a 53% decrease in clearance and an 84% increase in elimination half-life. Area under the plasma concentration-time curve (AUC) for suriclone and total antigenic products in the elderly were twice the values in younger volunteers when adjusted for different dosage. There were no significant changes in pulse rate or blood pressure during the study. One person showed a change from sinus rhythm to atrial fibrillation. Six people had transient adverse events including unsteadiness, vomiting, difficulty in reaching for objects, urinary incontinence and sedation.

Bifenthrin: a useful pyrethroid insecticide for treatment of mosquito nets.

Bifenthrin, a pyrethroid insecticide already used in agriculture was evaluated in laboratory conditions against susceptible and pyrethroid resistant mosquitoes, as a potential insecticide for treatment of mosquito nets. Two laboratory strains of Anopheles gambiae s.s. Giles, the major malaria vector in Africa, and two of Culex quinquefasciatus Say, a major pest mosquito in urban areas, were used. Compared with other pyrethroids such as permethrin and deltamethrin, the intrinsic toxicity of bifenthrin, measured by topical application with susceptible strains, was intermediate. By forced tarsal contact on filter papers (cylinder tests) or on netting materials (cone tests), bifenthrin was found slightly more effective against A. gambiae than against C. quinquefasciatus, in terms of mortality and knock-down effect. With free flying mosquitoes (tunnel tests), bifenthrin was very efficient in killing mosquitoes and inhibiting blood feeding. Against the two pyrethroid resistant strains, bifenthrin was relatively efficient against A. gambiae but the impact of resistance was greater with C. quinquefasciatus. In tunnel tests, blood feeding remained almost entirely inhibited with the two species despite resistance. The high mortality of susceptible mosquitoes and excellent blood feeding inhibition of susceptible and resistant strains makes bifenthrin a good candidate for treatment of netting materials, particularly in areas where C. quinquefasciatus, the main nuisance in urban areas, is resistant to pyrethroids. The slower knock-down and lower irritant effect also makes this insecticide especially attractive when a mass killing effect on mosquito populations is expected.

Distribution of organophosphate and carbamate resistance in Culex pipiens quinquefasciatus (Diptera: Culicidae) in West Africa.

The distribution of organophosphate and carbamate resistance was investigated in 33 samples of Culex pipiens quinquefasciatus Say from 25 cities in Côte d'Ivoire and Burkina Faso. Organophosphate resistance levels were higher in Côte d'Ivoire than in Burkina Faso. Chlorpyrifos resistance ratios at LC95 ranged from 4 to 30 times in Côte d'Ivoire and from 3 to 6 times in Burkina Faso. For temephos, ratios ranged from 3 to 18 and from 1 to 2, respectively. Of 27 samples from Côte d'Ivoire, 25 also displayed cross resistance to carbamates as shown by a mortality plateau in bioassays with propoxur and carbosulfan (similar to chlorpyrifos). Cross resistance to organophosphates and carbamates was caused by an insensitive acetylcholinesterase allele (AceR). This gene was absent from Burkina Faso, except in Niangoloko near the Côte d'Ivoire border. Organophosphate resistance also was associated with the presence of A2-B2 overproduced esterases which had higher frequencies in Côte d'Ivoire (75-100%) than in Burkina Faso (40-50%). Two other esterases with the same electrophoretic mobility as C2 from Puerto Rico and B1 from California were identified for the 1st time in West Africa. "C2" was widespread, whereas "B1" was present in only a few mosquitoes from Côte d'Ivoire. These differences in resistance patterns should be taken into consideration in planning urban mosquito control strategies within 2 countries.

Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine.

Zolpidem is a new imidazopyridine derivative acting as a hypnotic which may be prescribed with H2 receptor antagonists in patients with peptic ulcer. A cross-over study (cimetidine, 1 g daily for 19 days; ranitidine, 300 mg daily for 19 days; wash-out period: 20 days) was carried out in six healthy volunteers. Zolpidem, 20 mg was administered orally at 09h00 prior to any treatment and on days 2 and 17 of each treatment period. Antipyrine clearance was also determined before and on day 18 of each treatment period. Under these experimental conditions, the inhibitory effect of cimetidine on the Cyt P-450 mono-oxygenase system has been demonstrated (reduced clearance of antipyrine, p less than 0.01) but the pharmacokinetics of zolpidem did not appear to be modified. Zolpidem induced hypnotic effects for the first 3 h which tend to be prolonged by the combination with cimetidine. Psychometric and pharmacokinetic evaluations did not show significant interactions with either anti-H2 receptor agent following zolpidem administration.

[Value of clinical tests in the diagnosis of breast cancer: report of 2,626 cases]. / Valeur de l'examen clinique dans le diagnostic du cancer du sein: à propos de l'étude de 2,626 observations.

The present study has assessed the value of clinical examination of breast cancers in a retrospective study of 2,626 cases of operated mammary lesions. Anatomopathology is used as basic reference. The fiability of the cancer diagnosis is 94%, its sensitivity is 90% and specificity 96%. The total error only amounts to 6%, with 2/3 false negatives and 1/3 false positives. The errors are for the most part due to the anatomopathologic nature of the tumor, its size, the area of the body it is situated in and also to the examiner and to the of the patient. Nevertheless clinical examination still remains the first diagnostic step, and is indispensable in all breast pathology.

Diversity of malaria in rice growing areas of the Afrotropical region.

It is well known that 'in many instances the rice agrosystem perfectly fits the ecological requirements of pathogens or vectors' and in fact 'malaria, schistosomiasis and Japanese encephalitis are important vector-borne diseases associated with rice production in developing countries' (IRRI, 1987). In spite of these fears, rice cultivation has been on the increase in the African region in response to demographic and economic pressures. However, although rice fields provide suitable breeding places for Anopheles mosquitoes and rice cultivation leads to an increase in the biting rates, the species which are adapted to these sites are not the same in all parts of Africa. Several examples illustrate this phenomenon: An. funestus in the rice fields of Madagascar, An. pharoensis in saline water rice fields in the delta of the Senegal river, An. arabiensis in northern Cameroon and Burundi, An. gambiae Mopti form in the Kou Valley (Burkina Faso) and An. gambiae Savanna form in the rice fields of Kafine near Bouaké (Côte d'Ivoire). The vectorial capacities of these species are not the same and malaria inoculation rates are not necessarily increased in the riceland agroecosystem. The consequences for malaria of introducing rice cultivation depend on the situation before its introduction: it could be worsened in unstable malaria areas but not in stable malaria areas. Therefore, sound epidemiological and entomological knowledge are needed before causing any environmental modifications for agricultural purposes and there should be regular monitoring to avoid any outbreak.

Current distribution of a pyrethroid resistance gene (kdr) in Anopheles gambiae complex from west Africa and further evidence for reproductive isolation of the Mopti form.

In the field, the kdr mutation, involved in pyrethroid resistance, has been found widely distributed in the Savanna form of Anopheles gambiae s.s., but never in wild populations of the Mopti form or An. arabiensis, even in areas where both occur in sympatry with resistant Savanna populations. Under laboratory conditions, Mopti and Savanna forms were fully able to interbreed and the kdr mutation was transmissible from one form to the other. Both forms appeared to be exposed to pyrethroid selection pressure in the field. The absence of the kdr mutation in the Mopti form and the total lack of Mopti-Savanna heterozygotes in field populations provides further evidence of a pre-copulatory barrier to gene flow between these two forms. Molecular markers, including kdr, are powerful tools for studying population genetics and circulation of resistance genes, and should be used through an integrated approach for a better understanding of the speciation process.

First report of the kdr mutation in Anopheles gambiae M form from Burkina Faso, west Africa.

The kdr mutation, conferring resistance to pyrethroid insecticides, has been reported in several West-African populations of Anopheles gambiae S form and in the M form populations from tropical forest of Benin. We report the finding of a single M specimen collected in the rice-field area of Vallée du Kou (Burkina Faso) showing the mutation at the heterozygous state. The monitoring of kdr mutation in An. gambiae forms/species is of paramount importance to implement effective malaria control tools and may greatly improve the knowledge of the relationship between and within An. gambiae populations.

Pyrethroid cross resistance spectrum among populations of Anopheles gambiae s.s. from Côte d'Ivoire.

Field samples of Anopheles gambiae s.s. from Côte d'Ivoire were tested with 5 pyrethroids (cyfluthrin, lambda-cyhalothrin, alpha-cypermethrin, deltamethrin, permethrin), 1 pseudo-pyrethroid (etofenprox), and an organochlorine (DDT). With the use of World Health Organization diagnostic tests, 5 out of 6 samples were found cross-resistant to these insecticides. A strong decrease in knockdown effect and mortality was also observed when testing deltamethrin-impregnated nettings. With a polymerase chain reaction amplification of specific alleles diagnostic test, resistance was found associated with the presence of a kdr mutation. The strong correlation between kdr allelic frequency and resistance to DDT or etofenprox indicated that kdr was the main resistance factor for these 2 insecticides. On the contrary, a lower correlation was observed between kdr frequency and resistance to 4 of the 5 pyrethroids tested, suggesting that another mechanism was also involved, likely a metabolic detoxification. These results point out the necessity to monitor pyrethroid resistance and the presence of kdr before implementation of any impregnated bed-net programs for malaria control.