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W H Wernsdorfer

Publications and source records attributed to W H Wernsdorfer.

At least 19 recordsLinked to original sources
PubMed1999

Synergism of benflumetol and artemether in Plasmodium falciparum.

Using a continuous in vitro culture system, the sensitivity of Plasmodium falciparum to artemether and a new antimalarial drug, benflumetol (lumefantrine), alone and in combination, was investigated with a multiresistant strain (T-996) from Thailand and a chloroquine-resistant strain (LS-21) from India. Both strains showed similar 50% inhibitory concentration (IC50) levels with artemether alone or benflumetol alone, but the IC90 was higher in strain T-996 compared with strain LS-21: for artemether, 34.45 and 7.11 nmol/L (10.28 and 2.12 ng/ml of erythrocyte-medium mixture [EMM]), and for benflumetol, 293.03 and 95.61 nmol/L (154.69 and 50.47 ng/ml of EMM). When tested in association at artemether:benflumetol (mol: mol) ratios between 100:1 and 1:100, substantial synergism was seen in both strains, especially at the IC90 and IC99 levels. This phenomenon resembles the synergistic interaction of artemisinin derivatives and mefloquine, first observed in laboratory models and later confirmed in clinical experience.

Animals↗
PubMed1999

In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.

Reported are the in vitro susceptibilities of Plasmodium falciparum to artesunate, mefloquine, quinine and chloroquine of 86 isolates and to dihydroartemisinin of 45 isolates collected from areas of high resistance to mefloquine within Thailand near the borders with Myanmar and Cambodia, and from southern Thailand where P. falciparum is generally still sensitive to mefloquine. All the isolates were highly sensitive to artesunate, but the geometric mean IC50S were higher in isolates from the Thai-Myanmar and Thai-Cambodian borders than in those from southern Thailand. The IC50S for mefloquine and artesunate were strongly correlated (Pearson r = 0.605; n = 86; P < 0.00001). As expected, the in vitro sensitivities to dihydroartemisinin and artesunate were similar and strongly correlated (at IC50, Pearson r = 0.695; n = 45; P < 0.00002). The correlation between the activity of mefloquine and artesunate requires further investigation in order to determine the potential for development of cross-resistance in nature. Our results suggest that combination with mefloquine is not the ideal way of protecting the usefulness of artemisinin and its derivatives. A search for more suitable partner drugs to these compounds and careful regulation of their use are necessary in the interest of ensuring their long therapeutic life span.

Adolescent↗
PubMed1998

Activity of benflumetol and its enantiomers in fresh isolates of Plasmodium falciparum from East Africa.

Benflumetol, a novel antimalarial compound belonging to the fluorenes (2,3-benzindenes), has high blood schizontocidal activity, in vitro and in vivo, against mammalian plasmodia, including chloroquine-resistant Plasmodium falciparum. Due to its molecular structure benflumetol occurs in the dextrorotatory and the laevorotatory form. Normal synthesis yields the racemate of both enantiomers. Enantiomers of some antimalarial drugs possess different specific activity. It was therefore of interest to compare the response of P. falciparum to the enantiomers and the racemate of benflumetol in a variety of fresh, natural isolates. Measuring the concentration-specific inhibition of schizont maturation, the parallel investigation of 29 isolates produced no evidence of substantial activity differences between (+)-benflumetol, (-)-benflumetol and racemic benflumetol, the mean EC-50 values being 8.87, 9.71 and 12.44 nmol/l blood-medium-mixture, respectively.

Animals↗
PubMed1998

Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand.

Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria. Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose pentoxifylline (1.67 mg/kg/hr). All 45 patients had one or more manifestations of severe malaria such as cerebral malaria (n = 18), renal failure requiring hemodialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). The overall severity was comparable in the three groups. Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients. In addition, a number of subsidiary outcome variables were examined in specific subgroups, including the recovery time from coma for patients with cerebral malaria, the duration of intubation in patients with respiratory distress, the number of hemodialysis treatments needed for patients with acute renal failure, and the number of units of blood administered to patients requiring transfusion. Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment. No significant differences among the three treatment groups were found for any of the outcome variables examined. We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit.

Adolescent↗
PubMed1997

A malariometric survey in a rural community in the Muheza district, Tanzania: age profiles in the development of humoral immune responses.

A malariometric survey was carried out in a rural community situated in a malaria holoendemic endemic area of Tanzania. A random sample (n = 228) of different age groups was taken to elucidate the association between anti-Pf155/RESA and anti-Pf332 antibody responses and classical malaria indices. Parasitaemia, fever, splenomegaly, haematocrit and antimalarial consumption were assessed. Antibody responses against Pf155/RESA and Pf332 peptides were determined by ELISA. The age profiles of parasite density, splenomegaly, fever, haematocrit values and prevalence of antibody responses indicated intensive malaria exposure and the highest impact of malaria in small children. Forty-five percent of the study population had detectable chloroquine and desethyl-chloroquine blood levels, and the highest frequency and concentrations were recorded in the 12-23 months old. There was no significant association between the presence of drug and parasite density in the different age groups, although in the < 15 years old there was lower parasite prevalence among the children positive for drug in their blood (P < 0.05). High prevalence of antibody responses to all antigens was observed already at an early age, but the mean anti-Pf155/RESA and anti-Pf332 antibody levels increased significantly only in the adult group (P < 0.01). Significantly lower mean parasite densities were observed in high responders to Pf155/RESA and Pf332 peptides for the > or = 10 years old. For the 1-9 years, a similar difference was only observed in the high responders to Pf332. For the whole material, anti-Pf155/RESA and anti-Pf332 antibody levels correlated positively with age. When the effect of age was allowed for in analysing the relationship between parasite density and antibody level against the different antigens, a significant negative correlation was found only with regard to Pf332 in the > = 10 years age group. These results suggest that anti-Pf332 antibodies appear to be a better indicator for antiparasitic immunity, but both antigens are important for immune protection.

Adolescent↗
PubMed1997

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers.

AIMS: To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers. METHODS: Six healthy male Malaysian subjects were given a single oral dose of 200 mg artemether. Blood samples were collected to 72 h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electro-chemical detection in the reductive mode. RESULTS: Mean (+/- s.d.) maximum concentrations of ARM, 310 +/- 153 micrograms l-1, were reached 1.88 +/- 0.21 h after drug intake. The mean elimination half-life was 2.00 +/- 0.59 h, and the mean AUC 671 +/- 271 micrograms l-1 h. The mean Cmax of DHA, 273 +/- 64 micrograms l-1 was observed at 1.92 +/- 0.13 h. The mean AUC of DHA was 753 +/- 233 micrograms h l-1'. ARM and DHA were stable at < or = -20 degrees C for at least 4 months in plasma samples. CONCLUSIONS: The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26 degrees C) it is recommended to store them at a temperature of < or = -20 degrees C as early as possible after sample collection.

Administration, Oral↗
PubMed1996

Determination of a new antimalarial drug, benflumetol, in blood plasma by high-performance liquid chromatography.

A rapid and selective high-performance liquid chromatographic assay for determination of a new antimalarial drug (benflumetol, BFL) is described. After extraction with hexane-diethyl ether (70:30, v/v) from plasma, BFL was analysed using a C18 Partisil 10 ODS-3 reversed-phase stainless steel column and a mobile phase of acetonitrile-0.1 M ammonium acetate (90:10, v/v) adjusted to pH 4.9 with ultraviolet detection at 335 nm. The mean recovery of BFL over a concentration range of 50-400 ng/ml was 96.8 +/- 5.2%. The within-day and day-to-day coefficients of variation were 1.8-4.0 and 1.8-4.2%, respectively. The minimum detectable concentration in plasma for BFL was 5 ng/ml with a C.V. of less than 10%. This method was found to be suitable for clinical pharmacokinetic studies.

Adult↗
PubMed1996

Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand.

One hundred one adult patients with acute uncomplicated falciparum malaria were treated with pyronaridine. All patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection. Sixty-nine patients (Group I) received pyronaridine 1,200 mg over a three-day period and 32 patients (Group II) received 1,800 mg pyronaridine over a five-day period. Cure rates for the two groups were 63% (38 of 60) for Group I and 88% (23 of 26) for Group II (P<0.05). No RII or RIII type response was seen. Mean fever and parasite clearance times were not significantly different in the two groups. The drug was well-tolerated. In vitro drug sensitivity tests of the paired parasite isolates obtained prior to treatment and after recrudescence indicated that the Plasmodium falciparum isolates of the successfully treated patients had a lower mean concentration for 50% inhibition of growth (IC50) and a much narrower range of the individual IC50 values (15.69 +or- 3.82 ng per ml (mean +or- SD)) as compared with those from the recrudescence cases (22.98 +or- 12.05 ng per ml). Nevertheless, there was no evidence of an increase of the IC50 and IC95 values after recrudescence. The results of the study show that pyronaridine alone at a total dose of 1,800 mg given over five days is well-tolerated in patients suffering from acute uncomplicated malaria and has evident activity against multidrug-resistant falciparum malaria. However, it cannot be recommended for use in Thailand as long as the recrudescence rate is as high as 12%. Further studies of its combinations with other antimalarial drugs are needed.

Acute Disease↗
PubMed1995

Malaria epidemiology in the province of Moyen Ogoov, Gabon.

In the course of epidemiological and immunological baseline studies parasitological surveys were conducted, in 1992, in three localities situated in our near rain forest in the area of Lambaréné, Gabon, western Central Africa. Anopheles gambiae s.s. and A. funestus are considered to be the main vectors of malaria. The three localities represent strata with obvious differences in the intensity of malaria transmission. The lowest parasite rates were recorded in the village around the Albert-Schweitzer-Hospital where environmental sanitation and easy access to diagnostic and therapeutic facilities afford a fair measure of malaria control. The villages of Bellevue and Tchad show a much higher prevalence of Plasmodium falciparum, followed by P. malariae and P. ovale. In all three villages parasite rates and geometric mean parasite densities of P. falciparum showed the age pattern typical for areas with stable, hyperendemic malaria. Analysis by season showed the period of the long rains to be the epidemiologically calmest while the dry season and even more the short rainy season produced an increase of parasite rates and densities. In Tchad, the most affected of the three villages, the parasite rates in female adults were significantly lower than in male adults. This was accompanied by lower parasite densities in female adults.

Adolescent↗
PubMed1994

Epidemiology of drug resistance in malaria.

In the late 1950's chloroquine resistance to Plasmodium falciparum occurred in South America and on the Indochina Subcontinent. Since then it has conquered most of the areas where the parasite species is endemic. This has necessitated the use of alternative drugs such as sulphonamide-pyrimethamine combinations, quinine/tetracyclines, mefloquine, halofantrine, and recently also artemisinin-based compounds. In wide areas of South-east Asia, western Oceania and South America sulphonamide-pyrimethamine combinations have lost adequate efficacy. The situation is most serious in the Thai/Cambodia and Thai/Myanmar border areas where multiresistance necessitated the shift to the last line drug, i.e., the artemisinin derivatives. Selection of resistant parasites due to drug pressure, and their subsequent propagation by local transmission and migration of reservoirs are key factors in the dynamics of drug resistance. Selection is the result of the interplay of parasite, drug and human host, and is largely influenced by immune factors and the pharmacokinetics and pharmacodynamics of the drug. Spread of resistance is determined by eco-epidemiological factors among which migration and vectorial parameters play a major role. Rational drug use, especially adequate, monitored, therapeutic administration according to strict criteria, should curb the onset and spread of resistance, but this concept may not be readily accepted by health services whose primary goal is clinical amelioration of the disease rather than the more stringent target of epidemiologically desirable results.

Animals↗
PubMed1994

A symposium on containment of mefloquine-resistant falciparum malaria in Southeast Asia with special reference to border malaria.

Important questions related to the factors responsible for and contributing to the origin and spread of multi-drug resistant falciparum malaria at the Thai-Cambodian and Thai-Myanmar border areas are discussed, including the current geographical distribution of multi-drug resistance and the prevention and control of this phenomenon. Specific recommendations are made on epidemiological surveillance, drug deployment, vector control, and the problem of migration which plays a major role in the dissemination of resistant parasite populations. The recent advent of mefloquine resistance of P. falciparum in Thailand may serve as fair warning in the absence of stern measures for preventing the occurrence of resistance to the next and currently last line of antimalaria drugs, especially those with a long half-life, in areas with intensive, uncontrolled malaria transmission, such as tropical Africa.

Aftercare↗
PubMed1994

Drug sensitivity of Plasmodium falciparum in Gabon. Activity correlations between various antimalarials.

The sensitivity of Plasmodium falciparum to chloroquine, mefloquine, quinine, halofantrine, and sulfadoxine/pyrimethamine has been investigated at Lambaréné, in the Gabonese rain forest, between April and September 1992. WHO standard micro in vitro tests were performed. Of 43 isolates tested for response to chloroquine all were resistant to the drug with mean EC 50 and EC 90 values of 1.86 and 4.18 mumol/l blood, respectively, indicating the highest degree of resistance ever reported from Central Africa. With sulfadoxine/pyrimethamine 19 out of 27 isolates showed 90% inhibition of schizont maturation at a pyrimethamine concentration of at least 75 nmol/l blood medium mixture, indicating 30% of resistance to sulfadoxine/pyrimethamine. In contrast all isolates tested were fully inhibited by mefloquine at 3.2 mumol/l blood (40 isolates), quinine at 5.12 mumol/l blood medium mixture (41 isolates) and halofantrine at 3 nmol/l blood medium mixture (40 isolates) indicating full sensitivity to these drugs. A significant positive correlation was found between responses to quinine and mefloquine. The response to halofantrine was positively correlated with the responses to quinine and mefloquine, in the case of chloroquine and halofantrine an inverse relationship was observed. Compared with previous data from Gabon, the findings suggest a substantial increase of chloroquine resistance, in contrast to reports from neighbouring countries, which show stabilising or even declining chloroquine resistance patterns.

Animals↗
PubMed1992

Emergence of multidrug-resistant Plasmodium falciparum in Thailand: in vitro tracking.

Mefloquine was introduced into Thailand in 1985 for the treatment of Plasmodium falciparum infection. Recently, clinical failure of mefloquine was observed in southeastern Thailand, where an epidemic of falciparum malaria occurred. Beginning in 1984 and continuing until 1989, in vitro monitoring of P. falciparum isolates from Borai, a border district in the southeastern part of the country, showed a progressive decrease in mefloquine sensitivity until 1989; in 1990, the degree and prevalence of resistance accelerated. A similar pattern of resistance was observed for halofantrine, an antimalarial drug not yet commercially available in Thailand. In vitro sensitivity patterns of mefloquine and halofantrine elsewhere in the country remained relatively unchanged. These observations suggest a serious deterioration in available drugs for the treatment of falciparum malaria in southeastern Thailand that is predicted to spread throughout the country and Southeast Asia.

Animals↗
PubMed1992

Malaria in infants whose mothers received chemoprophylaxis: response to amodiaquine therapy.

In October 1988, a project was implemented for assessing the malaria chemoprophylactic efficacy of weekly chloroquine (CQ) and daily proguanil (PROG) during pregnancy in Muheza-Tanzania. Resultant CQ and PROG-cohorts of infants were followed up for prompt diagnosis and treatment of malaria. Infections were primarily treated with 25 mg base amodiaquine/kg over 3 days. By September 1990, 49 and 60 infants from PROG and CQ cohorts respectively had completed one year follow up. Thirty-five (71%) infants of PROG and 44 (73%) for CQ-cohort were infected with malaria before 3 months of age. The one year mean infection episode rates were 7 (PROG-cohort) and 6.6 (CQ-cohort). Amodiaquine cleared 209 (80%) of PROG's total infections and 224 (81%) for CQ-cohort, and significantly reduced the infection load among clearance failures. Clearance failures had high pre-treatment parasite densities whilst post-treatment densities were higher in the CQ-cohort than PROG-cohort. Low malaria immunity and chloroquine's long residence time could explain these differences. We conclude that early infancy malaria is common and should always be suspected, looked for and adequately treated. Amodiaquine is better than chloroquine for malaria primary therapy during infancy and early childhood.

Administration, Oral↗
PubMed1992

The biological and epidemiological basis of drug resistance in malaria parasites.

Natural populations of Plasmodium falciparum without previous drug exposure are mixtures of individual parasites with different levels of response to a specific medicament. Exposure to sublethal drug concentrations will eliminate the highly and moderately sensitive individuals. The less sensitive part of the parasite population is being selected and given the opportunity of propagating. Underdosed mass drug administration and subcurative medication have this direct effect. An indirect effect with the same result is observed with drugs having a long half-life, where new infections invade the blood while subtherapeutic residual drug concentrations are still present. This militates against the use of drugs with long half-life in areas with intensive malaria transmission, and for a rational therapeutic use of alternative antimalarials based on reliable microscopic diagnosis, adequate dose regimens, post-treatment follow-up, further alternative treatment of recrudescences with the objective of radical cure.

Animals↗
PubMed1991

The dynamics of drug resistance in Plasmodium falciparum.

Drug resistance of Plasmodium falciparum is not a recent phenomenon, but it became a major problem when the parasite became resistant to chloroquine, the cheapest and initially the most effective antimalarial compound that could be used for treatment and suppression. In some areas this problem is compounded by resistance to the first line of alternative drugs, and rapid loss of sensitivity to the next line. The dynamics of drug resistance are regulated mainly by drug related selection pressure and intensity of malaria transmission. Mass drug administration in its various forms, and insufficient treatment are obviously the most important motors of selection.

Animals↗