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Biomedical subjects

K H Rieckmann

Publications and source records attributed to K H Rieckmann.

At least 19 recordsLinked to original sources
PubMed1992

A bioassay for mefloquine.

A bioassay method that allows for the estimation of serum concentrations of mefloquine is presented. Concentrations obtained by bioassay and high performance liquid chromatography showed a good correlation. This bioassay should be helpful in assessing prophylactic/treatment failures to mefloquine under field conditions.

Animals↗
PubMed1992

An inexpensive and simple method for screening potential antimalarial drugs.

The visual in vitro test proved to be a very useful tool for screening a series of 54 chemical analogues for their antimalarial activity. The test relies on the formation of dark pigment precipitates after an alkaline solution is added to synchronous cultures of Plasmodium falciparum. Pigment is produced when a chemical compound is unable to prevent the maturation of rings to schizonts during incubation. However, in the presence of effective concentrations of a compound, maturation is inhibited and, consequently, pigment and precipitation are not observed. By using this procedure, 36 of the inactive or less active compounds could be excluded from assessment by the radioisotopic hypoxanthine incorporation test. This resulted in a substantial reduction in the overall cost of screening these compounds.

Animals↗
PubMed1991

Pharmacokinetics of halofantrine and n-desbutylhalofantrine in patients with falciparum malaria following a multiple dose regimen of halofantrine.

Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax) = 896 and 491 ng.ml-1; time to reach the Cmax (tmax) = 15 and 56 h; elimination half-life (t1/2) = 91 and 79 h and the mean residence time (MRT) = 71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.

Antimalarials↗
PubMed1990

Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

1. The multiple-dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim (100 mg DDS plus 12.5 mg PYR). 2. After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml-1; elimination half-life (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg-1. The mean t1/2 of MADDS was 22 h. 3. The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4. The drug combination was assessed in vitro by measuring inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)- and PYR-sensitive FC-27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ- and PYR-resistant K1 strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.

Acetylation↗
PubMed1990

Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone.

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. Both FC-27 [chloroquine (CQ)- and pyrimethamine (PYR)-sensitive] and K1 (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.

Adult↗
PubMed1990

Human immunization with attenuated sporozoites.

Studies conducted between 1971 and 1975 showed that attenuated sporozoites can induce protection against human malaria. Three volunteers were protected against challenge with either a homologous or heterologous strain of Plasmodium falciparum after being exposed to a total of 440-987 X-irradiated mosquitos on 6-8 occasions over a period of 10-38 weeks. Protection lasted for at least 8 weeks, but not 16 weeks, after the last immunization with irradiated sporozoites. Another 7 volunteers were not protected against challenge with a homologous strain after exposure to a total of fewer than 200 irradiated mosquitos, infected with either P. falciparum or P. vivax, on 2-4 occasions over a period of 4-17 weeks. These studies provide an encouraging basis for pursuing the development of a sporozoite vaccine against human malaria.

Animals↗
PubMed1989

Plasmodium vivax resistance to chloroquine?

Two soldiers continued weekly prophylaxis with 300 mg chloroquine base on their return to Australia from Papua New Guinea but were not protected against Plasmodium vivax malaria. Both had symptoms and parasitaemia although plasma concentrations of chloroquine were considerably higher than those regarded as adequate for suppression of vivax malaria. Parasitaemia did not clear after one of the patients was treated with 600 mg chloroquine base. The results suggest the emergence of strains of P vivax with a reduced susceptibility to chloroquine.

Acute Disease↗
PubMed1988

Steady-state kinetics of proguanil and its active metabolite, cycloguanil, in man.

The pharmacokinetics of proguanil and its active metabolite, cycloguanil, were determined at steady-state in 6 healthy male volunteers after daily administration of 2 Paludrine tablets (200 mg proguanil hydrochloride). A maximum plasma proguanil concentration of 130.3 +/- 16.0 ng/ml (mean +/- SD) was reached at 3.8 +/- 1.3 h while a maximum cycloguanil concentration of 52.0 +/- 15.2 ng/ml was obtained at 5.3 +/- 1.0 h after dosing. The elimination half-lives of proguanil and cycloguanil were 14.5 +/- 3.0 h and 11.7 +/- 3.1 h, respectively. The plasma clearance of proguanil was 1.43 +/- 0.33 l/h/kg and the apparent volume of distribution was 30.7 +/- 12.3 l/kg. Renal clearance of proguanil (0.33 +/- 0.19 l/h/kg) was about 23% of the plasma clearance and 35.6 +/- 9.6% of the oral dose was recovered as proguanil and cycloguanil.

Administration, Oral↗
PubMed1988

Pharmacokinetics of chlorproguanil in man after a single oral dose of Lapudrine.

The pharmacokinetic parameters of chlorproguanil (Lapudrine) and its active metabolite, chlorcycloguanil, were determined in 6 healthy male volunteers after a single oral dose of 4 Lapudrine tables (80 mg). The mean maximum plasma chlorproguanil concentration was 36.7 +/- (SD) 7.9 ng/ml and was reached at 3.8 +/- 1.3 h. The chlorproguanil elimination half-life was 17.5 +/- 6.7 h and its plasma clearance was 1.28 +/- 0.12 l/h/kg. The mean whole blood to plasma ratio was 3.1 at 4 h after dosing. Chlorcycloguanil could not be quantified in plasma and whole blood at the detection limit of 10 ng/ml using a high-performance liquid chromatographic method. An excretion rate-time plot from urine data shows a rapid (t1/2 = 20 h) and a slow phase (t1/2 = 51 h) in the elimination of chlorcycloguanil. Our findings suggest that the current prophylactic regimen of chlorproguanil hydrochloride (20 mg weekly) may not be optimal in preventing infections with chloroquine-resistant falciparum malaria.

Administration, Oral↗
PubMed1987

Synergistic antimalarial activity of dapsone/dihydrofolate reductase inhibitors and the interaction of antifol, antipyrimidine and antipurine combinations against Plasmodium falciparum in vitro.

Using low folate, low p-aminobenzoic acid medium, 2 isolates of Plasmodium falciparum were tested in vitro against a wide range of antimetabolite compounds with known or potential antimalarial activity. ID50 values (the concentration of compound causing 50% inhibition of [3H]hypoxanthine incorporation) were determined for each compound against both isolates. The compounds tested may affect folate, pyrimidine or purine metabolism in malaria parasites and various combinations of compounds were examined for further synergistic antimalarial effects. The combination of any of the dihydrofolate reductase inhibitors cycloguanil, pyrimethamine or WR 99210 with the sulphone drug dapsone demonstrated strongly synergistic antimalarial activity. Combinations of dihydrofolate reductase inhibitors with the antipyrimidine compounds pyrazofurin or menoctone, or with the antipurine compounds tubercidin, bredinin or hadacidin, or with primaquine, failed to demonstrate synergistic activity. Most combinations of an antipurine with an antipyrimidine compound also failed to show any synergistic effect. However, weak synergism was consistently seen in the tubercidin/pyrazofurin and tubercidin/menoctone combinations. Over the 48 h intraerythrocytic cycle using tightly synchronized parasites, tubercidin demonstrated both a cytotoxic and a cytostatic effect.

Animals↗
PubMed1983

The activity of pyrimethamine and sulphadoxine against Plasmodium falciparum determined by the in vitro microtechnique.

The reported increase of infections of Plasmodium falciparum which are no longer susceptible to a combination of pyrimethamine and sulphadoxine--Fansidar--emphasizes the need for an in vitro test to determine the presence and prevalence of drug-resistant parasites. Studies with the pyrimethamine-sensitive FCB strain and the pyrimethamine-resistant FTA strain showed that the in vitro microtechnique can be used to determine differences in the susceptibility of these two strains to pyrimethamine and to pyrimethamine-sulphadoxine combinations. The FCB strain was almost six times more susceptible to pyrimethamine than the FTA strain. Although relatively high concentrations of sulphadoxine alone exerted no detectable antimalarial effects, the sulphonamide potentiated the activity of pyrimethamine against both strains of P. falciparum. This synergistic activity was relatively more pronounced against the pyrimethamine-resistant strain, particularly at lower concentrations of sulphadoxine. Further studies are indicated to determine to what extent findings obtained with the in vitro microtechnique can be correlated with the response of falciparum infection to treatment with pyrimethamine-sulphadoxine combinations.

Animals↗
PubMed1983

A rabbit--in vitro system to evaluate drug action against Plasmodium falciparum.

A rabbit-in vitro model system is described which can determine the activity of anti-malarial drugs against erythrocytic stages of Plasmodium falciparum. Serum samples, collected from rabbits at various times after drug administration, wee incubated with synchronized ring form parasites using the microtest system. The extent to which the presence of drugs in the serum inhibited parasite growth was usually determined after 32 to 40 hours of incubation. Anti-malarial activity was observed in sera obtained from rabbits which received chloroquine, mefloquine, pyrimethamine and cycloguanil, but not in those which received 4-4' diacetyldiaminodiphenylsulphone (DADDS). The effects against the drug-sensitive strain were more marked than against the drug-resistant one. The serum activity persisted for a longer period of time after administration of mefloquine, pyrimethamine, pamoate, and cycloguanil pamoate than after administration of chloroquine, a drug with a shorter biological half-life. The results indicate that this model may be a useful system for identifying potential agents against drug-resistant falciparum malaria, particularly compounds which are converted in vitro to their active metabolites or which exert a prolonged suppressive activity after drug administration.

Acedapsone↗