Biomedical subjects

F P Mockenhaupt

Publications and source records attributed to F P Mockenhaupt.

At least 19 recordsLinked to original sources

PubMed2005

Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86.

Although chloroquine (CQ) monotherapy is now generally inadequate for the treatment of Plasmodium falciparum malaria in northern Ghana--recently, 58% of 225 children failed treatment by day 14--use of the drug continues because of its low cost and wide availability. The risk factors associated with CQ-treatment failure in this region of Africa, including the T76 mutation in the chloroquine resistance transporter (pfcrt) gene and the Y86 mutation in the multidrug resistance (pfmdr1) gene of P. falciparum, have now been investigated, and genotype-failure indices (GFI) have been calculated. Treatment failure was found to be associated with young age, poor nutritional status, pfcrt T76 and pfmdr1 Y86, and early treatment failure (ETF) was also associated with high parasitaemia. The presence and concentration of 'residual' CQ in the blood of patients immediately before they were treated with CQ for the present study appeared to have no effect on outcome. Presence at recruitment of pfcrt T76 or pfmdr1 Y86 or both mutations increased the risk of treatment failure by 3.2-, 2.4- and 4.5-fold, and the risk of ETF by 9.8-, 2.7- and 10.2-fold, respectively. The pfcrt T76 GFI for clinical and all treatment failures were 2.8 and 1.4, respectively. These indices were relatively low in the younger children, those with malnutrition, and those with high parasitaemias when treated. Residual CQ did not affect the GFI substantially. Both pfcrt T76 and, to a lesser extent, pfmdr1 Y86 would be useful tools for the surveillance of CQ resistance in northern Ghana. In the current transition phase to alternative first-line treatment for P. falciparum malaria, it should be possible to provide estimates of the level of CQ resistance by monitoring the prevalences of these mutations.

ATP-Binding Cassette Transporters↗

PubMed2003

Renal dysfunction in children with uncomplicated, Plasmodium falciparum malaria in Tamale, Ghana.

In a study performed in Tamale, in the Northern region of Ghana, cystatin C, a new and sensitive indicator of the glomerular filtration rate (GFR), was used to estimate the frequency of renal dysfunction in 78 children with uncomplicated, Plasmodium falciparum malaria. The excretion in urine of albumin, immunoglobulin G and alpha1-microglobulin was also investigated. Plasma concentrations of cystatin C were found to be elevated in 17% of the children, indicating subclinical impairment of renal function. As most (85%) of the children had glomerular as well as tubular patterns of proteinuria, it appears that both glomerulonephritis and damage to tubular cells often occur in P. falciparum malaria.

Acute Kidney Injury↗

PubMed2002

Efficacy of chloroquine in the treatment of uncomplicated, Plasmodium falciparum malaria in northern Ghana.

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to growing malaria-attributable morbidity and mortality in sub-Saharan Africa. However, the extent and degree of such resistance vary considerably between endemic areas. Data on CQ resistance in northern Ghana are almost entirely lacking. The therapeutic efficacy of CQ in uncomplicated malaria was therefore assessed, in a standard, 14-day protocol, in 225 children aged <5 years in Tamale, in the Northern region of Ghana. Early treatment failure (ETF) was observed in 11% of the children and late treatment failure in 18%. High initial parasite density and young age were independent predictors for ETF. Resistant parasitological responses (RI-RIII) were seen in 57% of the cases that could be classified. More than half of these responses occurred in children fulfilling the criteria for adequate clinical response (ACR), indicating a considerable lack of agreement between parasitological and clinical outcome. During the follow-up period, haemoglobin levels increased by approximately 1g/dl not only in patients with ACR but also in those who experienced clinical failure more than 1 week post-treatment. As CQ-treatment failure occurred in >25% of the children and more than half of the parasitological responses indicated resistance, current recommendations for the treatment of uncomplicated malaria in young children in northern Ghana have to be reconsidered.

Age Factors↗

PubMed2001

Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children.

Alpha-thalassaemia is common in malaria-endemic regions and is considered to confer protection from clinical disease due to infection with Plasmodium falciparum. In vitro, sensitivity to chloroquine (CQ) of P. falciparum infecting alpha-thalassaemic erythrocytes is reduced. We examined, in a cross-sectional study of 405 Nigerian children, associations between alpha-globin genotypes, blood concentrations of CQ, and P. falciparum parasitaemia. Of the children, 44% were alpha+-thalassaemic (36.8% heterozygous, 7.6% homozygous). CQ in blood and P. falciparum-infection were observed in 52 and 80%, respectively. CQ was more frequently found in homozygous alpha+-thalassaemic (71%) than in non-thalassaemic children (50%; odds ratio, 2.42; 95% confidence interval, 1.01-5.8). Among children with CQ in blood and despite similar drug concentrations, alpha+-thalassaemic individuals had fewer infections below the threshold of microscopy which were detectable by PCR only, and they had a higher prevalence of elevated parasitaemia than non-thalassaemic children. No such differences were discernible among drug-free children. CQ displays a lowered efficacy in the suppression of P. falciparum parasitaemia in alpha+-thalassaemic children; hence protection against malaria due to alpha+-thalassaemia may be obscured in areas of intense CQ usage. Moreover, alpha+-thalassaemia may contribute to the expansion of CQ resistance.

Animals↗

PubMed2001

Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana.

The Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) T76 and multidrug resistance gene analogue (pfmdr1) Y86 mutations are associated with chloroquine(CQ)-resistance. In isolates from 172 pregnant women living in the area of Agogo, Ghana, pfcrt T76 was detected in 69% and pfmdr1 Y86 in 66%. Pfcrt T76 but not pfmdr1 Y86 was more prevalent in samples from women with residual CQ in urine or serum. Parasite densities and multiplicity of infection of pfmdr wild type but not of resistant isolates were reduced by CQ. Adjusted for CQ and pyrimethamine (PYR) in urine, the P. falciparum dihydrofolate reductase (pfdhfr) N108 mutation which confers PYR-resistance was 3.1 and 3 times, respectively, more likely to be detected in isolates containing pfcrt and pfmdr1 mutations than in those comprising wild type alleles. Pfcrt, pfmdr, and pfdhfr mutations are frequent in P. falciparum from this part of Ghana which may limit the choice of drugs for the prevention of malaria in pregnancy. The association of CQ- and PYR-resistance mutations independent of recent drug use could indicate accelerated development of resistance to structurally unrelated drugs. Alternatively, it may reflect selection of resistance in persisting infections due to no longer detectable drug pressure.

ATP-Binding Cassette Transporters↗

PubMed2001

In vitro antiplasmodial activity of 4-phenylcoumarins from Exostema mexicanum.

The stem bark of Exostema mexicanum (Rubiaceae) is used in Latin American folk medicine as a quinine substitute for malaria treatment. Bioassay-guided fractionation of lipophilic and hydrophilic extracts from the stem bark and branches yielded two previously undescribed 4-phenylcoumarins: 4',8-dihydroxy-5,7-dimethoxy-4-phenylcoumarin (exomexin A) and 3',4'-dihydroxy-5,7,8-trimethoxy-4-phenylcoumarin (exomexin B). Together with five known derivatives the in vitro activities against a chloroquine-sensitive strain (poW) and a chloroquine-resistant strain (Dd2) of Plasmodium falciparum have been evaluated. The most lipophilic compound, 4',5,7,8-tetramethoxy-4-phenylcoumarin (O-methylexostemin) revealed the strongest antiplasmodial activity (IC50 values: 3.6 microg/ml [poW], 1.6 microg/ml [Dd2]).

Animals↗

PubMed2001

Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women.

Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.

Alleles↗

PubMed2001

Multiplicity of Plasmodium falciparum infection in pregnancy.

Little is known about the distribution and disease association of multiple Plasmodium falciparum infections in pregnant women. Genotyping of the merozoite surface protein-1 region was performed in 332 P. falciparum infected pregnant women in Ghana, and clinical and epidemiologic data were obtained. Overall, 68% of the women were infected with more than one strain (mean number of strains per carrier = 2.9). The multiplicity of infection decreased significantly with an increasing number of pregnancies, and infection with multiple P. falciparum strains was significantly associated with anemia. In logistic regression, women infected with four or more strains were 2.3 times more likely to be anemic than women harboring fewer strains. This association, however, was only observed in women with up to three pregnancies. The results suggest that with increasing gravidity and subsequent infections with multiple strains effective immune mechanisms against more and more strains develop. In pregnant women, the multiplicity of infection may be an important factor for the acquisition and maintenance of immunity against malaria.

Anemia↗

PubMed2000

Red cell glucose-6-phosphate dehydrogenase status and pyruvate kinase activity in a Nigerian population.

Glucose-6-phosphate dehydrogenase A- (G6PD A-) deficiency is a common enzymopathy in Africa that sporadically leads to manifest haemolytic anaemia. It is not exactly known how far the haematological status of individuals with either homozygous or heterozygous G6PD A- deficiency differs from that of individuals with normal G6PD activity. In a field study in Nigeria, we determined G6PD gene variants, the corresponding G6PD and pyruvate kinase (PK) activities, and basic haematological parameters in clinically healthy individuals, who were, in part, asymptomatically infected by malaria parasites. Red blood cell counts and haemoglobin levels were lower in G6PD A- deficient than in G6PD normal subjects. PK activities were higher in G6PD deficients, indicating a younger red cell population in these individuals. These findings suggest that G6PD A- deficiency is accompanied by chronic subclinical haemolysis. As a consequence, the reduced life span of red cells leads to an impaired diagnosis of G6PD heterozygosity when applying routine biochemical methods.

Adolescent↗

PubMed2000

Submicroscopic Plasmodium falciparum infections in pregnancy in Ghana.

Malarial parasitaemia below the threshold of microscopy but detectable by polymerase chain reaction (PCR) assays is common in endemic regions. This study was conducted to examine prevalence, predictors, and effects of submicroscopic Plasmodium falciparum infections in pregnancy. In a cross-sectional study among 530 pregnant women in Ghana, plasmodial infections were assessed by microscopy and PCR assays. Concentrations of haemoglobin and C-reactive protein (CRP) were measured and antimalarial drugs (chloroquine, pyrimethamine) in urine were demonstrated by ELISA dipsticks. By microscopy, 32% of the women were found to harbour malaria parasites. This rate increased to 63% adding the results of the parasite-specific PCR. P. falciparum was present in all but one infection. With increasing gravidity, infection rates and parasite densities decreased and the proportions of submicroscopic parasitaemia among infected women grew. Correspondingly, anaemia, fever and evidence of inflammation (CRP > 0.6 mg/dl) were more frequent in primigravidae than in multigravidae. Antimalarial drugs were detected in 65% of the women and were associated with a reduced prevalence of P. falciparum infections and a raised proportion of submicroscopic parasitaemia. Both gravidity and antimalarial drug use were independent predictors of submicroscopic P. falciparum infections. These infections caused a slight reduction of Hb levels and considerably increased serum concentrations of CRP. Conventional microscopy underestimates the actual extent of malarial infections in pregnancy in endemic regions. Submicroscopic P. falciparum infections are frequent and may contribute to mild anaemia and inflammation in seemingly aparasitaemic pregnant women.

Adult↗

PubMed2000

Sipandinolide: a butenolide including a novel type of carbon skeleton from Siparuna andina.

From a lipophilic extract of leaves of Siparuna andina (Monimiaceae), which exhibited antiplasmodial activity in vitro, two new compounds have been isolated: sipandinolide (1), a compound with a novel type of carbon skeleton and (-)-cis-3-acetoxy-4',5,7-trihydroxyflavanone (2). Their structures were established by spectroscopic methods; 2 showed moderate antiplasmodial activity whereas 1 was inactive.

Animals↗

PubMed2000

Concentrations of chloroquine and malaria parasites in blood in Nigerian children.

Consumption of chloroquine (CQ) and subtherapeutic drug levels in blood are considered to be widespread in areas where malaria is endemic. A cross-sectional study was performed with 405 Nigerian children to assess factors associated with the presence of CQ in blood and to examine correlations of drug levels with malaria parasite species and densities. Infections with Plasmodium species and parasite densities were determined by microscopy and PCR assays. Whole-blood CQ concentrations were measured by high-performance liquid chromatography. Plasmodium falciparum, P. malariae, and P. ovale were observed in 80, 16, and 9% of the children, respectively, and CQ was detected in 52% of the children. CQ concentrations were >17 and <100 nmol/liter in 25% of the children, 100 to 499 nmol/liter in 14% of the children, and > or =500 nmol/liter in 13% of the children. Young age, attendance at health posts, and absence of parasitemia were factors independently associated with CQ in blood. With increasing concentrations of CQ, the prevalence of P. falciparum infection and parasite densities decreased. However, at concentrations corresponding to those usually attained during regular prophylaxis (> or =500 nmol/liter), 62% of children were still harboring P. falciparum parasites. In contrast, no infection with P. malariae and only one infection with P. ovale were observed in children with CQ concentrations of > or =100 nmol/liter. These data show the high prevalence of subcurative CQ concentrations in Nigerian children and confirm the considerable degree of CQ resistance in that country. Subtherapeutic drug levels are likely to further promote CQ resistance and may impair the development and maintenance of premunition in areas where malaria is endemic.

Age Factors↗

PubMed1999

The contribution of alpha+-thalassaemia to anaemia in a Nigerian population exposed to intense malaria transmission.

The proportion to which alpha-thalassaemia contributes to anaemia in Africa is not well recognized. In an area of intense malaria transmission in South-West Nigeria, haematological parameters of alpha-thalassaemia were examined in 494 children and 119 adults. The -alpha3.7 type of alpha+-thalassaemia was observed at a gene frequency of 0.27. Nine and 36.5% of individuals were homozygous and heterozygous, respectively. P.falciparum-infection was present in 78% of children and in 39% of adults. The alpha-globin genotypes did not correlate with the prevalence of P. falciparum-infection. alpha+-thalassaemic individuals had significantly lower mean values of haemoglobin, mean corpuscular volume, and mean corpuscular haemoglobin than non-thalassaemic subjects. Anaemia was seen in 54. 7% of children with a normal alpha-globin genotype, in 69.9% of heterozygous (odds ratio: 1.99, 95% confidence interval: 1.32-3.00, P = 0.001), and in 88.4% of homozygous alpha+-thalassaemic children (odds ratio: 7.72, 95% confidence interval: 2.85-20.90, P = 0.0001). The findings show that alpha+-thalassaemia contributes essentially to mild anaemia, microcytosis, and hypochromia in Nigeria.

Adolescent↗

PubMed1999

In vitro antiplasmodial activity of Central American medicinal plants.

The in vitro antiplasmodial activities of 14 plant species traditionally used in Central America for the treatment of malaria or fever were evaluated. Lipophilic extracts of Piper hispidum, Siparuna andina, S. pauciflora, S. tonduziana, and Xylopia cf. frutescens, proved to be active against both a chloroquine-sensitive and a resistant strain of Plasmodium falciparum. IC50 values ranged between 3.0 microg/ml and 21.9 microg/ml; however, moderate cytotoxicity of active extracts was observed. Bioactivity-guided fractionation of Piper hispidum yielded 2',4, 6'-trihydroxy-4'-methoxydihydrochalcone (asebogenin) as an active compound.

Animals↗

PubMed1999

Plasmodium falciparum infection: influence on hemoglobin levels in alpha-thalassemia and microcytosis.

Plasmodium falciparum malaria, alpha-thalassemia, and anemia are frequent in African children. In 494 nonhospitalized Nigerian children, P. falciparum infection rates, alpha-globin genotypes, and hematologic parameters were determined. P. falciparum infection was observed in 78% of the children. The gene frequency of alpha-thalassemia was 0.28. Infection rates and parasitemia were similar for the 3 alpha-globin genotypes. In contrast to nonthalassemic and heterozygous persons, infection in children with homozygous alpha-thalassemia did not influence hemoglobin values. Because microcytosis and anemia are common features of alpha-thalassemia, their significance in P. falciparum infection was examined. Microcytosis was significantly associated with protection from hemoglobin decrease due to P. falciparum. Moreover, the rate of infection was lower in microcytic than in normocytic anemia.

Blood Volume↗

PubMed1999

The role of red blood cell polymorphisms in resistance and susceptibility to malaria.

In regions highly endemic for Plasmodium falciparum malaria, red cell polymorphisms that confer resistance to severe disease are widespread. Sickle cell trait, alpha-thalassemia, glucose-6-phosphate dehydrogenase deficiency, and blood groups were determined in 100 children from Gabon with severe malaria who were matched with 100 children with mild malaria and followed up for evaluation of reinfections. The sickle cell trait was significantly associated with mild malaria and blood group A with severe malaria. During follow-up, the original severe cases had significantly higher rates of reinfection than the original mild cases, with higher parasitemia and lower hematocrit values. Incidence rates did not differ in the context of erythrocyte polymorphisms, but patients with sickle cell trait presented with markedly lower levels of parasitemia than those without. Thus, the severity of malaria is partly determined by the presence of blood group A and the sickle cell trait. The different presentation of reinfections in severe versus mild cases probably reflects different susceptibility to malaria.

ABO Blood-Group System↗

PubMed1999

High rate of mixed and subpatent malarial infections in southwest Nigeria.

The rate of malarial parasitemia in children and adults was assessed by microscopy and the polymerase chain reaction in a holoendemic area in Nigeria. A high rate of subpatent Plasmodium falciparum parasitemia (19.6%) was found. Plasmodium malariae and P. ovale infections were common in a rural area (26.1% and 14.8%) but were observed sporadically in individuals from an urban area. Simultaneous infections with P. falciparum, P. malariae, and P. ovale were frequent in the rural area (11.7% triple infections). The rate of triple infections was higher than expected from the prevalences of each species (P < 0.00001). Spleen enlargement was associated with mixed infections of P. falciparum and P. malariae (odds ratio [OR] = 5.9, 95% confidence interval [CI] 3.0-11.7) and less frequently observed in individuals without detectable parasitemia (OR = 0.06, 95% CI = 0.01-0.3). Spleen enlargement and titers of antibodies to schizonts were positively correlated with parasite densities. The results also suggest that in some individuals a long-lasting subpatent parasitemia might occur.

Adolescent↗

PubMed1999

Short report: high prevalence and imbalanced age distribution of the Plasmodium falciparum dihydrofolate reductase gene Asn108 mutation in an area of low pyrimethamine usage in Nigeria.

Resistance of Plasmodium falciparum to pyrimethamine is associated with a non-silent point mutation of the parasite dihydrofolate reductase (DHFR) gene (Ser108 --> Asn108). Wide-scale use of antimalarials is thought to contribute to the emergence of drug resistance. In 131 P. falciparum-infected children in rural Nigeria, the frequency of the resistant Asn108 genotype was assessed by enzymatic restriction digestion of polymerase chain reaction-amplified DHFR sequences and compared with residual pyrimethamine blood levels. The prevalence of the Asn108 variant was 41.2%. In 18.3% of the isolates, both the Asn108 and the wild-type alleles were present. In contrast to the high prevalence of resistant genotypes, residual pyrimethamine blood levels were detected in only 4%. Furthermore, age was found to be a determinant of the parasite genotype since the proportion of Asn108 variants decreased with age (P < 0.05). These findings indicate that additional, unidentified factors, rather than selection by residual drug levels alone, might be responsible for the emergence of pyrimethamine-resistant parasite genotypes.

Age Distribution↗