Is reduction of transmission desirable for malaria control?
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Letter↗
Biomedical subjects
J Meuwissen
Publications and source records attributed to J Meuwissen.
Study of treatment of congenital Toxoplasma gondii infection in rhesus monkeys with pyrimethamine and sulfadiazine.
The efficacy of the combination of pyrimethamine and sulfadiazine for the treatment of congenital Toxoplasma gondii infection in rhesus monkeys was studied. The dosage regimen for pyrimethamine and sulfadiazine was established by pharmacokinetic studies in two monkeys. Those studies showed that the distributions of both drugs followed a one-compartment model. The serum elimination half-lives were found to be 5.2 h for sulfadiazine and 44.4 h for pyrimethamine. Sulfadiazine reached a maximum concentration in serum of 58.7 micrograms/ml, whereas a maximum concentration in serum of 0.22 micrograms/ml was found for pyrimethamine. Ten monkeys were infected intravenously with T. gondii at day 90 of pregnancy, which is comparable to the second trimester of organogenetic development in humans. Treatment was administered to six monkeys, in whose fetuses infection was diagnosed antenatally. From the moment that fetal infection was proven, the monkeys were treated throughout pregnancy with 1 mg of pyrimethamine per kg of body weight per day and 50 mg of sulfadiazine per kg of body weight per day orally. The therapy was supplemented with 3.5 mg of folinic acid once a week. No toxic side effects were found with this drug regimen. The parasite was no longer detectable in the next consecutive amniotic fluid sample, taken 10 to 13 days after treatment was started. Furthermore, T. gondii was also not found in the neonate at birth. The parasite was still present at birth in three of four untreated fetuses that served as controls. Both drugs crossed the placenta very well. Concentrations in fetal serum varied from 0.05 to 0.14 micrograms/ml for pyrimethamine and from 1.0 to 5.4 micrograms/ml for sulfadiazine. In addition, pyrimethamine was found to accumulate in the brain tissue, with concentrations being three to four times higher than the corresponding concentrations in serum. Thirty percent of the sulfadiazine was found to reach the brain tissue when compared with the corresponding serum concentration. when administered early after the onset of infection, the combination of pyrimethamine and sulfadiazine was clearly effective in reducing the number of parasites in the fetus to undetectable levels.
Administration, Oral↗
Pharmacokinetics of spiramycin in the rhesus monkey: transplacental passage and distribution in tissue in the fetus.
Transplacental transfer of spiramycin was investigated in a rhesus monkey model to study whether the antibiotic reaches therapeutic levels in the fetus. Spiramycin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were determined for bioactive spiramycin as measured by the bioassay. Pharmacokinetic pilot studies showed that spiramycin distribution follows a two-compartment model in rhesus monkeys. Following a single intravenous dose of 50 or 250 mg, dose-dependent kinetics were observed. At a dose of 50 mg, 10% of the dose was excreted unchanged in the urine. At the higher dose of 250 mg, an oliguric effect was observed. Spiramycin concentrations in fetal serum were measured over time while the maternal concentration was maintained at a constant level. During a 5-h experiment, a maximum fetal-maternal serum ratio of 0.27 was found. In three fetuses, concentrations in serum and tissue were measured following intravenous administration of 50 mg of spiramycin twice daily to the mother for at least 7 days. The fetal-maternal serum ratios were found to be 0.4 to 0.58 after intravenous administration of the final dose of 50 mg to the mother. It appeared that spiramycin accumulated in the soft tissues, especially in the liver and spleen, of both the mother and the fetus. The concentration in placental tissue appeared to be 10 to 20 times that of the concentration in fetal serum. The concentration of spiramycin in amniotic fluid was about five times higher than the concentration in fetal serum. Another important observation was that absolutely no spiramycin was found in the brain.
Animals↗
Effectiveness of spiramycin for treatment of congenital Toxoplasma gondii infection in rhesus monkeys.
The effectiveness of spiramycin for the treatment of rhesus monkey fetuses congenitally infected with Toxoplasma gondii was studied. Eight monkeys were infected at day 90 of pregnancy. This is comparable to the second trimester of organogenetic development in humans. Transmission of infection was found prenatally in five of the eight monkeys by detection of the parasite in the amniotic fluid. Treatment with spiramycin (20 mg/kg/day in two intermittent doses given intravenously) was started as soon as fetal infection was proven and was continued until birth. Nine to 14 days after initiation of treatment, the parasite was still detectable in amniotic fluid samples from four of these five cases. However, the parasite was detected only by PCR and not by mouse inoculation. T. gondii was also detected only by PCR in the placenta of one monkey that delivered prematurely. This monkey received spiramycin treatment for only 2 weeks. In the four monkeys that received treatment for about 7 weeks, the parasite was not present at birth in the placenta nor in amniotic fluid or neonatal organs. Spiramycin accumulates mainly in maternal tissues. Although concentrations in neonatal tissue were found to be 5 to 28 times higher than the corresponding concentrations in neonatal serum, the concentrations in neonatal tissue were still 11 to 16 times lower than those found in the mothers. However, no spiramycin was found in the fetal brains. Early treatment with spiramycin may prevent transmission of infection to the fetus but most probably cannot interrupt an existing brain infection, which is the most severe outcome of congenital toxoplasmosis in humans.
Amniotic Fluid↗
Congenital toxoplasmosis: an experimental study in rhesus monkeys for transmission and prenatal diagnosis.
This paper describes a rhesus monkey model to study congenital transmission and the prenatal diagnosis of Toxoplasma gondii infection. Transmission to the fetus was investigated after maternal infection in the second (Day 90) or third trimester (Day 130) of pregnancy. A parasitemia was induced and lasted for about 10 days as proven by mouse inoculation and nested PCR on whole blood samples and peripheral blood mononuclear cells. Transmission of T. gondii was proven in 4 of 9 (44%) fetuses in the second trimester and in 3 of 9 fetuses in the third trimester of gestation. Six of the 7 proven fetal infections could be diagnosed antenatally. Postnatally, 4 additional fetuses that most likely were congenitally infected were found, although this could not formally be proven. The mothers of these 4 fetuses were infected in the third trimester. If we accept this group as being antenatally infected, an overall transmission rate is found of 11 of 18 cases (61%). This rate is similar to that found in humans. This is the first description of a monkey model for congenital toxoplasmosis, that is suitable to study the approach of antenatal diagnosis and the effectivity of treatment, with obvious relevance for Toxoplasma infections in humans.
Animals↗
Absence of seasonal variation in malaria parasitaemia in an area of intense seasonal transmission.
Parasitological surveys carried out in two villages of the Kilombero district of Tanzania indicated a very high prevalence of Plasmodium falciparum parasitaemia throughout the year (all ages mean prevalence = 69.2%) and a low, unstable prevalence of P. malariae (all ages mean prevalence = 4.5%). Fevers (temperature > or = 37.5 degrees C) in both children and adults showed irregular changes in prevalence over time, but there was no seasonal pattern. Neither was there seasonal variation in either P. falciparum parasite prevalence or parasite densities. This was despite marked seasonality in vectors caught in CDC light-traps and in estimated sporozoite inoculations determined by ELISA. The estimated mean annual inoculation rate was extremely high, over 300 infectious bites per person per year, the main vectors being members of the A. gambiae complex and Anopheles funestus. There was considerable variation between houses but even in houses with relatively low mosquito numbers the inoculation rate was sufficient to maintain a maximal P. falciparum prevalence. Heterogeneities in exposure cannot explain why the parasite prevalence is not always 100%. In areas of such high transmission, parasitaemias are likely to be determined mainly by the interaction of schizogony and anti-blood stage immunity, since parasites arising from new inoculations generally comprise only a small proportion of the total in the circulation. In any one individual, this will lead to periodic fluctuations in levels of parasitaemia. These are unlikely to show a close relationship to either seasonal variation in inoculations or to differences between households in the local inoculation rate.
Adolescent↗
Value of the polymerase chain reaction for the detection of Toxoplasma gondii in cerebrospinal fluid from patients with AIDS.
To investigate whether the polymerase chain reaction (PCR) on the BI gene of Toxoplasma gondii could contribute to the diagnosis of cerebral toxoplasmosis in patients with AIDS, we retrospectively tested CSF samples from 20 patients with AIDS suspected of having cerebral toxoplasmosis for the presence of T. gondii. Suspicion of cerebral toxoplasmosis was based on accepted criteria. Nine patients with AIDS with IgG antibodies to T. gondii but who were not suspected of having cerebral toxoplasmosis and four patients with AIDS seronegative for T. gondii served as negative control patients. T. gondii was demonstrated by PCR in the CSF from 13 of the 20 patients with AIDS suspected of having cerebral toxoplasmosis but was not demonstrated in the CSF samples from the nine control patients seropositive for T. gondii and the four control patients seronegative for T. gondii. The data were statistically evaluated. This study shows the value of PCR for the detection of T. gondii in CSF for the diagnosis of cerebral toxoplasmosis in patients with AIDS.
Acquired Immunodeficiency Syndrome↗
Identification of Toxoplasma gondii infections by BI gene amplification.
The diagnosis of toxoplasmosis in congenitally infected children or in immunocompromised patients can be difficult; serology is not reliable, and the diagnosis must be based on the combination of symptomatology and the direct demonstration of the parasite in clinical specimens by microscopy, antigen detection, or inoculation of samples into mice or tissue cultures. These techniques are either insensitive or time-consuming. To determine the value of the polymerase chain reaction (PCR) for the diagnosis of Toxoplasma gondii infections, we compared this technique with conventional detection techniques, such as microscopy, tissue culturing, and mouse inoculation. We were able to detect T. gondii by PCR in clinical specimens and tissue samples that were obtained postmortem from a bone marrow recipient with cerebral toxoplasmosis and from three congenitally infected children. The presence of T. gondii was demonstrated in brain tissue, cerebrospinal fluid, the heart, and skeletal muscle tested fresh or after fixation in Formalin. In only one sample was T. gondii isolated by mouse inoculation but not detected by PCR. Because it is a sensitive, relatively rapid, and specific method and because it can be applied to a variety of different clinical samples, PCR can be considered a valuable additional tool for the identification of T. gondii infections.
Adult↗
Follow-up of preschool age survivors of neonatal intensive care.
High risk birth status is related to a number of subsequent deficits in development. Factors such as maternal education and economic status of the family are hypothesized to affect the development of high risk children. In this study preschool aged survivors (n = 18) of a neonatal intensive care nursery were compared to a randomly selected control sample (n = 18) on measures of intelligence, receptive language, and visual motor integration. No significant effects were found for birth status alone. A significant interaction between level of maternal education and birth status was found on the measure of intelligence.
Child Development↗
Proceedings: Recent results with carcinogen binding proteins.
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Azo Compounds↗