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1. The metabolism of proguanil to the active metabolite cycloguanil has been evaluated in 135 British Troops and 26 Kenyan schoolchildren. 2. Large inter-subject variability was observed in both plasma and urinary concentrations of proguanil and cycloguanil after standard doses of drug. 3. Based on the ratio of proguanil to cycloguanil (P/C) in urine the British troops formed a non-normal distribution. 90% of the population formed a discrete distribution with P/C ranging from 0.5 to 9.0 while the remaining 10% were scattered throughout the distribution to an extreme value of 39. A similar pattern of variability was observed using P/C from a 6 h plasma sample. 4. This variability was due to differences in the ability of individuals to metabolise proguanil to cycloguanil. 5. Thirteen schoolchildren who had experienced malaria during prophylaxis with proguanil and thirteen matched controls each received proguanil (100 mg). We could not discriminate between the two groups based on P/C ratio in either a 6 h plasma or 0-6 h urine sample. [ABSTRACT FROM AUTHOR]

Twenty-one patients with moderate to heavy infections with O. volvulus were treated with 25 mg of diethylcarbamazine (DEC) citrate twice daily for 10 days. In 11 patients the urine was made alkaline with sodium bicarbonate, 2 g, administered 6 hourly for three doses daily beginning 1 day before DEC was started and continued throughout the DEC therapy. Ten patients served as controls. The mean pre-dose plasma DEC concentration during treatment and the mean plasma DEC half-life were significantly higher in bicarbonate treated patients as compared to controls. Total urinary excretion of DEC was significantly less in the bicarbonate treated group than in controls. Mean overall total reaction was higher in bicarbonate-treated patients but the difference was not significant. The bicarbonate-treated group achieved a significantly greater reduction in skin microfilarial counts than the control group as assessed 1 week after completion of therapy, but there was little difference at 1 month. Microfilarial killing was associated with microfilarial mobilisation, alteration in peripheral leucocytes and elevation in serum aminotransferases in both groups. There was no effect of DEC on the number of adult worms recovered in nodules removed at the end of the therapy. This study indicates that moderate urinary alkalinisation alters the kinetics of DEC and the therapeutic response. However the severity of clinical reaction coupled with the inadequate level of microfilarial killing achieved make it unlikely that manipulation of urinary pH will be of practical value in onchocerciasis chemotherapy. [ABSTRACT FROM AUTHOR]

1 The kinetics of primaquine have been studied in twenty volunteers after single and multiple dose regimes. 2 The kinetic parameters were similar in glucose-6-phosphate dehydrogenase (G6PD) normal Thais, G6PD deficient Thais and in Caucasians. 3 The Caucasian subjects showed about 1% of the dose was excreted in the urine. 4 The kinetic parameters obtained from multiple dose studies in Thais were very similar to those obtained from single dose studies in Thais. [ABSTRACT FROM AUTHOR]

Certification of global poliomyelitis eradication can only be accomplished when all countries have been certified as having achieved wild poliovirus eradication. In order to achieve certification of eradication of poliomyelitis in Malta an active acute flaccid paralysis (AFP) surveillance system comprising the whole population was set up. Surveillance became effective in January 1998. During 1998, there were nine reported cases of AFP (non-polio AFP rate: 2.38 per 100,000 population) two of whom were children under 15 years of age (non-polio AFP rate: 2.52 per 100,000 for the population aged <15 years). In 1999 five cases of AFP were reported (non-polio AFP rate: 1.32 per 100,000 population). One case occurred in a child under 15 years (non-polio AFP rate: 1.28 per 100,000 for population aged <15 years). Virological investigation did not detect any wild or Sabin-like polioviruses.

Over the past century, tropical medicine has passed through several overlapping phases. Initially, the picture was of endemic and epidemic diseases that wreaked havoc on people living in warm climates and visitors to these areas. High morbidity and mortality associated with these diseases reflected the poor state of knowledge about their causes and epidemiology and the lack of effective technologies for their control. At this stage, tropical medicine was dominated by parasitic and infectious diseases that had affinity for warm climates and some specific nutritional disorders. The next phase involved the steady accumulation of knowledge about the aetiological agents and, in the case of parasitic and infectious diseases, identification of reservoirs and vectors. The development of new and improved technologies for the control of tropical diseases characterised the third phase. The new products included drugs, diagnostic tools, vector control measures and vaccines. In the fourth phase, the new technologies are being deployed in programmes aimed at achieving disease control and, where feasible, total elimination of the problem. In the course of these operations, many useful lessons have been learnt from both the successes and failures of major schemes. In particular, experience has shown the important role of research not only in providing new technologies but also in optimising their effectiveness when applied in control programmes. The role of social and behavioural factors in the epidemiology and control of tropical diseases has drawn attention to the value of a multidisciplinary approach in designing and implementing control programmes. There is a sense of cautious optimism that, if the lessons learnt over the past century are carefully applied, further gains can be made in controlling and eliminating the classical problems that characterised tropical medicine at the beginning of this century.

Ninety-two males, infected with Onchocerca volvulus, from an area of on-going transmission in the forest zone of southern Ghana were treated with albendazole. 31 patients received 800 mg daily x 3, 31 received 1200 mg daily x 3 and 30 others received 800 mg daily x 7. Albendazole was given as a single daily dose with a fatty breakfast. Detailed systemic, ocular and laboratory examinations were performed pretreatment and at intervals over one year. Nodules were extirpated on days 30 and 60 and examined by histopathology. All the dose regimes were well tolerated but were neither microfilaricidal nor macrofilaricidal. The main effect was embryotoxicity affecting all intra-uterine stages. The most encouraging results were obtained in the 800 mg daily x 3 group in which a prolonged suppression of skin microfilarial counts occurred. Controlled studies in combination with ivermectin are recommended to determine whether an additive effect of the two drugs would result in permanent sterilisation of the adult worms.

Metrifonate has been studied in the treatment of infections with Onchocerca volvulus in West Africa. In doses of 10 mg/kg daily for six days, metrifonate was effective against the microfilariae but produced unpleasant reactions due both to the death of the microfilariae and to the muscarinic effects of the drug. In a comparison of 10 mg/kg metrifonate, for 3 doses at 10 day intervals, with diethylcarbamazine (D.E.C.) in a total dose of 6.6 g, metrifonate was significantly less effective than D.E.C. in killing microfilariae but produced significantly fewer adverse effects. In a final study comparing metrifonate 10 mg/kg/day given for 3 or for 6 days there was little difference in their therapeutic effect. However, metrifonate 10 mg/kg given for 6 days produced more severe adverse reactions due largely to the muscarinic and nicotinic effects of acetylcholine and these effects were not prevented by the administration of belladonna alkaloids. Metrifonate 10 mg/kg given for 3 doses at 10 day intervals is effective in the treatment of onchocerciasis but is unlikely to replace diethylcarbamazine. Metrifonate has no action on the adult worms.

The nutrition of a group of Nigerian children who received weekly chemoprophylaxis with chloroquine during their first one or two years of life was compared with the nutrition of a group of children exposed frequently to malaria. Fewer episodes of severe malnutrition and fewer deaths from malnutrition occurred among protected than among control children. Protected children tended to be taller and heavier than control children and to have a larger mid-upper arm circumference. Mean serum albumin and pre-albumin levels were higher in protected than in control children. However differences between the two groups were small and only in a few instances were they statistically significant.

This paper presents some statistical problems of analysing changes in patterns of microfilarial loads in onchocerciasis patients after chemotherapeutic treatment. Analyses are made of a pooled set of data from ten separate studies of diethylcarbamazine (DEC) conducted at the Onchocerciasis Chemotherapeutic Research Centre, Tamale, between 1978 and 1983. Regression models of microfilarial load at different intervals post-treatment are fitted with initial microfilarial load, total dose of DEC, duration of treatment and age of the patient as the independent variables. Appropriate transformations of the variables are chosen by examination of plots of residuals for violations of the assumptions underlying the regression models. A dose response curve for DEC is produced.

The antibody response to group C meningococcal polysaccharide vaccine was studied in a Nigerian village. Household clustering of poor responders to immunization was detected. Age had a marked effect on antibody response, maximal titres being obtained only in those over the age of 10 years. Children with malaria parasitaemia had a lower antibody response than those without parasitaemia and subjects with the genotype AA had a lower antibody response than those with the genotype AS. The antibody response to the vaccine was not influenced by mild degrees of malnutrition but children with clinical marasmus or kwashiorkor were excluded from the study.

The structures of malarial and schistosomal pigment within the parasites are distinct. The two pigments are distinguishable both before and after extraction from host liver.

Approximately one-quarter of the world's population is infected with either Ancylostoma duodenale or Necator americanus. Humans transmit the hookworm by fecal contamination of the soil. The eggs hatch and the larvae may survive several months in warm, damp soil. Humans are infected when the larvae penetrate the skin and migrate through the body to the intestines, where the median survival time of the hookworm is one year. The loss of red blood cells into the gut is proportional to the worm load. Symptoms result from iron deficiency anemia and protein loss caused by a heavy worm burden. The peak age-specific prevalence of infection occurs in adult life, but only a small proportion of those infected ever become symptomatic. Possible control measures include chemotherapy to reduce the intensity of infection and the transmission potential and sanitation.

Nineteen patients from an area of vector control in the savanna region of Northern Ghana, all with moderate to heavy infections with Onchocerca volvulus and some with ocular involvement, were treated with 50, 100, 150 or 200 micrograms kg-1 of ivermectin. Detailed monitoring of clinical and ocular reactions and of alterations in skin microfilarial counts and laboratory indices were carried out during the first 28 days. Microfilarial counts in skin snips and detailed ocular examinations were then repeated at intervals over a period of nine months. Ivermectin slowly eliminated microfilariae from the skin and eye without serious adverse clinical or ocular reactions in all treated groups. There was little difference in efficacy between doses of 100, 150 and 200 micrograms kg-1, and these were more effective than the 50 micrograms kg-1 dose. Very low levels of skin microfilariae were maintained for nine months. Microfilariae were not eliminated from the eye for at least three months. The drug was neither macrofilaricidal nor embryotoxic. However, it produced a dose-dependent stimulation of embryogenesis manifest at one month and succeeded by a suppression of embryogenesis at three months after therapy. In areas where transmission of onchocerciasis has been interrupted, ivermectin may need not be given more often than once a year. The efficacy of the drug on single dosage and the mild adverse reactions produced, if confirmed in subsequent controlled studies, would greatly simplify the treatment of onchocerciasis and would reintroduce new concepts of the role of chemotherapy in the control of onchocerciasis.

The immune response of 198 young Nigerian children protected against malaria by chemoprophylaxis with chloroquine to immunization with triple, poliomyelitis, measles, typhoid, meningococcal and BCG vaccines was compared with the immune response to vaccination of 185 control children. Good responses to triple, measles and BCG vaccines were shown by children in both groups; poorer responses were obtained to poliomyelitis, typhoid and meningococcal vaccines. The response to immunization of protected children was similar to that observed among control children for all the vaccines tested except for meningococcal polysaccharide vaccine. Protected children showed a significantly greater antibody response to both group A and group C meningococcal polysaccharides than control children. This finding supports the results of previous studies which have shown that the immune response to meningococcal polysaccharide vaccines is adversely affected both by acute malaria and by asymptomatic malaria parasitaemia.

After treatment with chloroquine and pyrimethamine/sulfadoxine, 118 school children aged 6 to 10 years living near the Kenyan coast were enrolled in a malaria chemoprophylaxis study and followed up for 20 weeks. Children were randomly assigned to receive either chlorproguanil 20 mg weekly (n = 78) or placebo (n = 37). The attack rate of Plasmodium falciparum infection was 42% in chlorproguanil recipients (39.8 episodes per 1000 person-weeks of prophylaxis) and 73% in placebo recipients (69.2 episodes per 1000 person-weeks, p less than 0.02). Sensitivity tests on 36 isolates successfully cultured in vitro showed that all 21 isolates from chloroproguanil recipients were resistant to dihydrofolate-reductase inhibitors, whereas only 3 of 15 isolates from the placebo group were resistant (p less than 10(-6)). Chlorproguanil in a weekly adult dose of 40 mg does not provide adequate prophylaxis against P falciparum in Kenya, probably because drug levels between doses fall below those required to suppress parasites resistant to dihydrofolate-reductase inhibitors.

An ELISA system showed a positive rate for Schistosoma mansoni infections of 33.4% in Tauorga school-children; qualitative stool examination detected only 6.9%. Subsequent sampling of the school population indicated that a mollusciciding programme involving the major water body in the area had prevented any overall increase in prevalence and had apparently produced a decrease in prevalence in certain locations. New housing, piped water, sanitary disposal of wastes and health education were additional favourable factors.

A sensitive and specific assay for primaquine in plasma and urine using gas chromatography/mass spectrometry has been developed and used to study the plasma kinetics of primaquine. Preliminary studies on the effects of single and multiple oral doses have been carried out. In both cases the drug was completely, or almost completely, removed from the plasma in 24 h. The concentration of primaquine in the plasma usually reached a peak 1-2 hours after oral administration. The plasma elimination half-life was about 4 h. Less than 1% of the dose was detected in the urine collected over a 24-h period following drug ingestion. When Caucasian volunteers were given primaquine and chloroquine concurrently, some of them developed significant methaemoglobinaemia. Primaquine was not detectable in the plasma of any of the volunteers, 24 h after each daily dose.

Two clinical trials of the phenanthrene methanol compound halofantrine in the treatment of Plasmodium falciparum were conducted in Malawi, in areas where the parasite was known to be chloroquine resistant. In the first trial all 46 patients had symptoms of malaria and parasite densities ranging from 2500/microliter to 212,000/microliter. They were given a single dose of halofantrine hydrochloride, 16 mg/kg body weight. The recrudescence rate on day 14 of follow up was unacceptably high (38%). In the second trial the dose given was 8 mg/kg 6 hourly for three doses. Of the 49 children followed up for 14 days, 47 became aparasitaemic--ie, the cure rate was 96%. In both trials the drug was very well tolerated. Halofantrine hydrochloride seems to be effective against P falciparum chloroquine sensitive and resistant strains in Africa.

Fifty-nine onchocerciasis patients with ocular involvement were randomly assigned to receive either 12 mg of ivermectin in a single dose or 1300 mg of diethylcarbamazine over eight days or matching placebo capsules. Detailed standardized follow-up examination was carried out for one year. Both ivermectin and diethylcarbamazine rapidly reduced skin microfilarial counts to a similar extent over six months, after which counts increased significantly more with diethylcarbamazine. Diethylcarbamazine rapidly eliminated microfilariae from the eye, while ivermectin did so over six months. Reactions to treatment were more severe with diethylcarbamazine, which also produced clinical ocular deficiency in two patients. Ivermectin produced intra-uterine sequestration and degeneration of microfilariae in adult worms, which may account for its ability to produce prolonged suppression of skin microfilariae. Ivermectin proved superior to diethylcarbamazine in safety, tolerance and efficacy, but further work is needed to assess fully its effects in patients with heavy intraocular microfilarial loads.

The antimalarial drug primaquine was analysed in plasma and urine by gas chromatography mass spectrometry, using a deuterated internal standard. After freeze-drying and extraction with trichloroethylene the sample plus internal standard was reacted with Tri Sil TBT (a 3:3:2 by volume mixture of trimethylsilylimidazole, N,O,-bis-(trimethylsilylacetamide and trimethylchlorosilane) and an aliquot injected into the gas chromatograph mass spectrometer. The gas chromatographic effluent was monitored at m/z 403 and m/z 406, the molecular ions of the bis-TMS ethers of primaquine and 6-trideuteromethoxy primaquine. Calibration curves were prepared from standards made up in plasma and urine. Data from the analysis of plasma and urine samples from a volunteer who ingested the equivalent of 45 mg primaquine are presented.

The epidemiology, clinical features, diagnosis, prognosis, management, chemotherapy and chemoprophylaxis of malaria are reviewed.

Haematological measurements were made in 198 Nigerian children aged three months to two years who received weekly malaria chemoprophylaxis with chloroquine from shortly after birth until the age of one or two years and in 185 age-matched control children. Children protected against malaria had a higher mean haemoglobin level and a higher packed cell volume than control children, and they showed fewer abnormalities of their red cells. Total and differential white blood cell counts, mean plasma folate and mean serum ferritin concentrations were similar in both groups of children. However, the geometric mean red cell folate level of children exposed to malaria was significantly higher than the mean level of control children; and it may be that malaria raises the red cell folate through intracellular synthesis by malaria parasites. Children with malaria parasitaemia had a significantly lower haemoglobin and packed cell volume and a significantly higher geometric mean red cell folate and ferritin level than children without parasitaemia. Serum ferritin is probably an unreliable index of iron status in children with malaria.

One hundred and ninety-eight Nigerian children who received weekly chemoprophylaxis with chloroquine from shortly after birth until the age of one year or two years and 185 age-matched controls were studied. Chemoprophylaxis with chloroquine was partially, but not completely, effective in controlling malaria. Clinical malaria was documented significantly less frequently in protected children than in control children, and only 9% of random blood films obtained from protected children were positive for Plasmodium falciparum while 41% of random blood films from control children were positive for this parasite. Mean malaria antibody levels were lower in protected than in control children; for ELISA and precipitin antibodies the difference between the two groups was less marked at two years than at one year. Mortality was similar among protected and among control children. No rebound mortality or morbidity was observed after chemoprophylaxis was stopped.

No association was found between bacteriuria and Schistosoma haematobium infection in the Malumfashi area, and no male had a confirmed significant bacteriuria. The overall bacteriuria prevalence rate in a separate group of schoolgirls was 0.96%, while in females over the age of 20 it was 1.37%; there was an estimated prevalence of 3.2% in women over the age of 30. These figures for females agree with those from populations which have no experience of bilharzia. No urinary S. typhi carriers were found. The lack of association between urinary bacterial infection and schistosomiasis probably reflects the low intensity of S. haematobium infection in the Malumfashi area of northern Nigeria.

The epidemiology of infection due to Neisseria meningitidis and Neisseria lactamica was studied in a northern Nigerian community. A low meningococcal carriage rate was observed throughout the two-year survey. Initially, most meningococci isolated from nasopharyngeal carriers belonged to serogroup C or to serogroup Y. Following an outbreak of group A meningococcal disease, more group A meningococcal carriers were detected. Antibody studies indicated that infection with group A meningococci had been more widespread in the community than was suggested by regular carrier surveys. Carriage of meningococci was detected most frequently in children one to nine years of age. Children were identified as the first carriers in households more frequently than adults. The half-life of carriage was three months. The meningococcal carriage rate did not increase during the hot dry season when epidemics of meningococcal disease occur most frequently in Nigeria. Neisseria lactamica was isolated from the nasopharynx of children more frequently than were meningococci.

For 228 of 425 deaths (54%) occurring among 26 100 people of known age in the Malumfashi area of northern Nigeria, data were collected on symptoms present prior to death. Information was obtained on monthly registration visits, as part of demographic investigations, and data for the period November 1977-October 1978 have been analysed. Enumerators used a carefully prepared list of 25 symptoms to elicit information from relatives of the deceased. Pyrexia, diarrhoea and measles accounted for 77% of all deaths. Epidemiological determinants were responsible for all cases of meningococcal infections in the dry season and most cases of diarrhoea in the wet season. Most deaths attributed to measles occurred in the late dry season and early wet season. Epidemics of measles seemed to be localized at any one time in certain villages and the micro-epidemiology of this feature is considered. Malaria does not appear to be responsible for all deaths from pyrexia in the nought to four age group.