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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.

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.

Thirty-four healthy adult males, moderately to heavily infected with Onchocerca volvulus, were treated daily with metrifonate at 10 mg/kg body weight for either three or six days. The patients' reactions and the effects on the microfilariae were measured on a 'single-blind' basis. Muscarinic effects of acetylcholine were prominent despite the use of belladonna alkaloids, and nicotinic effects--leading to a proximal muscle weakness--occurred in one patient after the fifth dose. A syndrome of polyarthritis, fever and elevated erythrocyte sedimentation rate occurred in 11 patients, in two of whom microfilariae were demonstrated in the joint fluid. The six-day regime destroyed 83% of the microfilarial load and the three-day regime destroyed 72%, but the difference was not statistically significant (as assessed one week after the completion of treatment). It seems unlikely that metrifonate will replace DEC as the 'reference' microfilaricide and attempts to improve its efficacy by employing higher dosage must employ an intermittent dose regime.

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.

Halofantrine hydrochloride given to 46 Kenyan children with falciparum malaria at 10 mg/kg for two doses, and to 60 other children at 8 mg/kg for three doses, resulted in rapid parasite clearance, mean parasite clearance times being 45.4 h and 54.8 h, respectively. In-vitro chemosensitivity tests showed that most infections were due to chloroquine-resistant parasites, and that parasite maturation was inhibited by considerably lower concentrations of halofantrine than of chloroquine.

Diethylcarbamazine (DEC), 0.5 mg/kg, was taken orally by six patients being treated for onchocerciasis. Blood samples were taken at timed intervals for 48 hr and urine and feces collected for 4 days. Plasma and urinary concentrations of DEC and DEC N-oxide were measured by gas-liquid chromatography. DEC appeared to be rapidly absorbed, with a peak plasma concentration of 150 to 250 ng/ml reached in 2 to 3 hr. There was a secondary rise in plasma DEC concentration at 5 to 6 hr in all patients. In contrast to the way the drug is eliminated in rats, in man it was by both renal and extrarenal routes, with small amounts (+/- 10%) being excreted as an N-oxide metabolite. DEC kinetics were also investigated in five normal subjects and the result were much the same. Clinical implications are discussed.

Sera were obtained from 119 Nigerian villagers two years after immunization with group A and group C meningococcal polysaccharide vaccines. Measurement of meningococcal antibody levels in individual serum samples by the haemagglutination technique showed that two years after vaccination the mean group A meningococcal antibody level was no higher in immunized subjects than in 140 age-matched, non-immunized controls. Over-all the mean group C meningococcal haemagglutinating antibody level was significantly higher in immunized subjects than it was in controls but this difference was not found in those under the age of 15 years at the time of vaccination. However, when pooled serum samples from the same subjects were tested for meningococcal antibodies by radioimmunoassay, immunized subjects were found to have significantly higher mean levels of both group A and group C meningococcal antibodies than the controls. The possible reasons for this discrepancy are considered and the significance of these findings in relation to plans for mass immunization with meningococcal vaccines in tropical Africa are discussed.

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.

No epidemiological information concerning the prevalence of rubella previously existed in Libya, thus precluding policy decisions in respect of possible immunization programme options. A random serological survey of school children, using the single-radial haemolysis-test, gave the following IgG positive rates. In Benghazi, 621 subjects yielded 58.8% at six years, the point of entry to the school system, rising to 78.3% at 12 years; in Gharian, 188 subjects yielded 61.1% at six years rising to 89.3% at 12 years. An additional random group of 70 Benghazi children, bled annually for four years, yielded positive rates of 55.7% at six years rising to 78.6% at nine years.

The effect of ivermectin, a new microfilaricide, was assessed in a double blind trial against diethylcarbamazine citrate (DEC) and placebo. Fifty-nine adult males with moderate to heavy infection with Onchocerca volvulus and with eye involvement were recruited from an area under Onchocerciasis Control Programme (OCP) vector control in Northern Ghana. They were randomly assigned to an eight-day treatment with ivermectin as a single dose of 12 mg on day 1 followed by placebo for the remaining seven days, or DEC, total dose 1.3 g, or placebo, and ophthalmological review was undertaken over a period of one year. DEC acted quickly to eliminate microfilariae from the eye and was associated with reactive ocular changes and in a few cases functional deficit. Ivermectin eliminated microfilariae slowly from the anterior chamber of the eye over a period of six months. The ocular inflammatory reaction was minimal and no functional deficit occurred. It is postulated that the observed slow action of ivermectin on the eye may be attributed in part to its instability to cross the blood-aqueous humour barrier because of its molecular size as a macrocyclic lactone causing microfilariae to leave the eye gradually along a newly created gradient. Ivermectin is an effective microfilaricide with minimal ocular adverse effect and could therefore be suitable for widespread application without strict supervision.

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.

In Libya traditional animal husbandry and the practice of domestic slaughter of food animals contribute to the maintenance of the Echinococcus cycle. The cost of echinococcosis is high and may significantly affect the national economy. This study, employing the ELISA test, has indicated an approximately 10% infection rate in children and young adults from the environs of Benghazi, no difference being apparent between rural and urban dwellers. The prevalence of the infection should be determined in both animals and man and possible disease inter-relationships investigated. Surveys are required in all alleged endemic areas and in sheep and camel breeding areas. It is also necessary to determine the importance of foxes, hyaenas and jackals in transmission among other animals. A clinical trial is recommended to assess the value of mebendazole against Echinococcus cysts.

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 immune response of young Nigerian children to a full course of infant immunizations was studied in relation to their nutritional state at the time of vaccination. No significant correlations were found between anthropometric measurements made at the time of vaccination and the antibody response to triple, polio, measles, meningococcal and typhoid vaccines. Significant correlations were found between serum pre-albumin levels and the response to group A meningococcal polysaccharide vaccine and between serum albumin levels and the response to group C meningococcal polysaccharide vaccine. These correlations may reflect the depressive effect of malaria both on serum albumin and pre-albumin levels and on immune responsiveness to meningococcal polysaccharides. No significant correlations were found between nutritional state at the time of BCG vaccination and the development of a positive tuberculin reaction five weeks later. We conclude that under-nutrition has little or no effect on the immune response to vaccines used in routine infant immunization programmes.

In a single-blind comparative study of diethylcarbamazine (DEC) and metrifonate against onchocerciasis, 20 patient received a total dose of 6.6 g DEC over a two-week period and 20 patients each received one dose of metrifonate 10 mg/kg body weight at ten-day intervals, three times. Both the efficacy and the severity of reaction to treatment were measured. DEC proved the more effective, destroying 98.9% of the microfilarial load while metrifonate destroyed only 75.4% (assessed one week after completion of treatment). The reaction to treatment was much more severe in patients treated with DEC. The persistence of significant postural cardiovascular effects for two weeks after the completion of DEC needs to be considered in mass therapy. The pattern of re-emergence of skin microfilariae indicated no difference between the two drugs over a six-month period. It is concluded that DEC is more effective than metrifonate and remains the 'reference' microfilaricide although its effects are more severe than those of metrifonate.

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 patients with moderate to heavy infections with Onchocerca volvulus were randomly assigned to receive single doses of 100, 150 or 200 mcg/kg of ivermectin or matching placebo capsules. Detailed systemic, ocular and parasitological examinations were carried out at intervals over a period of one year. Nodules were excised twelve months after treatment to evaluate the effect of the treatment with ivermectin in adult O. volvulus. The three ivermectin-treated groups produced massive reductions in skin microfilariae (over 97%) with low levels being maintained over one year. The 150 and 200 mcg/kg doses were however superior to the 100 mcg/kg dose in achieving a greater reduction in skin microfilarial counts initially and in maintaining significant lower levels throughout the period of observation. There was no difference between the 150 and 200 mcg/kg doses at anytime. The three ivermectin doses were equally effective in the clearance of ocular microfilariae. The proportion of dead adult worms was very high in all treatment groups, which is effected by the successful ten years lasting vector control in northern Ghana. In spite of this superannuation of the worm population, an impact of the treatment with ivermectin on the reproductivity of the parasite could be shown. Systemic total clinical reaction was mild and was similar in the ivermectin treated groups. However, severe symptomatic postural hypotension (SSPH) was limited to patients treated with 150 or 200 mcg/kg of ivermectin. Ocular reactions were mild in all patients and no ocular deficiency occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper considers some of the procedures used and problems encountered in the collection of demographic data for a large-scale medical project: the Endemic Diseases Research Project at Malumfashi in northern Nigeria, 1974-1979. 43,216 people were enumerated and a subset of 26,100 were visited monthly for one year for the purpose of registration of vital events. The majority of problems encountered are relevant to similar studies in developing countries. Some difficulties cannot be avoided, but it is considered helpful to identify them. Other situations, however, deserve particular attention, such as the development of adequate on-site data-checking mechanisms, as these are areas in which future programmes could benefit from the experience of the demographic studies in Malumfashi. More effort still needs to be put into the improvement of data collection methods themselves.

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