M. Homeida

Antipyrine disposition and liver size in the elderly.

SummaryThis study has examined the contribution of decrease in liver size to the decline in drug metabolising capacity which occurs with ageing. Liver volume and antipyrine kinetics were measured in two groups of healthy individuals aged 20 to 29 years and 75 to 86 years and in a group of hospitalised patients aged 70 to 89 years. Liver volume was reduced in both groups of elderly people compared to the young group. Antipyrine plasma half-life was prolonged and antipyrine clearance was reduced in the group of elderly normal individuals. In this group the index — antipyrine clearance per unit liver volume — was also reduced in comparison to that of the young group. Measurements of antipyrine elimination in the hospitalised elderly group did not differ significantly from those in the young group. It is concluded that both decreased liver mass and decreased hepatic enzyme activity contribute to the impairment of drug oxidation which occurs in the elderly and which may warrant a reduction in dosage of some drugs. However, differences have been demonstrated between groups of elderly people suggesting that under certain circumstances standard doses of such drugs may be normally tolerated.

Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus

Objective:To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 μg kg−1.Setting:Medical Department at Soba University Hospital, Khartoum.Patients:Twenty five patients and fourteen healthy volunteers.Methods:Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay.Results:The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml−1; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 ng⋅h ml−1. In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations.Conclusion:Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.

APOC’s strategy of community-directed treatment with ivermectin (CDTI) and its potential for providing additional health services to the poorest populations

Abstract Since its inauguration in 1995, the African Programme for Onchocerciasis Control (APOC) has made significant progress towards achieving its main objective: to establish sustainable community-directed treatment with ivermectin (CDTI) in onchocerciasis-endemic areas outside of the remit of the Onchocerciasis Control Programme in West Africa (OCP). In the year 2000, the programme, in partnership with governments, non-governmental organizations and the endemic communities themselves, succeeded in treating 20,298,138 individuals in 49,654 communities in 63 projects in 14 countries. Besides the distribution of ivermectin, the programme has strengthened primary healthcare (PHC) through capacity-building, mobilization of resources and empowerment of communities. The community-directed-treatment approach is a model that can be adopted in developing other community-based health programmes. The approach has also made it possible to bring to the poor some measure of intervention in some other healthcare programmes, such as those for malaria control, eye care, maternal and child health, nutrition and immunization. CDTI presents, at all stages of its implementation, a unique window of opportunity for promoting the functional integration of healthcare activities. For this to be done successfully and in a co-ordinated manner, adequate funding of CDTI within PHC is as important as an effective sensitization of the relevant policy-makers, healthworkers and communities on the value of integration (accompanied by appropriate training at all levels). Evaluation of the experiences in integration of health services, particularly at community level, is crucial to the success of the integration.

Immunocompetence may be important in the effectiveness of Mectizan® (ivermectin) in the treatment of human onchocerciasis

Mectizan (Ivermectin) has been proved to be central to the control of onchoceriasis through self-sustainable community-based treatment. The possibility of parasitological unresponsiveness to this treatment or selection for drug resistance has emerged recently in many occasions. The reason for the reduced ability of Mectizan to maintain low levels of dermal microfilariae and early recurrent pruritus can only be speculated upon. Here, we report our own findings to address this particular issue.

Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomiasis.

The pharmacokinetics of a novel praziquantel preparation (Distocide) were investigated in Sudanese patients with hepatosplenic schistosomiasis and in healthy volunteers, and compared with those of Biltricide. The results of the first study indicated greater (P less than 0.05) plasma concentrations of Biltricide at 1.5, 2, 3 and 5 h after administration than with Distocide; plasma elimination half-lives (t 1/2) were not significantly different. In patients with hepatosplenic schistosomiasis, higher plasma levels of Distocide were noted (P less than 0.05 at 8 h) compared to healthy controls; however, due to wide inter-individual variations, there were no significant differences in maximum plasma concentration, time to maximum plasma concentration, area under the plasma concentration curve (AUC), volume of distribution, or clearance; t 1/2 was greater (P less than 0.05) in patients (11.9 +/- 5.4 h) than controls (2.3 +/- 0.4 h). In the presence of food, higher plasma concentrations of Distocide occurred compared to the fasting state; AUCs were greater (P less than 0.01) in both food groups, although the values of t 1/2 were shorter. The lower plasma levels and longer duration of action of Distocide may be advantageous in reducing side effects and prolonging exposure of the schistosomes to the drug.

Elimination of onchocerciasis from Africa: possible?

Human onchocerciasis, a parasitic disease found in 28 African countries, six Latin American countries and Yemen, causes blindness and severe dermatological problems. In 1987, efforts to control this infection shifted from vector approaches to include the mass distribution of ivermectin - a drug donated by Merck & Co. for disease control in Africa and for disease elimination in the Americas. Currently, almost 25 years later, with the Americas being highly successful and now approaching elimination, new evidence points towards the possibility of successful elimination in Africa. We suggest several major changes in the programmatic approach that through focused goal-directed effort could achieve global elimination of onchocerciasis by 2025.

Drug metabolism in malnourished children: a study with antipyrine.

The effect of malnutrition on hepatic drug-metabolising enzymes was investigated in 8 Sudanese children aged between 9 and 12.5 years using as a model the drug antipyrine. Antipyrine half-life and clearance were measured in the malnourished state and after 3 or 4 weeks of good nutrition. Associated with the improvement in nutritional state was a shortening of antipyrine half-life and an increase in its clearance. There was also a rise in serum triiodothyronine. It is concluded that poor nutrition is associated with impairment of drug metabolic capacity and that many factors are responsible.

Pharmacokinetic interaction between praziquantel and albendazole in Sudanese men

It has been suggested that praziquantel (40 mg/kg) and albendazole (400 mg) administered together may have a synergistic effect on intestinal parasites. In the present study, the pharmacokinetics of these agents, alone and in combination, were investigated in the presence and absence of food in two groups of Sudanese males. The results indicated that praziquantel pharmacokinetics were not effected by co-administration of albendazole although, in the presence of food, the area under the curve (AUC(0-infinity)) of praziquantel increased 2.6 fold. The AUC(0-infinity) of albendazole sulphoxide (the active metabolite of albendazole) increased 4.5-fold when administered with praziquantel, eight-fold when given with food and 12-fold when given with praziquantel and food. The balance between the therapeutic efficacy of this combination of drugs and its safety profile needs to be studied, especially with regard to albendazole.

Antipyrine clearance per unit volume liver: an assessment of hepatic function in chronic liver disease.

Liver size has been estimated clinically and by a non-invasive ultrasound technique in 16 normal subjects, 16 patients with cirrhosis, 10 patients with chronic biliary obstruction, and three patients with primary hepatoma. Antipyrine disposition was also measured in each subject. Hepatomegaly was not clinically detectable until there was approximately a 20% increase in liver size. Additional increases in size correlated significantly with clinical estimates of hepatomegaly. Antipyrine clearance had a three-fold range in normal subjects. Its mean value was significantly reduced in each subgroup of patients with liver disease. However, 48% of patients with liver disease had values within the normal range. In normal subjects there was a significant correlation between antipyrine clearance and liver volume. Thus, intersubject variation in clearance normalised for liver volume was less than clearance alone. Antipyrine clearance normalised for liver volume in patients with liver disease was significantly lower than in normal subjects and there was no overlap with normal subjects. In conclusion, assessment of drug metabolising efficiency per unit volume of liver increased the discrimination in differentiating subjects with normal from abnormal livers.

Onchocerciasis control strategies

Sir—Frank Richards and colleagues (May 13, p 1663) raise strategic issues relating to the onchocerciasis control programmes. The strategy of the African Programme for Onchocerciasis Control (APOC) is based on annual mass treatment with ivermectin. Richards and colleagues state that APOC accepts that this strategy “will not stop transmission” and that “treatment may need to be continued indefinitely”. However, community trials have shown that mass treatment with ivermectin results in a major reduction in onchocerciasis transmission and that repeated ivermectin treatment reduces the productivity of adult O volvulus. Computer simulations indicate that interruption could be achieved after 15–25 years of annual treatment. The objective of APOC is to establish sustainable, communitydirected treatment with ivermectin by 2007, when the programme will come to an end, with the goal of eliminating onchoceriasis as a public health and socioeconomic problem throughout Africa. APOC does envisage an endpoint for yearly ivermectin treatment but the required duration is being determined by the establishment of a monitoring system to assess the decline in infection and transmission levels. In most of the area covered by the Onchocerciasis Control Programme in West Africa (OCP) that has been under effective control, the parasite has been virtually eliminated. In these areas, vector control ceased in 1989 and although the vector returned to pre-control densities within weeks, transmission has remained interrupted and no further intervention has been needed. OCP established a surveillance system for early detection of possible recrudescence and had developed an intervention strategy that aims to quickly stop transmission by ivermectin treatment. Thus, for much of the OCP area, surveillance by national teams will be the only intervention when OCP comes to an end in 2002. Contrary to Richards and Colleagues’ assumptions, only the OCP areas that have not fully benefited from vector control, will switch to the APOC strategy. In an isolated focus in Senegal, ivermectin treatment was given biannually in an attempt to interrupt transmission. Preliminary results indicate that this aim has been achieved after 9 years of intervention. If confirmed, these results might warrant further experimentation with 6-monthly treatment in large hyperendemic areas in Africa. Richards and colleagues also refer to 6-monthly treatment in Guatemala and Ecuador. However, experiences in Africa and South America are difficult to compare because of differences in vectors and numbers of people affected. Doubling the number of treatments would have major implications, and Richards and colleagues do not recognise the logistics and costs of additional treatment. These include geopolitical realities of distribution in complex emergencies; the need to continue expansion of APOC into the remaining hyperendemic and mesoendemic areas; and the uncertainties about onchocerciasis transmission in hypoendemic areas. Whatever the frequency of treatment, a definite solution will be difficult with ivermectin alone. Research on alternative drugs that would kill or sterilise the adult worms is going ahead. Promising results have been obtained with moxidectin. Work on the effect of albendazole 400 on onchocerciasis, whether alone or in combination with ivermectin (the same dose as recommended for lymphatic filariasis elimination), shows that albendazole 400 had no effect on the viability or reproductive capacity of adult O volvulus. We agree the lymphatic filariasis programme offers synergy and reinforcement of control. But annual treatment with albendazole and ivermectin is unlikely to have more effect on onchocerciasis than ivermectin alone.