CYP3A5 genotype has an impact on the metabolism of the HIV protease inhibitor saquinavir.

CYP3A is the main enzyme subfamily involved in the metabolism of the HIV protease-inhibitor saquinavir. We hypothesized that individuals homozygous for CYP3A5*1 might have a higher oral clearance of saquinavir, compared with subjects lacking functional CYP3A5 alleles. A single-dose pharmacokinetic trial of saquinavir soft gel capsules, 1,200 mg, was performed in 16 black Tanzanian healthy volunteers with two functional CYP3A5 alleles (*1/*1) and in 18 volunteers without functional CYP3A5 alleles (both alleles being either *3, *6, or *7). The median area under the plasma concentration-time curve (AUC)0-24 reached among subjects with two functional alleles was 1,410 ng h/ml (interquartile range (IQR) 826-1,929), whereas it was 2,138 ng h/ml (IQR 1,380-3,331) in subjects without (P=0.0533, Mann-Whitney U-test). The median ratio of saquinavir over its M2 plus M3 hydroxy metabolites in urine was 64 (IQR 52-73) in subjects with two functional alleles, whereas it was 145 (IQR 89-181) in those without (P=0.000078, Mann-Whitney U-test). In conclusion, saquinavir is metabolized by CYP3A5. The median AUC0-24 for saquinavir among individuals with two functional CYP3A5 alleles was 34% lower than among those with no functional alleles. To clarify the clinical importance of the CYP3A5 polymorphism, further studies should be conducted on saquinavir, dosed to steady state, in the presence of ritonavir boosting.

Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients.

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.

Evaluation of risk factors for Alzheimer's disease in elderly east Africans.

A number of biological risk factors have been implicated for Alzheimer's disease (AD). The investigation of prevalence rates of AD in crosscultural populations has much potential in validating these factors. We previously assessed brain amyloid beta (A beta) protein deposition and other lesions associated with AD as possible markers for preclinical AD in elderly nondemented East Africans. In further analysis, we demonstrate that 17-19% of elderly East African subjects without clinical neurological disease exhibited neocortical A beta deposits and minimal neurofibrillary changes at necropsy that was qualitatively and quantitatively similar to that in an age-matched elderly control sample from Cleveland, OH. A beta deposits varied from numerous diffuse to highly localized neuritic plaques and were predominantly reactive for the longer A beta 42 species. In parallel studies, we evaluated another recently implicated factor in AD, the apolipoprotein E genotype. We found relatively high frequencies of the apolipoprotein E-epsilon 4 allele in elderly nondemented East Africans. The frequencies were comparable to those in other African populations but higher than in subjects from developed countries. Our limited study suggests that elderly East Africans acquire cerebral lesions found in AD subjects but the apolipoprotein E-epsilon 4 allele may not be a highly specific factor for the disease among East Africans.

Apolipoprotein E polymorphism in elderly east Africans.

Current advances have shown the apolipoprotein E (APOE)-epsilon 4 allele to be highly associated with late-onset familial and sporadic Alzheimer's disease (AD) in Western populations. The association of APOE allele frequencies and dementia remain unknown in populations from developing countries. We recently initiated a project to examine APOE frequencies in non-demented and demented elderly East Africans. Blood DNA collected from two hospital-based populations showed that the APOE allele frequencies in a group of non-demented 67 Tanzanians over the age of 65 years were found to be 14% for epsilon 2, 61% for epsilon 3 and 25% for epsilon 4. By comparison, the frequency of APOE-epsilon 4 in an age-matched demented group was also 25%. Assessment of APOE genotypes in the group of elderly Kenyan subjects from Nairobi also revealed high frequencies of the epsilon 4 allele with no clear difference in frequency between demented and non-demented subjects. Our preliminary observations suggest that elderly East Africans with no apparent clinical AD possess relatively high APOE-epsilon 4 allele frequencies compared to normal ageing subjects from Western countries including African-Americans. These results appear similar to those reported in a recent study in Nigerian Africans where a lack of correlation between APOE-epsilon 4 allele frequency and Alzheimer type of dementia was noted, and imply that APOE-epsilon 4 allele may not necessarily be a risk factor in some populations of Africa.

Cerebral amyloid beta protein deposits and other Alzheimer lesions in non-demented elderly east Africans.

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid beta (A beta) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age-matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical A beta deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound A beta deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact A beta deposits that were also predominantly reactive for the longer A beta 42 species compared to A beta 40. We also noted that A beta plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed A beta deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest A beta deposition and some NFT in brains of non-demented East Africans are qualitatively and quantitatively similar to that in age-matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.

Knowledge and management of malaria in Dar es Salaam, Tanzania.

A study of knowledge and management of malaria was undertaken prospectively in 20 dispensaries, 20 drug stores, 120 patients attending dispensaries and 120 customers at drug stores in Dar es Salaam, Tanzania. This was a descriptive study where two different questionnaires were developed and administered to the target groups in oral interview. All the respondents were aged 14 years and above. The results of the interview showed that the knowledge of rural medical aides (RMA's) on signs and symptoms of malaria and which drugs cure malaria was satisfactory. However, only 65% of the RMA's could remember the correct dose of chloroquine for an adult. Although the knowledge of drug sellers on signs and symptoms of malaria was adequate, 45% of them did not know the correct dose of chloroquine. In view of the fact that only 30% of patients and 20% of shoppers knew the correct dose of chloroquine for adults, it appears that their management of malaria is inadequate. To improve the management of malaria at dispensary and drug store level, there is a need to introduce treatment charts and/or guidelines and the Ministry of Health should promote health education to the public.

PIP: In early 1992 in Tanzania, trained research assistants interviewed 20 rural medical aides (RMAs), 20 drug sellers, 120 patients at 20 dispensaries, and 120 customers of drug stores, all in Dar es Salaam, to examine knowledge and practices of health workers, drug sellers, and patients concerning malaria. The RMAs had adequate knowledge of the signs and symptoms of malaria (e.g., 90% for fever, 85% for headache, and 80% for painful joints). The drug sellers also had adequate knowledge of signs and symptoms (e.g., 80% for fever, 45% for headache, and 50% for painful joints). Even though chloroquine-resistant strains of Plasmodium falciparum malaria exist in Tanzania, all RMAs and most drug sellers (85%) believed that chloroquine could cure malaria. Further, it is the only antimalarial that the Ministry of Health provides its dispensaries. Just 65% of RMAs knew the correct dosage of chloroquine for people 14 years old and older. An even lower percentage of drug sellers knew the correct dosage (50%). Just 33.7% of patients and 22.5% of customers knew the correct dosage of chloroquine. An inadequate supply of chloroquine was available at 15% of dispensaries and 30% of drug stores. RMAs sometimes gave patients too few chloroquine tablets for a full course of therapy. Other drugs mentioned by RMAs to treat malaria were quinine, amodiaquine, cotrimoxazole, halofantrine, pyrimethamine/sulphalene, and pyrimethamine/sulphadoxine. Those mentioned by drug sellers included aspirin plus chloroquine, cotrimoxazole, pyrimethamine/sulphadoxine, and traditional medicines. These findings suggest that irrational drug therapy of malaria promotes resistant strains and prolongs the duration of illness. Introduction of treatment charts and health education promotion to the public are needed to improve malaria management at dispensaries and drug stores.

Studies on the nöotropic potential of some angiotensin converting enzyme inhibitors in the mouse.

1. The effects of captopril, epicaptopril and fosenopril were compared with codergine mesylate in a number of tests which may be predicative of potential nöotropic activity. None of the drugs tested protected against KCN induced hypoxic seizures. However, in the acute atropine sulphate induced hyperactivity test, in which the behaviour of the mice in the 'open field' apparatus was assessed, both captopril and codergine mesylate were found to reverse the atropine induced hypermotility. The effect of captopril would not appear to be a direct reflection of its angiotensin converting enzyme (ACE) inhibitory activity as fosenopril is also a potent ACE inhibitor. 2. Only codergine mesylate was found to reverse the atropine sulphate induced amnesia in a one trial avoidance task, captopril and its analogues being inactive in such a test. 3. Chronically administered codergine mesylate, captopril and its analogues reversed the hypermobility in the 'open field' apparatus that occurred following the injection of a single dose of the neurotoxin trimethyltin. 4. None of the changes in locomotor activity would appear to be due to adverse effect of the drugs on motor coordination. 5. It is concluded that captopril may be worthy of more detailed studies as a potential nöotropic agent.