The effects of induced diabetes and cutaneous Leishmania infection on the pharmacokinetics of antimony in hamsters.

Patients with certain diseases appear to be at greater risk of developing adverse drug interactions, either because of the disease state itself or the drugs used to treat it. The effects of streptozotocin-induced diabetes and/or cutaneous Leishmania major infection on the pharmacokinetics of antimony (SbV) have now been investigated, in hamsters treated with sodium stibogluconate (Pentostam). The animals were randomly divided into five groups, each of 20 hamsters, known as D (for diabetes without leishmaniasis), DL (diabetes induced prior to the leishmaniasis), L (leishmaniasis without diabetes), LD (diabetes induced after leishmanial infection) and C (the control group, of animals with neither diabetes nor leishmaniasis). After its diabetes and/or leishmaniasis (if any) was established, each animal was given an intramuscular dose of sodium stibogluconate (80 mg/kg) each day for 3 weeks. Blood samples were collected after the first or last doses, to allow the pharmacokinetic parameters of SbV after single and multiple dosing to be compared. Although the between-dose interval (24 h) was more than 10 times longer than the terminal elimination rate constant (t1/2) at steady state, there was a significant increase in the mean peak SbV concentration (Cmax), as the result of multiple dosing, in all five groups (P<0.001 for each). The hamsters with diabetes showed the least accumulation of SbV in their blood, whether or not they were infected with L. major. In the non-diabetic animals of groups L and C, the apparent total clearance of SbV (CL/F) was decreased by multiple dosing, being, respectively, 34.5% and 23.0% lower after the 21st dose than after the first. An increase in urine volume was the reason for the significant increase in CL/F in group D (P<0.001), and this offset the decrease in CL/F seen in the L group, resulting in no change in CL/F in the animals of the DL group. Three weeks of antileishmanial treatment produced no significant reductions in the leishmanial lesions on the parasite-inoculated foot-pads of the hamsters in the L or DL groups but such reductions were detected in the animals of the LD group (P<0.001). In conclusion, it appears that the administration of SbV over a few weeks may cause renal toxicity and, in clinical use, should therefore be accompanied by the regular monitoring of renal function. A cautious increase in SbV dosing may be necessary for the effective treatment of L. major (and perhaps other species of Leishmania) in diabetic patients.

Phylogeography of Biomphalaria glabrata and B. pfeifferi, important intermediate hosts of Schistosoma mansoni in the New and Old World tropics.

The historical phylogeography of the two most important intermediate host species of the human blood fluke Schistosoma mansoni, B. glabrata in the New World, and B. pfeifferi in the Old World, was investigated using partial 16S and ND1 sequences from the mitochondrial genome. Nuclear sequences of an actin intron and internal transcribed spacer (ITS)-1 were also obtained, but they were uninformative for the relationships among populations. Phylogenetic analyses based on mtDNA revealed six well-differentiated clades within B. glabrata: the Greater Antilles, Venezuela and the Lesser Antilles, and four geographically overlapping Brazilian clades. Application of a Biomphalaria-specific mutation rate gives an estimate of the early Pleistocene for their divergence. The Brazilian clades were inferred to be the result of fragmentation, due possibly to climate oscillations, with subsequent range expansion producing the overlapping ranges. Within the Venezuela and Lesser Antilles clade, lineages from each of these areas were estimated to have separated approximately 740 000 years ago. Compared to B. glabrata, mitochondrial sequences of B. pfeifferi are about 4x lower in diversity, reflecting a much younger age for the species, with the most recent common ancestor of all haplotypes estimated to have existed 880 000 years ago. The oldest B. pfeifferi haplotypes occurred in southern Africa, suggesting it may have been a refugium during dry periods. A recent range expansion was inferred for eastern Africa less than 100 000 years ago. Several putative species and subspecies, B. arabica, B. gaudi, B. rhodesiensis and B. stanleyi, are shown to be undifferentiated from other B. pfeifferi populations.

Overweight and obesity in Saudi females of childbearing age.

OBJECTIVE: Overweight and obesity are among the most frequently encountered multifactorial disorders in most populations of the world. The aim of this study was to determine the prevalence of overweight and obesity in Saudi females of childbearing age. MATERIALS AND METHODS: The study was approved by the University Scientific Committee. It included a group of 600 randomly recruited healthy females with age ranging from 16-45 y. Four hundred and twenty one were students and 179 were housewives attending outpatient clinics for minor illnesses. Informed consent was obtained. Height and weight were recorded on one occasion. Body mass index (BMI) was calculated. RESULTS: Height, weight and BMI showed normal Gaussian distribution in these females and there was a significant positive correlation between BMI and age of each subject (r=0.505; P

Experimental chemotherapy of leishmaniasis with adenosine analogue Formycin A, in combination with inhibitor of nucleoside transport, nitrobenzylthioinosinate.

A single dose of the adenosine analogue Formycin A (FoA) (20 mg/kg), combined with nitrobenzyl mercaptopurine ribonucleoside 5'-monophosphate (NBMPR-P) (10 mg/kg), a prodrug of nitrobenzylthioinosine (NBMPR), was effective in reducing the size of the foot pad lesions from 7.4 +/- 0.2 to 3.9 +/- 0.2 of Syrian golden hamsters infected with Leishmania major. There was a statistical difference (p < 0.01) in the size of the foot pad by the fifth day between the infected groups that received treatment and the controls, as well as between the groups that were treated with combined drugs and FoA only. The initial reduction in size of the foot pad noted in the group that received only FoA was transient. The effect of FoA or FoA combined with NBMPR on the in vitro cultured promastigotes was similar, indicating that the transport inhibitor might be manipulating the availability of FoA in the host's macrophages where the leishmania amastigotes are resident. The results further indicate the need to explore the usefulness of combining cytotoxic nucleoside analogues with host protecting nucleoside transport inhibitors in the treatment of protozoan parasitic infections.

Leishmania donovani: characteristics of adenosine and inosine transporters in promastigotes of two different strains.

The nucleoside transport characteristics of two strains of Leishmania donovani promastigotes were studied. Strain S1, growing in fully defined medium, and strain S2 (MHOM/ET/67/HA3) both transported adenosine and inosine, but only strain S1 transported uridine and thymidine. Competition studies in the presence of 100 microM of unlabeled adenosine, inosine, guanosine, 2'-deoxyadenosine, tubercidin, formycin B, 3'-deoxyinosine as well as uridine, thymidine and cytidine, with either 1 microM [3H]adenosine or [3H]inosine as permeant, were carried out. The inhibition profile with [3H]inosine as permeant was essentially identical in S1 and S2 promastigotes, indicating that the same inosine transporter was present in both strains. However, with [3H] adenosine as permeant, significant differences were noted between the two strains. Thus, only adenosine, 2'-deoxyadenosine, tubercidin, uridine, and thymidine were strongly inhibitory in S1 promastigotes, while essentially all nucleosides tested were effective in S2 promastigotes. This indicates that adenosine transport in S2 promastigotes seems to involve a transporter differing from that described for S1 promastigotes.