Two plants
Cardiospermum halicacabum L. and
Momordica foetida Schumch. Et Thonn traditionally used to treat symptoms of malaria in parts of East and Central Africa were screened for in vitro and in ...vivo antimalarial activity. Using the nitro tetrazolium blue-based parasite lactate dehydrogenase assay as used by Makler, M.T., Ries, J.M., Williams, J.A., Bancroft, J.E., Piper, R.C., Gibbins, B.L., Hinrichs, D.J., 1993. Parasite lactate dehydrogenase as an assay for
Plasmodium falciparum drug sensitivity. American Journal of Tropical Medicine and Hygiene 48, 739–741, water extracts from the two plants were found to have weak in vitro antiplasmodial activity with 50% inhibitory concentrations (IC50s) greater than 28.00
μg/ml. In vivo studies of water extracts from the two plants showed that
Momordica foetida given orally in the dose range 10, 100, 200 and 500mg/kg twice daily prolonged survival of
Plasmodium berghei (Anka) infected mice from 7.0
±
1.8 to 17.9
±
1.8 days. The water extract of
Cardiospermum halicacabum L was toxic to mice, none surviving beyond day 4 of oral administration, with no evidence of protection against
Plasmodium berghei malaria. The study emphasizes the discrepancy that might be found between in vitro and in vivo testing of plant-derived antimalarial extracts and the need to consider in vitro antiplasmodial data with this in mind. Further studies on
Momordica foetida as a source of an antimalarial remedy are indicated on the basis of these results.
Four traditional medicinal plants of east and central Africa, Emilia discifolia (Oliv.) C. Jeffrey, Senecio stuhlmannii, Indigofera emarginella A. Rich. and Aspilia africana (Pers) C.D. Adams, were ...screened for in vitro antimalarial activity using the nitro-tetrazolium blue-based parasite lactate dehydrogenase assay. The plant parts were collected in two batches: one in the wet season and the other in the dry season. The ethyl acetate extract of A. africana had the highest antiplasmodial activity against both the chloroquine-sensitive D10 inhibitory concentration (IC)₅₀ = 9.3; 7.7-10.9 μg ml⁻¹ and the chloroquine-resistant K1 (IC₅₀ = 11.5; 8.7-14.3 μg ml⁻¹) strains of P. falciparum. There was a positive correlation between the antiplasmodial activity of the extracts against the D10 and K1 strains of P. falciparum (Pearsons' coefficient, r = 0.9691, P =0.05). Yields of extracts and their antiplasmodial activity varied with season in some plant species. This study shows that some East African medicinal plants can serve as a source of lead compounds for the development of new drugs against the chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. The need for optimization of the conditions of harvest to maximize yields is also highlighted.
Traditional antimalarial medicinal preparations are widely used concurrently with antimalarial drugs in malaria endemic areas. The plant
Aspilia africana (Pers.) C.D. Adams is commonly used for ...traditional treatment of malaria symptoms in East and Central Africa. An in vitro study of interactions between an extract from this plant with artemisinin against two strains of
Plasmodium falciparum showed an antagonist relationship against both the chloroquine-sensitive D10 and the chloroquine- and sulphonamide-resistant K1 strains of
Plasmodium falciparum. The extract reduced accumulation of radiolabelled dihydroartemisinin (
3H-DHA) by erythrocytes infected with the chloroquine- and sulphonamide-resistant K1 strain of
Plasmodium falciparum while it increased its accumulation by erythrocytes infected with the chloroquine-sensitive D10 strain. These results suggest complex interactions between the antimalarial medicinal plant and artemisinin. This study also proposes an in vitro approach to investigating interactions between antimalarial drugs and traditional medicines.
Background
Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to ...be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV‐infected Ugandans.
Methods
Efavirenz plasma concentrations were obtained for 66 HIV‐infected Ugandans initiating efavirenz‐ based regimens, with blood samples collected at eight time‐points over 24 h on day 1 of treatment, and at a further eight time‐points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz.
Results
The mean steady‐state minimum plasma concentration (Cmin) of efavirenz was 2.9 µg/mL, the mean area under the curve (AUC) was 278.5 h µg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (Cmax) of efavirenz was >4 µg/mL in 96.6% of participants, while Cmin was <1 µg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2‐week period, and 95% of these participants were found to have efavirenz plasma concentrations >4 µg/mL, although only half maintained a high concentration until at least 8 h after dosing.
Conclusion
The findings of this study show that HIV‐infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to Cmax, regardless of the sampling time.
An ethnobotanical survey on traditional treatment of malaria was carried out in Mbarara District, western Uganda, a malaria‐endemic area. From this study, traditional healers understood malaria ...symptoms. Malaria was reported to be the most common condition treated by traditional healers in this area. Plants were the single most important source of natural products used for malaria treatment. Most of the plants used in malaria treatment belong to the family Asteraceae. The most commonly used plant parts were the leaves. Water was the most common solvent and the oral route was the most commonly used. From this study there are a number of plants in Mbarara district that can be used as sources of herbal remedies for malaria. A number of these plants can be incorporated in the national primary healthcare package after scientific studies on safety and efficacy are done.
Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate at two million deaths per year while one third of the world's population is infected with the TB ...bacillus.
To determine the efficacy of the crude extracts of Erythrina abyssinica root bark on rifampicin-resistant TB.
Crude extracts of root bark of Erythrina abyssinica, were screened against three strains of Mycobacterium tuberculosis including rifampicin-resistant TMC-331. Susceptibility tests used the disc diffusion method and were done on solid Middle brook 7H10, while the Minimum Inhibitory concentration (MICs) and minimum bactericidal concentration (MBCs) were determined by the Microtitre plate method using Middle brook 7H9 broth.
The total crude methanol extract showed activity against all the three strains of mycobacterium used, at 50mg/ml and diameters of zones of inhibition of up to 26 mm. Erythrina abyssinica total crude methanol extract showed the highest activity on the pan sensitive strain H37Rv (0.39±0.0 mg/ml) and the rifampicin resistant strain (TMC-331) (2.35±1.11 mg/ ml) and was also active on Mycobacterium avium (0.39±0.mg/ml. The values for isoniazid were 0.25µg/ml and 9.38µg/ml for H37Rv and TMC-331 respectively, while for rifampicin the MIC value was 0.25µg/ml for H37Rv but it was not active on TMC-331. Acute toxicity test gave an LD50 of 776.2mg/kg body weight while the phytochemical analysis showed the presence of alkaloids, tannins and flavones.
The conclusion from the study was that Erythrina abbyssinica has antimycobacterial activity and reasonable safety that merits further research.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population ...pharmacokinetics has not yet been fully explored.
• CYP2B6*6 influences efavirenz steady‐state pharmacokinetics. Together with sex it explains 11% of the between‐subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified.
• ABCB1 (3435C→T) may have effect on efavirenz single‐dose and steady‐state pharmacokinetics.
WHAT THIS STUDY ADDS
• A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single‐dose pharmacokinetics.
• A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single‐dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population.
AIMS
Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single‐dose efavirenz pharmacokinetics among Ugandan subjects, using nonmem.
METHODS
Efavirenz plasma concentrations (n= 402) from 121 healthy subjects were quantified by high‐performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two‐compartment model with zero‐ followed by first‐order absorption.
RESULTS
Apparent oral clearance (95% confidence interval) was 4 l h l−1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men.
CONCLUSIONS
The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single‐dose administration. Use of mixed‐effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
HIV infection, anti-tuberculosis and efavirenz therapy are associated with neuropsychological effects. We evaluated the influence of rifampicin cotreatment, efavirenz pharmacokinetics and ...pharmacogenetics on neuropsychiatric disorders in Ugandan HIV patients with or without tuberculosis coinfection.
197 treatment naïve Ugandan HIV patients, of whom 138 were TB co-infected, enrolled prospectively and received efavirenz based HAART. TB-HIV confected patients received concomitant rifampicin based anti-TB therapy. Genotypes for CYP2B6 (*6, *11), CYP3A5 (*3, *6, *7), ABCB1 (c.3435C>T and c.4036 A/G rs3842), CYP2A6 (*9, *17) and NR1I3 rs3003596 T/C were determined. Efavirenz plasma concentrations were serially quantified at 3rd day, 1st, 2nd, 4th, 6th, 8th and 12th weeks during therapy. Efavirenz neuropsychiatric symptoms were evaluated in terms of sleep disorders, hallucinations and cognitive effects at baseline, at two and twelve weeks of efavirenz treatment using a modified Mini Mental State Examination (MMSE) score.
During the first twelve weeks of ART, 73.6% of the patients experienced at least one efavirenz related neuropsychiatric symptom. Commonest symptoms experienced were sleep disorders 60.5% (n=124) and hallucination 30.7% (n=63). Neuropsychiatric symptoms during HAART were significantly predicted by efavirenz plasma concentrations consistently. Rifampicin cotreatment reduced plasma efavirenz concentrations significantly only during the first week but not afterwards. There was no significant difference in the incidence of neuropsychiatric symptoms between patients receiving efavirenz with or without rifampicin cotreatment. CYP2B6*6 and ABCB1 c.4036 A/G genotype significantly predicted efavirenz concentrations. The tendency of CYP2B6*6 genotype association with higher incidence of having vivid dream (p=0.05), insomnia (p=0.19) and tactile hallucination (p=0.09) was observed mainly at week-2.
Efavirenz related neuropsychiatric symptoms are common among Ugandan HIV patients receiving ART and is mainly predicted by higher efavirenz plasma concentrations and CYP2B6 genotype but not by rifampicin based anti-TB co-treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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