LACTONE-CARBOXYLATE INTERCONVERSION AS A DETERMINANT OF THE CLEARANCE AND ORAL BIOAVAILABILTY OF THE LIPOPHILIC CAMPTOTHECIN ANALOG AR-67

The third generation camptothecin analog, AR-67, is undergoing early phase clinical trials as a chemotherapeutic agent. Like all camptothecins it undergoes pH dependent reversible hydrolysis between the lipophilic lactone and the hydrophilic carboxylate. The physicochemical differences between the lactone and carboxylate could potentially give rise to differences in transport across and/or entry into cells. In vitro studies indicated reduced intracellular accumulation and/or apical to basolateral transport of AR-67 lactone in P-gp and/or BCRP overexpressing MDCKII cells and increased cellular uptake of carboxylate in OATP1B1 and OATP1B3 overexpressing HeLa-pIRESneo cells. Pharmacokinetic studies were conducted in rats to study the disposition and oral bioavailability of the lactone and carboxylate and to evaluate the extent of the interaction with uptake and efflux transporters. A pharmacokinetic model accounting for interconversion in the plasma was developed and its performance evaluated through simulations and in vivo transporter inhibition studies using GF120918 and rifampin. The model predicted well the likely scenarios to be encountered clinically from pharmacogenetic differences in transporter proteins, drug-drug interactions and organ function alterations. Oral bioavailability studies showed similarity following lactone and carboxylate administration and indicated the significant role ABC transporters play in limiting the oral bioavailability

Teratogenic Effect of High Dose of Syzygium guineense (Myrtaceae) Leaves on Wistar Albino Rat Embryos and Fetuses

Syzygium guineense is an important medicinal plant effective against hypertension, diabetes mellitus, and cancer but with no evidence of its teratogenicity. This study was planned to investigate the teratogenic potential of S. guineense leaves on rat embryos and fetuses. Five groups of Wistar albino rats, each consisting of ten pregnant rats, were used as experimental animals. Groups I-III rats were treated with 250, 500, and 1000 mg/kg of hydroethanolic extract of S. guineense leaves, and groups IV and V were control and ad libitum control, respectively. Rats were treated during day 6–12 of gestation. Embryos and fetuses were retrieved at day 12 and day 20 of gestation, respectively. The embryos were assessed for developmental delays and growth retardation. The fetuses were examined for gross external, skeletal, and visceral anomalies. In 12-day old rat embryos, crown-rump length, number of somites, and morphological scores were significantly reduced by the treatment of 1000 mg/kg of the extract. The external morphological and visceral examinations of rat fetuses did not reveal any detectable structural malformations in the cranial, nasal, oral cavities, and visceral organs. The ossification centers of fetal skull, vertebrae, hyoid, forelimb, and hindlimb bones were not significantly varied across all groups. However, even if not statistically significant, high-dose treated rat fetuses had a reduced number of ossification centers in the sternum, caudal vertebrae, metatarsal, metacarpal, and phalanges. Treatment with the hydroethanolic extract of S. guineense leaves produced no significant skeletal and soft tissue malformations. The plant extract did not produce significant teratogenic effects on rat embryos/fetuses up to 500 mg/kg doses but retarded the growth of embryos at high dose (1000 mg/kg) as evidenced by decreased crown-rump length, number of somites, and morphological scores. Therefore, it is not advisable to take large doses of the plant during pregnancy

MIC of selected plant extracts against gram positive bacterial strains.

MIC of selected plant extracts against gram positive bacterial strains.</p

MIC of selected plant extracts against gram negative bacterial strains.

MIC of selected plant extracts against gram negative bacterial strains.</p

Raw data for minimum inhibitory concentration (MIC) determination.

Raw data for minimum inhibitory concentration (MIC) determination.</p

Antibacterial activity of 80% ethanol and aqueous leaf extracts against pathogenic organisms.

Antibacterial activity of 80% ethanol and aqueous leaf extracts against pathogenic organisms.</p

Ethnobotanical data on medicinal plants selected for antibacterial tests and phytochemical screening.

Ethnobotanical data on medicinal plants selected for antibacterial tests and phytochemical screening.</p

Phytochemical screening tested medicinal plants.

Ethiopia’s healthcare system relies on traditional medicinal practices that use medicinal plants to treat human and livestock ailments. However, the lack of empirical validation regarding the efficacy of these treatments against specific infectious diseases necessitates rigorous scientific investigations. The objective of this study was to investigate the antibacterial activity and phytochemical screening on five selected medicinal plant species, namely Solanum somalense Franchet., Verbascum sinaiticum Benth., Rumex nervosus Vahl, Withania somnifera (L.) Dunal and Calpurnia aurea (Ait.) Benth. The plants were first identified jointly with local informants and later considering mainly their high informant consensus and fidelity level values for their efficacy in treating infectious diseases in the area. Ethanol and aqueous extracts were prepared from the plant materials, and their antibacterial activities were evaluated against standard bacterial strains, representing both gram-positive and gram-negative types. To assess the antibacterial activity of the extracts, the minimum inhibitory concentration (MIC) was determined using the broth dilution method. Additionally, phytochemical screening was performed using standard qualitative tests to identify various secondary metabolites. The results indicated antibacterial efficacy in the ethanol extracts of S. somalense, W. somnifera, and C. aurea against particular bacterial strains (S. somalense against S. agalactiae with MIC of 1.5 mg/mL; W. somnifera against S. aureus and E. coli, with MIC of 2 mg/mL; C. aurea against E. coli and K. pneumoniae, with MICs of 3 mg/mL and 3.5 mg/mL, respectively). The results of the phytochemical screening indicated the presence of steroids, alkaloids, flavonoids, saponins, and terpenoids. The selected medicinal plants demonstrated promising antibacterial activity against certain bacterial strains. The current findings support the long-standing claim of the traditional medical system of the study area for their continued use of these plants in their treatment of infectious diseases. Further investigation is required to isolate the responsible active compounds and characterize the constituents and description of their antibacterial effect for possible use in areas where these infectious diseases are major health problems.</div