Population Pharmacokinetic Characteristics of Amikacin in Suspected Cases of Neonatal Sepsis in a Low-Resource African Setting: A Prospective Nonrandomized Single-Site Study.

BACKGROUND: Amikacin exhibits marked pharmacokinetic (PK) variability and is commonly used in combination with other drugs in the treatment of neonatal sepsis. There is a paucity of amikacin PK information in neonates from low-resource settings. OBJECTIVES: To determine the PK parameters of amikacin, and explore the influence of selected covariates, including coadministration with aminophylline, on amikacin disposition in neonates of African origin. METHODS: Neonates with suspected sepsis admitted to an intensive care unit in Accra, Ghana, and treated with amikacin (15 mg/kg loading followed by 7.5 mg/kg every 12 hours), were recruited. Serum amikacin concentration was measured at specified times after treatment initiation and analyzed using a population PK modeling approach. RESULTS: A total of 419 serum concentrations were available for 247 neonates. Mean (SD) trough amikacin concentration (from samples collected 30 minutes before the fourth dose) among term (n = 25), and preterm (<37 weeks' gestation n = 36) neonates were 6.2 (3.4) and 9.2 (5.7) µg/mL, respectively (P = 0.02). A 1-compartment model best fitted amikacin disposition, and birth weight was the most important predictor of amikacin clearance (CL) and distribution (V). The population CL and V of amikacin were related as CL (L/h) = 0.153 (birth weight/2.5)1.31, V (L) = 2.94 (birth weight/2.5)1.18. There was a high between-subject variability (58.9% and 50.7%) in CL and V, respectively. CL and V were 0.058 L/h/kg and 1.15 L/kg, respectively, for a mean birth weight of 2.1 kg, and the mean half-life (based on 1-compartment model), was 13.7 hours. CONCLUSIONS: The V and half-life of amikacin in this cohort varied from that reported in non-African populations, and the high trough and low peak amikacin concentrations in both term and preterm neonates suggest strategies to optimize amikacin dosing are required in this population.

A comprehensive study of Easter lily poisoning in cats.

This study was conducted with 3 objectives in mind: first, to identify the toxic fraction (aqueous or organic) in leaves and flowers; second, to identify diagnostic marker(s) of toxicosis in cats; and, third, to evaluate the morphologic effects of intoxication. The study was conducted in 2 phases. Phase 1 was to identify which extract, organic or aqueous, was nephrotoxic and also to determine the appropriate dose for use in the phase 2 studies. Results indicated that only the aqueous extracts of leaves and flowers were nephrotoxic and pancreotoxic. To identify the proximate toxic compound, cats in the phase 2 study were orally exposed to subfractions of the aqueous flower extract, 1 subfraction per cat. Results confirmed vomiting, depression, polyuria, polydipsia, azotemia, glucosuria, proteinuria, and isosthenuria as toxic effects of the Easter lily plant. Another significant finding in serum was elevated creatinine kinase. Significant histologic kidney changes included acute necrosis of proximal convoluted tubules and degeneration of pancreatic acinar cells. Renal ultrastructural changes included swollen mitochondria, megamitochondria, edema, and lipidosis. Subfraction IIa3 of the aqueous floral extract contained most of the toxic compound(s). These studies reproduced the clinical disease, identified the most toxic fraction of the Easter lily, and helped characterize the clinical pathology, histopathology, and ultrastructural pathology associated with the disease.

Natural cocoa ingestion reduced liver damage in mice infected with Plasmodium berghei (NK65).

PURPOSE: This study tested whether natural cocoa powder ingestion could mitigate hepatic injury coincident with murine malaria. Plasmodium berghei infection causes liver damage including hepatic sinusoidal distension, and elevated serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. According to literature, these pathologies largely result from activity of reactive oxygen species (ROS) and may be extenuated by antioxidants. ANIMALS AND METHODS: Thirty Balb/c mice were randomly assigned to three equal groups. One of two groups of mice inoculated with 0.2 mL of P. berghei-parasitized red blood cells (RBCs) was given unrestricted 24-hour access to a natural cocoa powder beverage (2% by weight) in place of water. The third group of mice were neither infected nor given cocoa. All mice were fed the same standard chow. After 6 days, mice were sacrificed and their livers processed for histomorphometric assessment of mean hepatic sinusoidal diameter as a quantitative measure of altered morphology. Serum ALT and AST were measured as a gauge of functional impairment. RESULTS: Compared with uninfected mice, hepatic sinusoidal diameter in P. berghei-infected mice not given cocoa increased by 150%, whereas a smaller increase of 83% occurred in infected mice that ingested cocoa. Mean serum ALT increased by 127% in infected mice not given cocoa and 80% in infected mice that consumed cocoa, compared with the value for uninfected mice. Similarly, mean serum AST was raised by 141% in infected mice not given cocoa and 93% in infected mice that drank cocoa. CONCLUSION: Distension of hepatic sinusoidal diameter in P. berghei-infected mice was reduced by 67%, whereas respective elevations of serum ALT and AST concentrations were reduced by 47% and 48% via ingestion of cocoa. Anti-inflammatory and antioxidant components of cocoa probably mediated the demonstrated hepatoprotective benefit by blunting pernicious ROS activity in P. berghei-infected mice.

In vitro activity of extract and fractions of natural cocoa powder on Plasmodium falciparum.

Several flavonoids isolated from certain plants have demonstrated antiplasmodial activity, after their initial indigenous use in malaria treatment. Cocoa has been found to be a rich food source of flavonoids in comparison with many common foods and beverages. The aim of this work was to investigate the in vitro activity of natural cocoa powder on the growth of Plasmodium falciparum. Prepared crude methanol extract was partitioned successively with petroleum ether, ethyl acetate, chloroform, and butanol. Total flavonoid concentration in the crude methanol extract and fractions was measured by the AlCl(3) colorimetric assay. Direct inhibitory activity of the natural cocoa powder was assessed by culturing extract and fractions with P. falciparum in vitro. Greater antiplasmodial activity was observed in nonpolar solvent fractions (chloroform, ethyl acetate, and petroleum ether) compared with polar solvents. The chloroform fraction was most active, with mean±SEM 50% and 90% inhibition concentrations of 48.3±0.9 and 417±7.8 µg/mL, respectively. The study showed a weak association between total flavonoid concentration and antiplasmodial activity. Early trophozoite (ring-stage) synchronized cultures treated with the chloroform fraction of natural cocoa powder showed a decline in growth. Further reduction in parasitemia was also observed for other erythrocytic stages. These results suggest that natural cocoa powder has measurable direct in vitro inhibitory effect on P. falciparum and support the anecdotal reports of its ability to prevent malaria as a result of regular intake as a beverage.