Effects of slowed gastrointestinal motility on levodopa pharmacokinetics

P. 67-72Autonomic disorders are often seen in Parkinson's disease, with disturbances of the gastrointestinal tract occurring most frequently. These disorders, mainly a delay in gastric emptying and slowed gastrointestinal motility, can modify the pharmacokinetics and effectiveness of drugs used to treat Parkinson's disease and administered orally. In this study, we evaluated in a rabbit model the pharmacokinetics of levodopa (administered with carbidopa) in the context of gastrointestinal motility slowed by the administration of an anticholinergic drug. Levodopa+carbidopa (20:5 mg/kg) and the anticholinergic biperiden (100 μg/kg) were orally administered to rabbits over one of two time periods (7 or 14 days) to verify the stabilization of levodopa concentrations. The values of the area under the curve (AUC) and Cmax were higher on the final day of treatment with an increase in AUC of 25% on day 7 and 33.4% on day 14; for Cmax, the increase was 15% on day 7 and 12.8% on day 14. The values of AUC and Cmax were lower than those obtained when levodopa was administered to rabbits with normal gastrointestinal motility. The values obtained for Cmin (baseline sample obtained before administration) also increased with treatment duration (24% and 47.4% on days 7 and 14, respectively). These values were higher than those obtained in the absence of anticholinergic administration. We conclude that, under our experimental conditions of slowed gastrointestinal motility, levodopa absorption diminishes, and final concentrations and Cmin are higher than under conditions of normal motility.S

Hypoglycemic and hypolipidemic potential of a high fiber diet in healthy versus diabetic rabbits

P. 960568 - 960575The aim of this study was to investigate potential hypoglycaemic and hypolipidemic effects of Plantago ovata husk included in the diet, in healthy and diabetic rabbits. We also examined the effects of this fiber in other biochemical parameters. Two groups of 18 rabbits were used.The first group was fed with standard chow and the second with chow supplemented with Plantago ovata husk (3.5mg/kg/day). On day 14 diabetes mellitus was induced by the intravenous administration of alloxan (80mg/kg). After an oral glucose load (3 g), glucose, insulin, and other biochemical parameters were determined on day 14 (healthy rabbits) and on day 28 (diabetic rabbits). In healthy rabbits, fiber did not modify glucose or insulin levels but decreased significantly total cholesterol, LDL-cholesterol, atherogenic index, and glycosylated hemoglobin. In diabetic rabbits, fiber was more beneficial in mild diabetics than in severe diabetics with significant decreases in glucose levels and increases in insulin concentrations. In these animals fiber caused an important reduction in cholesterol, indicating a beneficial effect of Plantago ovata husk in diabetic rabbits. Although further studies in patients are necessary, we think that Plantago ovata husk offers interesting perspectives to be administered to patients with diabetes mellitus.S

Haemoglobin interference and increased sensitivity of fluorimetric assays for quantification of low-parasitaemia Plasmodium infected erythrocytes

<p>Abstract</p> <p>Background</p> <p>Improvements on malarial diagnostic methods are currently needed for the correct detection in low-density <it>Plasmodium falciparum </it>infections. Microfluorimetric DNA-based assays have been previously used for evaluation of anti-malarial drug efficacy on <it>Plasmodium </it>infected erythrocytes. Several factors affecting the sensitivity of these methods have been evaluated, and tested for the detection and quantification of the parasite in low parasitaemia conditions.</p> <p>Methods</p> <p>Parasitaemia was assessed by measuring SYBRGreen I^®(SGI) and PicoGreen^®(PG) fluorescence of <it>P. falciparum </it>Dd2 cultures on human red blood cells. Different modifications of standard methods were tested to improve the detection sensitivity. Calculation of IC₅₀for chloroquine was used to validate the method.</p> <p>Results</p> <p>Removal of haemoglobin from infected red-blood cells culture (IRBC) increased considerably the fluorescent signal obtained from both SGI and PG. Detergents used for cell lysis also showed to have an effect on the fluorescent signal. Upon depletion of haemoglobin and detergents the fluorescence emission of SGI and PG increased, respectively, 10- and 60-fold, extending notably the dynamic range of the assay. Under these conditions, a 20-fold higher PG vs. SGI fluorescent signal was observed. The estimated limits of detection and quantification for the PG haemoglobin/detergent-depleted method were 0.2% and 0.7% parasitaemia, respectively, which allow the detection of ~10 parasites per microliter. The method was validated on whole blood-infected samples, displaying similar results as those obtained using IRBC. Removal of white-blood cells prior to the assay allowed to increase the accuracy of the measurement, by reducing the relative uncertainty at the limit of detection from 0.5 to 0.1.</p> <p>Conclusion</p> <p>The use of PG microassays on detergent-free, haemoglobin-depleted samples appears as the best choice both for the detection of <it>Plasmodium </it>in low-density infections and anti-malarial drugs tests.</p

Parasitostatic effect of maslinic acid. II. Survival increase and immune protection in lethal Plasmodium yoelii-infected mice

<p>Abstract</p> <p>Background</p> <p>The anti-malarial activity of maslinic acid (MA), a natural triterpene which has been previously shown to exert a parasitostatic action on <it>Plasmodium falciparum </it>cultures, was analysed <it>in vivo </it>by using the <it>Plasmodium yoelii </it>17XL murine model.</p> <p>Methods</p> <p>ICR mice were infected with <it>P. yoelii </it>and treated with a single dose of MA by a intraperitoneal injection of MA (40 mg kg^-1day^-1) followed by identical dose administration for the following three days. Parasitaemia and accumulation of intraerythrocytic stages was monitored microscopically. To assess protective immunity, cured mice were challenged with the same dose of parasites 40 days after recovery from the primary infection and parasitaemia was further monitored for 30 days. Humoral response was tested by ELISA and visualization of specific anti-<it>P. yoelii </it>antibodies was performed by Western-blotting.</p> <p>Results</p> <p>ICR mice treated with MA increased the survival rate from 20% to 80%, showing an arrest of parasite maturation from day 3 to 7 after infection and leading to synchronization of the intraerythrocytic cycle and accumulation of schizonts by day 6, proving that MA also behaves as a parasitostatic agent <it>in vivo</it>. Mice which survived the primary infection displayed lower rates of parasitic growth, showing a decline of parasitaemia after day 15, and complete clearance at day 20. These mice remained immunoprotected, showing not malaria symptoms or detectable parasitaemia after rechallenge with the same lethal strain. The analysis of specific antibodies against <it>P. yoelii</it>, present in mice which survived the infection, showed a significant increase in the number and intensity of immunoreactive proteins, suggesting that the protected mice may trigger a strong humoral response.</p> <p>Conclusion</p> <p>The survival increase observed in MA-treated mice can be explained considering that the parasitostatic effect exerted by this compound during the first days of infection increases the chances to develop effective innate and/or acquired immune responses. MA may represent a new class of anti-malarial compounds which, as a consequence of its parasitostatic action, favours the development of more effective sterilizing immune responses.</p

The hydrosoluble fiber Plantago ovata husk improves levodopa (with carbidopa) bioavailability after repeated administration

P. 15-20The influence of treatment duration (7 or 14 days) with Plantago ovata husk/levodopa/carbidopa in the bioavailability and other pharmacokinetic parameters of levodopa were evaluated in rabbits. Fiber was administered at two different doses, 100 and 400 mg/kg, and the dosage of levodopa/carbidopa was 20:5 mg/kg. These doses were administered once a day. When 100 mg/kg of fiber was administered, the mean AUC value obtained for levodopa increased 20.2% from day 1 to day 7, and 27.2% from day 1 to day 14; Cmax was 8.6% higher on day 7 and 11.7% higher on day 14. When administering 400 mg/kg of fiber, the increase in AUC values was 17.6% on day 7 and 24.9% on day 14, and that of Cmax 11.1% on day 7 and 11.3% on day 14. The concentration determined immediately before drug administration (Cmin) increased progressively with the duration of treatment, and the highest increase (53.2%) was observed on day 14 with 100 mg/kg of fiber. There was also a delay in levodopa elimination (higher MRT and lower Cl) in a fiber-dose dependent manner. In summary, we found that there was an improvement in the extent of levodopa absorbed with higher final concentrations and that levodopa elimination was slower with the administration of P. ovata husk.S

The Pharmacokinetics and interactions of ivermectin in humans—A mini-review

P. 42-46Ivermectin is an antiparasitic drug with a broad spectrum of activity, high efficacy as well as a wide margin of safety. Since 1987, this compound has a widespread use in veterinary medicine and it use has been extended in humans. Here we present a brief review of the information availabile regarding the pharmacokinetics and interactions of ivermectin in humans. Awareness of these characteristics could improve the clinical efficacy of Ivermectin. All Authors declare that they do not have any Conflict of interest and that the work is original. All Authors agree that the contents of the manuscript are confidential and will not be copyrighted, submitted, or published elsewhere (including the Internet), in any language, while acceptance by the Journal is under consideration.S

The pharmacokinetics and metabolism of ivermectin in domestic animal species

P. 25-37The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy. The kinetics of ivermectin are characterised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of which contribute to differences in drug efficacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several domestic animal species.S

Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

P. 389-395The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2- (n = 5) or 3- (n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (Vss) of 1.759 ± 0.3149 L/kg, a total clearance (Cl) of 3.045 ± 0.5264 mL/ kg/min and an elimination half-life (t1/2b) of 7.027 ± 1.128 h. Comparative values obtained from the 3-compartmental mean values were: Vss of 1.801 ± 0.3429 L/kg, a Cl of 2.634 ± 0.6376 mL/kg/min and a t1/2b of 12.11 ± 2.060 h. Mean residence time (MRT0_1) was 11.18 ± 3.152 h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (Cmax), 2.130 ± 0.950 lg/mL; time to reach Cmax (tmax), 3.595 ± 3.348 h, and absorption half-life (t1=2k01 ), 36.28 ± 14.57 h. Non-compartmental parameter values were: Cmax, 2.182 ± 0.9117 lg/mL; tmax, 3.432 ± 3.307 h; F, 35.77 ± 10.20%, and mean absorption time (MAT0–∞), 25.55 ± 15.27 h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.S