Current Issue : April - June Volume : 2013 Issue Number : 2 Articles : 8 Articles
Background: Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for\r\nthe treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited\r\ndata is available on pharmacokinetic interactions between these drugs.\r\nMethods: In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria,\r\nreceived either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of\r\namodiaquine (SP) or one dose of SP plus 3 daily doses of artesunate (SP). Exactly 100 �µl of capillary blood\r\nwas collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug\r\nadministration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.\r\nResults: Fourty, 38 and 31 patients in the SP, SP and SP arms, respectively were included in this study.\r\nThe concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP\r\nand SP treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-\r\n44.05] �µg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There\r\nwere statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00\r\n[3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and\r\n4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young\r\nchildren when compared with adult malaria patients.\r\nConclusion: Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these\r\ndata show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP\r\nin combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children....
Hwangryunhaedok-Tang (HR) and berberine-containing single herbs are used to treat bacterial infection and inflammatory\r\ndiseases in eastern Asia. The combination of berberine-containing herbal medicines and ciprofloxacin can be an excellent\r\nantibacterial chemotherapy against multidrug resistance bacteria. To evaluate the pretreatment effect of berberine and HR,\r\nvehicle, berberine (25 and 50 mg/kg/day), and HR (1.4 g/kg/day) were daily administered to rats for five consecutive days. On\r\nday 6, ciprofloxacin was administered (10 mg/kg, i.v. and 20 mg/kg, p.o.) to rats. To assess cotreatment effect of berberine and\r\nciprofloxacin, berberine (50 mg/kg) and ciprofloxacin (20 mg/kg) were coadministered by single oral gavage. Pharmacokinetic data\r\nwere estimated by noncompartmental model. Compared with ciprofloxacin alone (control group), coadministration of berberine\r\n(50 mg/kg) and ciprofloxacin significantly decreased Cmax of ciprofloxacin (P < 0.05). In addition, the pretreatment of berberine\r\n(50 mg/kg/day) and HR (1.4 g/kg/day) significantly decreased Cmax and AUC0?8, compared with control group (P < 0.05). The\r\noral bioavailability of ciprofloxacin was reduced by cotreatment of berberine and pretreatment of berberine and HR. Our results\r\nsuggest that the expression of P-glycoprotein and organic anion and/or organic cation transporters (OAT/OCT) could take a role\r\nin reduced oral bioavailability of ciprofloxacin by berberine and HR....
The influence of lovastatin on the hypoglycaemic effect of glimepiride was studied in normal/diabetic rats and normal rabbits. Lovastatin and Glimepiride were studied at a dose of 0.36 mg/200 g, 0.018 mg/200 g in normal/diabetic rats and at a dose of 1.4 mg/1.5 kg, 0.07 mg/1.5 kg in rabbits, respectively. All the animals were fasted for 18 h prior to experimentation; during this period the animals were fed with water ad libitum. All the drugs used in this study were administered orally. The blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours and analysed for glucose levels using glucometer in normal/diabetic rats and rabbits. The blood samples were also analysed for the glimepiride concentration by HPLC in rabbits. Glimepiride exhibited a maximum reduction of blood glucose levels at the 4th hour in normal and diabetic rats and at the 4th hour in rabbits. Lovastatin exhibited a maximum hypoglycaemic activity at the 8th hour in normal rats. In single and multiple dose interaction, the onset and duration of the hypoglycaemic activity exhibited by glimepiride was not altered whereas the hypoglycaemic effect was increased significantly in combination with lovastatin. In case of single dose and multiple dose interaction study, the pharmacokinetic parameters like AUC (0- ), Cmax were significantly altered. Hence the interaction was found to be pharmacodynamic and pharmacokinetic. The study indicates that lovastatin pre-treatment elevates the hypoglycaemic effect of glimepiride by a possible rise in insulin sensitivity or by the inhibition of hepatic glucose production by down regulation of HMG CoA enzyme or may be due to the inhibition of CYP2C9. The study also suggests the necessity to readjust the dose of glimepiride when used concomitantly with lovastatin....
The research is aimed to study the effect of the anti-diabetic drugs Glipizide, Metforminin individually and in combination on blood glucose levels. Initially different generic formulations of Glipizide (G1-G3), Metformin (M1-M3) and formulations containing the combination of Glipizide-Metformin (GM1-GM3) are available in Indian market, were evaluated for various quality control tests including the in-vitro drug release studies. Among these formulations, G1 (Glipizide) showed a high drug release of 98.98±1.54, M1 (Metformin) and Glipizide-Metformin combination showed drug release of 98.72±1.65 and 99.64±1, 98-99.69±1.39 respectively at the end of 20 minutes. These G1, M1 and GM2 formulations were further evaluated for in-vivo studies. In-vivo studies were performed to study the pharmacodynamic changes between two drugs and also for co-administration of formulations containing same active ingredient. The results ascertain that of all four treatments, combination of Glipizide-Metformin had shown considerable results (45.1±1.05, % reduction in blood glucose level) when compared to remaining three treatments....
Background: Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in\r\nchronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves\r\nlung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction\r\neffects between inhaled formoterol and oral roflumilast.\r\nMethods: This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In\r\nRegimen A, healthy men were treated with roflumilast (500 �µg tablet once daily; Day 2-18) and concomitant\r\nformoterol (24 �µg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 �µg twice\r\ndaily; Day 2-18) and concomitant roflumilast (500 �µg once daily; Day 9-18). Steady-state plasma pharmacokinetics\r\nof roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-t) as well as pharmacodynamics - blood\r\npressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood\r\neosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8\r\n(Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast\r\nplus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling\r\ndays and Day 19. Adverse events were monitored throughout the study.\r\nResults: Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic\r\ninteractions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular\r\nparameters as measured by ZCG, and these parameters were not affected during concomitant administration.\r\nFormoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval,\r\nwithout changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic\r\nassessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns\r\nwere seen after concomitant administration. No severe or serious adverse events were reported, and no adverse\r\nevents led to premature study discontinuation.\r\nConclusions: No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral\r\nroflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation.\r\nRoflumilast was well tolerated...
Pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug\r\nuse by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response\r\nrelationship should provide information for the prediction of the level of response to a certain level of drug dose. This paper\r\ndescribes the experimental details of the preformulation study, tablet manufacture, optimization, and bioanalytical methods for\r\nthe estimation of dexibuprofen in human plasma. The hydrophilic matrix was prepared with xanthen gum with additives Avicel\r\nPH 102. The effect of the concentration of the polymer and different filler, on the in vitro drug release, was studied. Various\r\npharmacokinetic parameters including AUC0ââ?¬â??t, AUC0ââ?¬â??8, Cmax, Tmax, T1/2, and elimination rate constant (Kel) were determined\r\nfrom the plasma concentration of both formulations of test (dexibuprofen 300 mg) and reference (dexibuprofen 300 mg tablets).\r\nThe merits of PK-PD in the development of dosage forms and how PK-PD model development necessitates the development of\r\nnew drugs and bio analytical method development and validation are discussed. The objectives of the present study, namely, to\r\ndevelop and validate the methods to estimate the selected drugs in the biological fluids by HPLC, the development of in vitro\r\ndissolution methods, and PK-PD model development have been described....
Background: In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn\r\nresuscitation occurs in at least 200 of the 180ââ?¬â??185.000 newly born infants per year. International randomized controlled\r\ntrials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia\r\nneonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the\r\npharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ\r\nfailure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are\r\nlacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences\r\nthe distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.\r\nMethods/Design: Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic\r\nEncephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be\r\neligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to\r\ninvestigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual\r\ndrug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated\r\nhow clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into\r\naccount. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to\r\npharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.\r\nDiscussion: On basis of the derived population PK-PD models dosing guidelines will be developed for the application\r\nof drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug\r\ntreatment of hypothermic neonatal patients. Results will be published in a national web based evidence based\r\npaediatric formulary, peer reviewed journals and international paediatric drug references...
A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like\r\nbehavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored\r\nby lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was\r\ninvestigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of\r\nproinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics\r\nwere constructed from transduction and indirect response models. A delay in the onset of increased\r\nproinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized\r\nby series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect\r\nresponse model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would\r\npeak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after\r\npeak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior\r\nindexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines\r\nlevel in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease\r\nprogression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in\r\nthe different time phases and conditions...
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