Displaying publications 241 - 260 of 524 in total

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  1. Reliability of the reported ingested dose of acetaminophen for predicting the risk of toxicity in acetaminophen overdose patients
    Zyoud SH, Awang R, Sulaiman SA
    Pharmacoepidemiol Drug Saf, 2012 Feb;21(2):207-13.
    PMID: 21812068 DOI: 10.1002/pds.2218
    The present study examines the relationship between the dose of acetaminophen reported to have been ingested by patients and the occurrence of serum acetaminophen levels above the 'possible toxicity' line in patients presenting at the hospital after acetaminophen overdose. The prognostic value of patient-reported dosage cut-offs of 8, 10 and 12 g was determined.
    Matched MeSH terms: Acetaminophen/pharmacokinetics; Analgesics, Non-Narcotic/pharmacokinetics
  2. Fulltext In vitro pharmacodynamic profile of Loranthus ferrugineus: evidence for noncompetitive antagonism of norepinephrine-induced vascular contraction
    Ameer OZ, Salman IM, Najim HS, Abdullah GZ, Abdulkarim MF, Yam MF, et al.
    J Acupunct Meridian Stud, 2010 Dec;3(4):272-82.
    PMID: 21185543 DOI: 10.1016/S2005-2901(10)60048-9
    The mode by which Loranthus ferrugineus methanol extract antagonizes and/or modulates norepinephrine-induced vasoconstriction was investigated in rat aortic rings. The vascular effects of three different concentrations of this extract were challenged against cumulative additions of norepinephrine. Phentolamine, a nonselective α-adrenoceptor antagonist, verapamil, an L-type calcium channel blocker, and papaverine, a phosphodiesterase inhibitor, were used in three different concentrations as positive controls. Log concentration-response curves and double-reciprocal plots were constructed for the extract and each vasorelaxant. To characterize antagonism reversibility, the norepinephrine maximum contractile effect was examined before extract addition to the aortic ring chamber and after its removal. Phentolamine shifted the norepinephrine log concentration-response curve to the right with no significant depression in the maximum response. Similar to verapamil and papaverine, the extract produced a rightward shift in norepinephrine log concentration-response curve and a significant drop in maximum response. The double-reciprocal plots showed comparable y-intercept values for all phentolamine concentrations, a characteristic of competitive antagonism. In contrast, different y-intercept values on double-reciprocal plots were obtained for each concentration of extract, verapamil, and papaverine, typical of noncompetitive antagonism. The norepinephrine maximum contractile response was approximately similar before the addition of extract and after its removal. The data collectively showed that L. ferrugineus methanol extract exerted its vascular effect by reversible noncompetitive antagonism of norepinephrine-induced vasoconstriction. These findings add to the understanding of the cardiovascular mechanisms by which L. ferrugineus, a plant traditionally used for the management of hypertension, elicits its action.
    Matched MeSH terms: Plant Extracts/pharmacokinetics*; Vasodilator Agents/pharmacokinetics*
  3. p53 Status does not affect photodynamic cell killing induced by hypericin
    Lee HB, Ho AS, Teo SH
    Cancer Chemother Pharmacol, 2006 Jul;58(1):91-8.
    PMID: 16211395
    Given that p53 is a tumor suppressor that plays a central role in the cellular response to DNA damage and that more than 50% of all cancers have mutated p53, the wider utility of photodynamic therapy (PDT) in the treatment of cancer will depend on an understanding of whether p53 status modulates response to PDT. In this study, we investigated the photosensitivity of isogenic cell lines that differ only in their p53 status to PDT using hypericin as the photosensitizer.
    Matched MeSH terms: Perylene/pharmacokinetics; Radiation-Sensitizing Agents/pharmacokinetics
  4. A new and simple solid-phase extraction method for LC determination of pyronaridine in human plasma
    Ramanathan S, Karupiah S, Nair NK, Olliaro PL, Navaratnam V, Wernsdorfer WH, et al.
    J Chromatogr B Analyt Technol Biomed Life Sci, 2005 Sep 25;824(1-2):45-50.
    PMID: 16046285
    A new approach using a simple solid-phase extraction technique has been developed for the determination of pyronaridine (PND), an antimalarial drug, in human plasma. After extraction with C18 solid-phase sorbent, PND was analyzed using a reverse phase chromatographic method with fluorescence detection (at lambda(ex)=267 nm and lambda(em)=443 nm). The mean extraction recovery for PND was 95.2%. The coefficient of variation for intra-assay precision, inter-assay precision and accuracy was less than 10%. The quantification limit with fluorescence detection was 0.010 microg/mL plasma. The method described herein has several advantages over other published methods since it is easy to perform and rapid. It also permits reducing both, solvent use and sample preparation time. The method has been used successfully to assay plasma samples from clinical pharmacokinetic studies.
    Matched MeSH terms: Antimalarials/pharmacokinetics; Naphthyridines/pharmacokinetics
  5. Determination of mitragynine in plasma with solid-phase extraction and rapid HPLC-UV analysis, and its application to a pharmacokinetic study in rat
    Parthasarathy S, Ramanathan S, Ismail S, Adenan MI, Mansor SM, Murugaiyah V
    Anal Bioanal Chem, 2010 Jul;397(5):2023-30.
    PMID: 20454783 DOI: 10.1007/s00216-010-3707-7
    A new solid phase extraction method for rapid high performance liquid chromatography-UV determination of mitragynine in plasma has been developed. Optimal separation was achieved with an isocratic mobile phase consisting of acetonitrile-ammonium acetate buffer, 50 mM at pH 5.0 (50:50, v/v). The method had limits of detection and quantification of 0.025 and 0.050 microg/mL, respectively. The method was accurate and precise for the quantitative analysis of mitragynine in human and rat plasma with within-day and between-day accuracies between 84.0 and 109.6%, and their precision values were between 1.7 and 16.8%. Additional advantages over known methods are related to the solid phase extraction technique for sample preparation which yields a clean chromatogram, a short total analysis time, requires a smaller amount of plasma samples and has good assay sensitivity for bioanalytical application. The method was successfully applied in pharmacokinetic and stability studies of mitragynine. In the present study, mitragynine was found to be fairly stable during storage and sample preparation. The present study showed for the first time the detailed pharmacokinetic profiles of mitragynine. Following intravenous administration, mitragynine demonstrated a biphasic elimination from plasma. Oral absorption of the drug was slow, prolonged and was incomplete, with a calculated absolute oral bioavailability value of 3.03%. The variations observed in previous pharmacokinetic studies after oral administration of mitragynine could be attributed to its poor bioavailability rather than to the differences in assay method, metabolic saturation or mitragynine dose.
    Matched MeSH terms: Plant Extracts/pharmacokinetics; Secologanin Tryptamine Alkaloids/pharmacokinetics
  6. Optimization and validation of RP-HPLC-UV method with solid-phase extraction for determination of buparvaquone in human and rabbit plasma: application to pharmacokinetic study
    Venkatesh G, Majid MI, Ramanathan S, Mansor SM, Nair NK, Croft SL, et al.
    Biomed Chromatogr, 2008 May;22(5):535-41.
    PMID: 18205140 DOI: 10.1002/bmc.965
    A simple, sensitive and specific reversed-phase high-performance liquid chromatographic method with UV detection at 251 nm was developed for quantitation of buparvaquone (BPQ) in human and rabbit plasma. The method utilizes 250 microL of plasma and sample preparation involves protein precipitation followed by solid-phase extraction. The method was validated on a C18 column with mobile phase consisting of ammonium acetate buffer (0.02 m, pH 3.0) and acetonitrile in the ratio of 18:82 (v/v) at a flow rate of 1.1 mL/min. The calibration curves were linear (correlation coefficient>or=0.998) in the selected range. The method is specific and sensitive with limit of quantitation of 50 ng/mL for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and BPQ was found to be stable. Partial validation studies were carried out using rabbit plasma and intra- and inter-day precision and accuracy were within 7%. This method is simple, reliable and can be routinely used for preclinical pharmacokinetic studies for BPQ.
    Matched MeSH terms: Antiprotozoal Agents/pharmacokinetics; Naphthoquinones/pharmacokinetics*
  7. Multinuclear MR and multilevel data processing: an insight into morphologic assessment of in vivo knee articular cartilage
    Hani AF, Kumar D, Malik AS, Walter N, Razak R, Kiflie A
    Acad Radiol, 2015 Jan;22(1):93-104.
    PMID: 25481518 DOI: 10.1016/j.acra.2014.08.008
    Quantitative assessment of knee articular cartilage (AC) morphology using magnetic resonance (MR) imaging requires an accurate segmentation and 3D reconstruction. However, automatic AC segmentation and 3D reconstruction from hydrogen-based MR images alone is challenging because of inhomogeneous intensities, shape irregularity, and low contrast existing in the cartilage region. Thus, the objective of this research was to provide an insight into morphologic assessment of AC using multilevel data processing of multinuclear ((23)Na and (1)H) MR knee images.
    Matched MeSH terms: Sodium Isotopes/pharmacokinetics; Radiopharmaceuticals/pharmacokinetics
  8. Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration
    Jamal JA, Mat-Nor MB, Mohamad-Nor FS, Udy AA, Wallis SC, Lipman J, et al.
    Int J Antimicrob Agents, 2015 Jan;45(1):41-5.
    PMID: 25455853 DOI: 10.1016/j.ijantimicag.2014.09.009
    The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic/pharmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both sampling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L; P < 0.01]. CVVH contributed to ca. 50% of meropenem total clearance in these patients. The administered meropenem doses resulted in plasma drug concentrations that were >4× the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH.
    Matched MeSH terms: Anti-Bacterial Agents/pharmacokinetics*; Thienamycins/pharmacokinetics*
  9. Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria
    Reuter SE, Upton RN, Evans AM, Navaratnam V, Olliaro PL
    J Antimicrob Chemother, 2015 Mar;70(3):868-76.
    PMID: 25377567 DOI: 10.1093/jac/dku430
    BACKGROUND: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate.

    PATIENTS AND METHODS: Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM.

    RESULTS: A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h).

    CONCLUSIONS: This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F.

    Matched MeSH terms: Antimalarials/pharmacokinetics*; Mefloquine/pharmacokinetics*
  10. Fulltext Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application
    Mahmood S, Taher M, Mandal UK
    Int J Nanomedicine, 2014;9:4331-46.
    PMID: 25246789 DOI: 10.2147/IJN.S65408
    Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon(®) 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a homogeneous distribution and low polydispersity index (0.08). They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 μg/cm(2)/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser scanning microscopy proved an enhanced permeation of coumarin-6-loaded transfersomes, to a depth of approximately160 μM, as compared with rigid liposomes. These ex vivo findings proved that a raloxifene hydrochloride-loaded transfersome formulation could be a superior alternative to oral delivery of the drug.
    Matched MeSH terms: Drug Carriers/pharmacokinetics*; Raloxifene Hydrochloride/pharmacokinetics*
  11. Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: A randomised controlled trial of continuous infusion versus intermittent bolus administration
    Jamal JA, Roberts DM, Udy AA, Mat-Nor MB, Mohamad-Nor FS, Wallis SC, et al.
    Int J Antimicrob Agents, 2015 Jul;46(1):39-44.
    PMID: 25881872 DOI: 10.1016/j.ijantimicag.2015.02.014
    Here we describe the pharmacokinetics of piperacillin administered by continuous infusion (CI) versus intermittent bolus (IB) dosing in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and compare the frequency of pharmacodynamic/pharmacokinetic (PK/PD) target attainment with each dosing strategy. This was a prospective pharmacokinetic trial in 16 critically ill patients with severe sepsis or septic shock undergoing CVVH and randomised to receive either CI or IB administration of a standard daily dose of piperacillin/tazobactam (11.25g/day on Day 1 followed by 9g/day). Serial blood samples were measured on two occasions. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. Blood concentrations were compared with established PK/PD targets. On occasion 1 (Days 1-3 of therapy), IB administration resulted in significantly higher piperacillin peak concentrations (169 vs. 89mg/L; P=0.002), whereas significantly higher steady-state concentrations were observed in CI patients (83 vs. 57mg/L; P=0.04). Total clearance and clearance not mediated by CVVH were significantly higher with CI administration [median (interquartile range), 1.0 (0.7-1.1) and 0.8 (0.6-1.0)mL/kg/min; P=0.001 and 0.001, respectively]. The estimated unbound piperacillin concentrations were four times above the target susceptibility breakpoint (16mg/L) for the entire dosing interval (100%fT>4xMIC) in 87.5% of patients receiving CI administration (sampling occasion 1), compared with 62.5% of IB patients achieving the desired target (50%fT>4xMIC). Compared with IB dosing, and despite similar CVVH settings, CI administration of piperacillin results in a pharmacokinetic profile that may optimise outcomes for less susceptible pathogens.
    Matched MeSH terms: Anti-Bacterial Agents/pharmacokinetics*; Piperacillin/pharmacokinetics*
  12. Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
    Teh LK, Hamzah S, Hashim H, Bannur Z, Zakaria ZA, Hasbullani Z, et al.
    Ther Drug Monit, 2013 Oct;35(5):624-30.
    PMID: 23942539 DOI: 10.1097/FTD.0b013e318290acd2
    Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine.
    Matched MeSH terms: Antimetabolites, Antineoplastic/pharmacokinetics*; Fluorouracil/pharmacokinetics*
  13. A model of chlorpyrifos distribution and its biochemical effects on the liver and kidneys of rats
    Tanvir EM, Afroz R, Chowdhury M, Gan SH, Karim N, Islam MN, et al.
    Hum Exp Toxicol, 2016 Sep;35(9):991-1004.
    PMID: 26519480 DOI: 10.1177/0960327115614384
    This study investigated the main target sites of chlorpyrifos (CPF), its effect on biochemical indices, and the pathological changes observed in rat liver and kidney function using gas chromatography/mass spectrometry. Adult female Wistar rats (n = 12) were randomly assigned into two groups (one control and one test group; n = 6 each). The test group received CPF via oral gavage for 21 days at 5 mg/kg daily. The distribution of CPF was determined in various organs (liver, brain, heart, lung, kidney, ovary, adipose tissue, and skeletal muscle), urine and stool samples using GCMS. Approximately 6.18% of CPF was distributed in the body tissues, and the highest CPF concentration (3.80%) was found in adipose tissue. CPF also accumulated in the liver (0.29%), brain (0.22%), kidney (0.10%), and ovary (0.03%). Approximately 83.60% of CPF was detected in the urine. CPF exposure resulted in a significant increase in plasma transaminases, alkaline phosphatase, and total bilirubin levels, a significant reduction in total protein levels and an altered lipid profile. Oxidative stress due to CPF administration was also evidenced by a significant increase in liver malondialdehyde levels. The detrimental effects of CPF on kidney function consisted of a significant increase in plasma urea and creatinine levels. Liver and kidney histology confirmed the observed biochemical changes. In conclusion, CPF bioaccumulates over time and exerts toxic effects on animals.
    Matched MeSH terms: Chlorpyrifos/pharmacokinetics; Environmental Pollutants/pharmacokinetics
  14. Formulation of Gastric Floating System Using Bio-Sourced Terminalia Catappa Gum and in vivo Evaluation
    Meka VS, Murthy Kolapalli VR
    Curr Drug Deliv, 2016;13(6):971-81.
    PMID: 26452534
    A central composite design was applied to design a novel gastric floating drug delivery system comprising propranolol HCl in Terminalia catappa gum and to evaluate the buoyancy, in vitro drug release behavior, and pharmacokinetic parameters. All formulations exhibited good buoyancy properties in vitro reflected by floating lag time of 1-110 sec, total floating time of 9-16 h and prolonged release behaviour (upto 12 h). Statistically optimised formulation (PBGRso) was orally administered to human volunteers under both fasted and fed conditions to evaluate gastric floating behavior under different food conditions by X-ray evaluation. In vivo studies of optimised formulations revealed that the gastric residence time of floating tablets was enhanced in the fed but not in the fasted state. Pharmacokinetic studies of the optimised Terminalia catappa formulation and a commercial product (Ciplar LA 80) carried out on healthy human volunteers showed a significant improvement in the bioavailability (132%) of propranolol HCl released from from the experimental Terminalia catappa formulations compared with Ciplar LA 80.
    Matched MeSH terms: Delayed-Action Preparations/pharmacokinetics; Propranolol/pharmacokinetics*
  15. Nanoemulsion-based Parenteral Drug Delivery System of Carbamazepine: Preparation, Characterization, Stability Evaluation and Blood-Brain Pharmacokinetics
    Tan SL, Stanslas J, Basri M, Abedi Karjiban RA, Kirby BP, Sani D, et al.
    Curr Drug Deliv, 2015;12(6):795-804.
    PMID: 26324229
    Carbamzepine (CBZ) was encapsulated in a parenteral oil-in-water nanoemulsion, in an attempt to improve its bioavailability. The particle size, polydispersity index and zeta potential were measured using dynamic light scattering. Other parameters such as pH, osmolality, viscosity, drug loading efficiency and entrapment efficiency were also recorded. Transmission electron microscopy revealed that emulsion droplets were almost spherical in shape and in the nano-range. The in vitro release profile was best characterized by Higuchi's equation. The parenteral nanoemulsion of CBZ showed significantly higher AUC0→5, AUC0→∞, AUMC0→5, AUMC0→∞, Cmax and lower clearance than that of CBZ solution in plasma. Additionally, parenteral nanoemulsion of CBZ showed significantly higher AUC0→∞, AUMC0→∞ and Cmaxthan that of CBZ solution in brain. The parenteral nanoemulsion of CBZ could therefore use as a carrier, worth exploring further for brain targeting.
    Matched MeSH terms: Anticonvulsants/pharmacokinetics; Carbamazepine/pharmacokinetics
  16. Fulltext Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits
    Razavi M, Karimian H, Yeong CH, Chung LY, Nyamathulla S, Noordin MI
    Drug Des Devel Ther, 2015;9:4373-86.
    PMID: 26273196 DOI: 10.2147/DDDT.S86263
    The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1-F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide ((153)Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics.
    Matched MeSH terms: Hypoglycemic Agents/pharmacokinetics; Metformin/pharmacokinetics
  17. Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers
    Leong CW, Yee KM, Liew I, Khaleb NA, Ahmad S, Rani TA, et al.
    Clin Pharmacol Drug Dev, 2024 Aug;13(8):890-896.
    PMID: 38685874 DOI: 10.1002/cpdd.1409
    The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.
    Matched MeSH terms: Drugs, Generic/pharmacokinetics; Factor Xa Inhibitors/pharmacokinetics
  18. Fulltext Enhancing the Bioavailability of the Ellagitannin, Geraniin: Formulation, Characterization, and in vivo Evaluation
    Elendran S, Shiva Kumar V, Sundralingam U, Tow WK, Palanisamy UD
    Int J Pharm, 2024 Jul 20;660:124333.
    PMID: 38866080 DOI: 10.1016/j.ijpharm.2024.124333
    Geraniin (GE), an ellagitannin (ET) renowned for its promising health advantages, faces challenges in its practical applications due to its limited bioavailability. This innovative and novel formulation of GE and soy-phosphatidylcholine (GE-PL) complex has the potential to increase oral bioavailability, exhibiting high entrapment efficiency of 100.2 ± 0.8 %, and complexation efficiency of 94.6 ± 1.1 %. The small particle size (1.04 ± 0.11 μm), low polydispersity index (0.26 ± 0.02), and adequate zeta potential (-26.1 ± 0.12 mV), indicate its uniformity and stability. Moreover, the formulation also demonstrates improved lipophilicity, reduced aqueous and buffer solubilities, and better partition coefficient. It has been validated by various analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. Oral bioavailability and pharmacokinetics of free GE and GE-PL complex investigated in rabbits demonstrated enhanced plasma concentration of ellagic acid (EA) compared to free GE. Significantly, GE, whether in its free form or as part of the GE-PL complex, was not found in the circulatory system. However, EA levels were observed at 0.5 h after administration, displaying two distinct peaks at 2 ± 0.03 h (T1max) and 24 ± 0.06 h (T2max). These peaks corresponded to peak plasma concentrations (C1max and C2max) of 588.82 ng/mL and 711.13 ng/mL respectively, signifying substantial 11-fold and 5-fold enhancements when compared to free GE. Additionally, it showed an increased area under the curve (AUC), the elimination half-life (t1/2, el) and the elimination rate constant (Kel). The formulation of the GE-PL complex prolonged the presence of EA in the bloodstream and improved its absorption, ultimately leading to a higher oral bioavailability. In summary, the study highlights the significance of the GE-PL complex in overcoming the bioavailability limitations of GE, paving the way for enhanced therapeutic outcomes and potential applications in drug delivery and healthcare.
    Matched MeSH terms: Ellagic Acid/pharmacokinetics; Tannins/pharmacokinetics
  19. Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination
    Sengupta P, Chatterjee B, Pal TK
    Regul Toxicol Pharmacol, 2017 Dec;91:151-158.
    PMID: 29107617 DOI: 10.1016/j.yrtph.2017.10.029
    The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination.
    Matched MeSH terms: Benzimidazoles/pharmacokinetics*; Benzoates/pharmacokinetics*; Thiazolidinediones/pharmacokinetics*
  20. Fulltext Ruthenium-conjugated chrysin analogues modulate platelet activity, thrombus formation and haemostasis with enhanced efficacy
    Ravishankar D, Salamah M, Attina A, Pothi R, Vallance TM, Javed M, et al.
    Sci Rep, 2017 07 18;7(1):5738.
    PMID: 28720875 DOI: 10.1038/s41598-017-05936-3
    The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio-chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio-coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents.
    Matched MeSH terms: Fibrinolytic Agents/pharmacokinetics; Flavonoids/pharmacokinetics; Ruthenium/pharmacokinetics
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