Bioavailable Dose Research Articles

Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase.

Methotrexate (MTX) toxicity varies depending on factors such as dosing frequency (acute or repeated), dosage (low or high) and the administration route (oral, parenteral or intrathecal). Renal impairment can trigger or exacerbate MTX toxicity. Acute oral low-dose MTX (LDMTX) overdoses seldom lead to toxicity due to the saturable maximal bioavailable dose, but toxicity risks increase with repeated low doses (>3 days), high-dose MTX (HDMTX) or intrathecal poisoning. Folinic acid shares MTX transporters in the gut and cells and bypasses the MTX-induced dihydrofolate reductase inhibition. The required folinic acid dosage differs for low-dose and high-dose MTX toxicities. Acute LDMTX poisoning rarely requires folinic acid, while chronic LDMTX poisoning needs low-dose folinic acid until cellular function is restored. In HDMTX toxicities, early intravenous folinic acid administration is recommended, with dose and duration being guided by MTX concentrations and clinical improvement. In intrathecal MTX poisoning, folinic acid should be administered intravenously. Glucarpidase, a recombinant bacterial enzyme, has a high affinity for MTX and folate analogues in the intravascular or intrathecal systems. It decreases serum MTX concentrations by 90%-95% within 15 min. Its primary indication is for intrathecal MTX poisoning. It is rarely indicated in HDMTX toxicity unless patients have renal injury. However, there is no literature evidence supporting its use in HDMTX poisoning. Its use is limited by its significant cost and lack of availability. Haemodialysis can be potentially useful for MTX removal in cases where glucarpidase is not available. Additionally, fluid hydration, renal support and urine alkalinization are important adjunctive therapies for managing MTX toxicities.

Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma.

As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.

Cladribine suppresses disease activity in neuromyelitis optica spectrum disorder: a 2-year follow-up study.

Neuromyelitis optica spectrum disorder (NMOSD) is a difficult condition to treat. Cladribine selectively and transiently depletes B and T lymphocytes, leading to long-lasting immune reconstitution. This report describes observations from 24months of follow-up after cladribine in NMOSD patients. This is a retrospective analysis of a case series including 12 seropositive patients with NMOSD. Patients were given cladribine by subcutaneous injections in a series of several 2-day cycles of 20mg administered at intervals of 4-6weeks. Thus, the full treatment course delivered a cumulative bioavailable dose similar to that approved for treatment of multiple sclerosis. Annualized relapse rate (ARR), disability (Expanded Disability Status Scale [EDSS] score) and safety in the 24months preceding and the 24months following the initiation of cladribine treatment were assessed. The mean ARR in the 24months preceding cladribine treatment was 1.04 (95% confidence interval [CI] 0.67-1.62). The mean ARR in the 24months following initiation of cladribine treatment was 0.21 (95% CI 0.08-0.56). The ratio in the rate of events post versus prior cladribine initiation was 0.20 (95% CI 0.07-0.59) and highly significant (p=0.0073). The EDSS score did not change over the follow-up period (2.5±1.7; mean±SD) compared to baseline (2.5±1.5; mean±SD). No serious adverse events considered to be linked to cladribine were observed during follow-up. Cladribine was safe in NMOSD patients over a 2-year observation period. Cladribine treatment was associated with clinical stabilization, as evidenced by significantly decreased ARR and no progression of EDSS score.

Formulation and evaluation of anti-diabetic activity of repaglinide nanosuspension

Diabetes is one of those metabolic disorders that are typically characterized by an increase in blood glucose level, glycosuria and ketonemia. This widely spread disease and its complications result in thickening of vascular tissue, PVD, neuropathy and retinopathy. Repaglinide is the first member of the newer class of drugs that are designed to lower the postprandial glucose. The most prevalent problem faced by those drugs are very low solubility and thereby causing the oral delivery very inefficient leading to low bioavailability and improper dose and release proportionality. Research attempts are being put towards enhancing the oral bioavailability of repaglinide kind of lipophilic drugs to improve the clinical effect. Out of those methods to improve the solubility and bioavailability, Nano suspensions have been a promising method to facilitate the above problem. Nano suspensions can be applied to enhance the solubility of Repaglinide too. So, in this research, Repaglinide particle size reduction has been performed, and nanosuspensions were tested for their clinical efficacy invivo. A nanoprecipitation method was developed to prepare Repaglinide nanosuspension using poloxamer as a stabilizer. The prepared formulations had been tested for the clinical efficacy invivo in albino Wistar rats. The results showed that the nanosuspensions have been very efficient in lowering the postprandial blood glucose levels and also facilitated the consistent release of the drug, which is evident from the constant lowering of glucose level. The prepared nanosuspensions showed a very potent and found to clinically efficient compared to the pure drug and drug suspensions.

Quantification of freely dissolved effect concentrations in in vitro cell-based bioassays.

Improved understanding of chemical exposure in in vitro bioassaysis required for quantitative in vitro-in vivo extrapolation (QIVIVE). In this study, we quantified freely dissolved concentrations in medium sampled from in vitro cell-based bioassays (Cfree,medium) for nine chemicals with different hydrophobicity and speciation at the time point of dosing and after an incubation period of 24h using solid-phase microextraction. The chemicals were tested in two reporter gene assays, the AREc32 assay indicative of the oxidative stress response and the PPARγ-GeneBLAzer assay that responds to chemicals which bind to the peroxisome proliferator-activated receptorgamma. For seven of the nine chemicals, Cfree,medium did not change significantly over time in both assays and the experimentally determined Cfree,medium generally agreed well with predictions of a mass balance model that describes the partitioning between proteinaceous and lipidous medium constituents, cells and the aqueous phase. Two chemicals showed a decrease of Cfree,medium in the AREc32 assay over time that was probably caused by cellular metabolism. Furthermore, Cfree,medium of the acidic chemical diclofenac deviated from the model predictions by more than a factor of 10 at higher concentrations, which indicates nonlinear binding and saturation of the medium proteins. Bioassay results are typically reported as nominal effect concentrations (ECnom), although it is established that freely dissolved effect concentrations (ECfree) are a better measure for the bioavailable dose and the method developed here provides a simple experimental approach to measure and model ECfree in in vitro bioassay for improved QIVIVE models.

In vitro percutaneous absorption and metabolism of Bisphenol A (BPA) through fresh human skin

Bisphenol A (BPA) is a high production volume compound. It is mainly used as a monomer to make polymers for various applications including food-contact materials. The primary route of exposure to BPA in the general population is through oral intake (EFSA 2015) however, other potential sources of exposure have also been identified, such as dermal contact. In the present study, the percutaneous absorption through human skin has been investigated in an in vitro study according to OECD TG 428 (Skin Absorption: In Vitro Method). In order to investigate potential dermal BPA metabolism during absorption, radiolabelled BPA was applied to fresh, metabolically competent, human skin samples (ring labelled 14C BPA concentrations tested were 2.4, 12, 60 and 300mg/L). Measured as total radioactivity the mean absorbed dose (receptor compartment) ranged from 1.7–3.6% of the applied doses and the dermal delivery (epidermis+dermis+receptor compartment), sometimes also named bioavailable dose was 16–20% of the applied doses, with the majority of the radioactivity associated with epidermis compared to dermis and receptor fluid. No metabolism was observed in any of the epidermis samples; however some metabolism was observed in dermis and receptor fluid samples with formation of BPA-glucuronide and BPA-sulfate, and some polar metabolites.

Characterizing Nanoparticles in Biological Matrices: Tipping Points in Agglomeration State and Cellular Delivery In Vitro.

Understanding the delivered cellular dose of nanoparticles is imperative in nanomedicine and nanosafety, yet is known to be extremely complex because of multiple interactions between nanoparticles, their environment, and the cells. Here, we use 3-D reconstruction of agglomerates preserved by cryogenic snapshot sampling and imaged by electron microscopy to quantify the "bioavailable dose" that is presented at the cell surface and formed by the process of individual nanoparticle sequestration into agglomerates in the exposure media. Critically, using 20 and 40 nm carboxylated polystyrene-latex and 16 and 85 nm silicon dioxide nanoparticles, we show that abrupt, dose-dependent "tipping points" in agglomeration state can arise, subsequently affecting cellular delivery and increasing toxicity. These changes are triggered by shifts in the ratio of the total nanoparticle surface area to biomolecule abundance, with the switch to a highly agglomerated state effectively changing the test article midassay, challenging the dose-response paradigm for nanosafety experiments. By characterizing nanoparticle numbers per agglomerate, we show these tipping points can lead to the formation of extreme agglomeration states whereby 90% of an administered dose is contained and delivered to the cells by just the top 2% of the largest agglomerates. We thus demonstrate precise definition, description, and comparison of the nanoparticle dose formed in different experimental environments and show that this description is critical to understanding cellular delivery and toxicity. We further empirically "stress-test" the commonly used dynamic light scattering approach, establishing its limitations to present an analysis strategy that significantly improves the usefulness of this popular nanoparticle characterization technique.

Development of a Gastric Absorptive, Immediate Responsive, Oral Protein-Loaded Versatile Polymeric Delivery System.

A multifunctional platform to deliver three diverse proteins of insulin, interferon beta (INF-β) and erythropoietin (EPO), using a novel copolymeric microparticulate system of TMC-PEGDMA-MAA, was synthesised as an intelligent pH-responsive 2-fold gastric and intestinal absorptive system. Physiochemical and physicomechanical studies proved the degree of crystallinity that supported the controlled protein delivery of the microparticulate system. The copolymer was tableted before undertaking in vitro and in vivo analysis. After 2.5h in simulated gastric fluid (SGF), insulin showed a fractional release of 3.2% in comparison to simulated intestinal fluid (SIF), in which a maximum of 83% of insulin was released. Similarly, INF-β and EPO released 3 and 9.7% in SGF and a maximum of 74 and 81.3% in SIF, respectively. In vivo studies demonstrated a significant decrease in blood glucose by 54.19% within 4h post-dosing, and the comparator formulation provided 74.6% decrease in blood glucose within the same time period. INF-β peak bioavailable dose in serum was calculated to be 1.3% in comparison to an SC formulation having a peak concentration of 0.9%, demonstrating steady-state release for 24h. EPO-loaded copolymeric microparticles had a 1.6% peak bioavailable concentration, in comparison to the 6.34% peak concentration after 8h from the SC comparator formulation.

Visualization of plasma and tissue binding using dose fractions parameter.

A novel concept of dose fractions, based on the distribution of total bioavailable dose between the six combinations of location and binding state in Øie-Tozer's model is suggested as a way to visualize the distribution pharmacokinetics of a drug. The concept of dose fractions provides a sharper terminology in discussions of drug distribution allowing for a more precise description of the state and location of a drug within a system. In medicinal chemistry literature, the free fraction of a drug in plasma is a commonly discussed factor affecting the exposure to free drug while tissue binding is less well addressed. The free dose fraction, defined as the fraction of the bioavailable dose existing in free form, is suggested as a potentially valuable term for such discussions. Presently, drugs with high (>95%) plasma protein binding are viewed with skepticism, the rational behind which is questioned. The plasma protein bound dose fraction defined as the fraction of the total available dose, which is bound to plasma proteins, is suggested as a measure of the risk for problems related to fluctuations in free drug exposure due to variations in the concentration of drug binding plasma protein.

Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose.

Nevirapine (NVP) extensive data obtained after oral single dose administration of 200 mg in a crossover study involving 16 healthy subjects was used to develop a descriptive population pharmacokinetic model including drug recirculation, since secondary peaks were observed in plasma concentration-time profiles for all subjects. Through implementation of model event time feature in NONMEM 7.3.0, a simple mechanistic model physiologically consistent with the process of drug cycling was able to describe multiple peaks phenomena and quantify its pharmacokinetic parameters, achieving a better performance than its analogue conventional one. Absorption process, between subject and-between occasion variability of pharmacokinetic parameters was also assessed. Estimated mean fraction of NVP bioavailable dose undergoing recirculation process was 51.6 %, a magnitude which could hardly be explained by enterohepatic cycling. In this work we propose an alternative disposition process to explain NVP drug recirculation: gastric secretion with posterior intestinal reabsorption. Due to physicochemical and pharmacokinetic properties of the drug, this neglected phenomenon is more likely to explain the results obtained, and might be present in disposition of several basic drugs.

Moxifloxacin-Induced Immune-Mediated Thrombocytopenia in a Chronic Kidney Disease Patient Receiving Hemodialysis

To alert clinicians to a serious complication from a commonly prescribed medication, moxifloxacin. A 65-year-old male, septic, hemodialysis patient developed thrombocytopenia following exposure to vancomycin, ceftazidime, and moxifloxacin. Drug-specific immunoglobulin testing showed positive autoantibodies against only moxifloxacin, and the probability stratification proposed by Naranjo et al would give this case a score of 7-a probable association between moxifloxacin and the adverse event. Idiopathic thrombocytopenic purpura (ITP) results in immune-mediated platelet destruction, with bleeding risk frequently manifested by purpuric skin and mucosal lesions. Although many drugs are associated with ITP, moxifloxacin has only been characterized in 2 previous case reports. This is the first case report where specific immunoglobulin antibody testing showed a positive association between ITP and moxifloxacin. Moxifloxacin is a commonly prescribed medication because of its wide spectrum of activity, high bioavailability, and convenient dose schedule. Clinicians need to be aware of this little-known side effect of this commonly prescribed antibiotic.

Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation.

The pharmacokinetics and oral bioavailability studies of columbianetin in rats after oral and intravenous administration

Ethnopharmacological relevanceThe roots of Angelica pubescens Maxim. f. biserrata Shan et Yuan (RAP) has been used as Traditional Chinese medicine to treat rheumatic disease in China since ancient times, but its action mechanisms was not well understood. Columbianetin is one of the main active constituents isolated from RAP, which has been shown to have various biological activities, but the absorption characteristics and oral bioavailability dose proportionality of columbianetin in vivo were not studied. Materials and methodsMale Sprague Dawley rats (210–230g) received either an intravenous (i.v. 5, 10 and 20mgkg−1) or oral (5, 10 and 20mgkg−1) dose of columbianetin. The levels of columbianetin in plasma were measured by a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. The simple liquid–liquid extraction with ethyl acetate was used for sample preparation. Osthole was selected as internal standard (IS). ResultsThe chromatographic separation was accomplished on a C18 column at a flow rate of 1mLmin−1, where water–methanol was used as mobile phase. The calibration curve of the method was linear in the concentration range of 0.05–2000μgmL−1. The intra and inter-day accuracy for columbianetin in rat plasma samples were within 8% and the variation was less than 8.3%. This method was suitable for the determination and pharmacokinetic study of columbianetin in rat plasma after both intravenous and oral administration. The results indicated that maximum plasma concentrations(Cmax) for the columbianetin (17–42μgmL−1) were achieved at 0.3–0.5h post-oral dosing and the apparent volume of distribution (V/F) ranged from 0.38 to 0.44L. Absolute bioavailability of columbianetin was assessed to be 81.13±45.85, 81.09±33.63 and 54.30±23.19%, respectively. Terminal elimination half-life (T1/2) of the columbianetin after oral dosing was 60–90min and were 2.5–3.3 fold longer than those observed for the i.v. dosing. ConclusionsThe pharmacokinetic properties of columbianetin in rat after oral administration were characterized as rapid oral absorption, quick clearance and good absolute bioavailability. The bioavailability of columbianetin ranged from 54 to 81% for 5, 10 and 20mgkg−1 oral doses. The bioavailability of columbianetin is independent of the doses studied. Columbianetin showed dose proportionality over the dose range 5–20mgkg−1. The results clearly demonstrated that columbianetin was one of the material bases of RAP. Furthermore, an HPLC method was demonstrated in this study for the research of traditional Chinese medicine.

Sex related differences on valproic acid pharmacokinetics after oral single dose

Plasma concentration-time data obtained after an oral single dose of 500-mg valproic acid (VPA) in a delayed release formulation was used to model enterohepatic cycling of the drug. Fourteen healthy subjects (seven women and seven men) were enrolled, food intake was standardized, blood samples were withdrawn up to 48h post dosing and VPA plasma concentrations were analyzed by HPLC-UV method. Secondary peaks of VPA were observed in almost all subjects. A population pharmacokinetic analysis with sex, weight, age and contraceptive therapy as possible covariates was performed. Women without contraceptive therapy presented a longer lag time, a lower VPA hepatic output and a higher reabsorbed fraction than men. Weight affected both volume of the central compartment and the absorption rate constant. Women under contraceptive therapy showed similar disposition parameters to men. Reabsorbed fraction of bioavailable dose was 46.2% in women and 21.8% in men, revealing important sex differences in drug hepatobiliar output. These results showed that VPA displays sex-related pharmacokinetic differences due to different metabolic and transporter-mediated disposition.

Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil

Gabapentin exposure following administration of certain doses of gabapentin or its pro-drug gabapentin enacarbil has been previously reported in the literature, with variable results. Meta-analyses of dose-exposure relationships were conducted to maximise precision and minimise bias. Study-level mean data for gabapentin systemic exposure, in terms of bioavailable dose and steady-state average plasma concentration, were modelled as a function of daily dose. Several linear and non-linear candidate models were tested. An Emax model best described the dose-exposure relationships for gabapentin. The ED50 was 3,080 mg/day for bioavailable dose or 3,370 mg/day for steady-state concentration; and the maximum exposure was 2,340 mg/day or 16.9 mg/L. For gabapentin enacarbil, a power model was most suitable, with a power of 0.925 for bioavailable dose or 0.844 for steady-state concentration. All parameters were estimated with < 20 % standard error. Simulations confirmed that these models accurately reflected the distribution of the respective data, and bootstrapping showed high precision for the estimated dose-exposure curves. The meta-analyses addressed issues associated with between-study variability; and confirmed the highly non-linear nature of dose-exposure relationships for gabapentin and the essentially linear relationships for gabapentin enacarbil. The resulting models could be used to simulate exposure at any clinically relevant dose and bridge therapeutic dose range between the two drugs.

Flavanol metabolites distribute in visceral adipose depots after a long-term intake of grape seed proanthocyanidin extract in rats

A considerable number of epidemiological investigations and intervention studies have supported an association between the intake of flavanol- and proanthocyanidin-containing foods and a decreased risk of metabolic diseases. Nonetheless, less is know about the capacity of tissues to accumulate flavanols and/or their metabolites. The main objective of the present study was to determine (n 20) plasma bioavailability and disposition in the liver, muscle, brown adipose tissue (BAT) and white adipose tissues (mesenteric and perirenal) in rats after a long-term consumption of three doses of grape seed phenolic extract (5, 25 and 50 mg/kg body weight) for 21 d in order to determine whether there is a dose-response relationship. Glucuronidated conjugates (total glucuronidated conjugates: C(5 mg/kg) 1·9; C(25 mg/kg) 6·4; C(50 mg/kg) 27·7 μmol/l plasma) followed by methyl glucuronidated conjugates (total methyl glucuronidated conjugates: C(5 mg/kg) 1·98; C(25 mg/kg) 4·48; C(50 mg/kg) 12·5 μmol/l plasma) were the main flavanol metabolites quantified in plasma, also detecting a dimer in its free form (C(25 mg/kg) 0·74; C(50 mg/kg) 0·79 μmol/l plasma). Each of the studied organs has a particular behaviour of accumulation and response to the assayed grape seed extract doses, with an exponential bioavailability-dose relationship in BAT, in which flavanols could play an important role in the reduction or prevention of obesity, modulating the functionality of that tissue.

P 11: Role of herbal extracts in the prevention of oxidative stress and modulation of atherogenic risk factors in experimentally-induced DM

Background and aims Complementary and alternative medicine modalities of treating diabetes mellitus and cardiovascular diseases (D&CVD) have been used in various parts of the world. Chemoprevention and chemotherapies using the naturally occurring nontoxic natural compounds has been advanced as a feasible strategy for D&CVD management. Diabetes and cardiovascular diseases are currently the leading cause of death globally. Diabetes has a distinctive association with CVD. Diabetes is well known to induce physiological stress response that involves activation of inflammatory, metabolic, and immunological mediators. Considerable data indicate that reactive oxygen species (ROS) and oxidative stress are important features of CVD including atherosclerosis, hypertension, and congestive heart failure. Clinical research has confirmed the efficacy of phytotherapy in the modulation of oxidative stress-induced CVDs associated with DM. Increasing number of studies reported that an increase in plasma total antioxidant capacity (TAC) is associated with intake of herbs, fruits and vegetables which are rich in antioxidants. This is based on findings that Leaf extract components, especially flavonoids have the free radical scavenging activity, showing the potential of antioxidant properties. Consequently, the present study was designed to investigate the hypoglycemic, hypolipidemic and antioxidtive effects of crude extract from leaves of Zizyphus spina-christi (ZS), Morus alba (MA) and Olea europeaea (OE) in experimentally induced DM. Materials and Methods Fresh leaves were dried, extracted by methanol, and then vacuum evaporated. Crude extracts from leaves of Zizyphus spina-christi (ZS), Morus alba (MA) and Olea europeaea (OE) were freshly dissolved in distilled water just before oral administration. Experimental rat model of T2DM was induced in male rats by a single ip injection of 50 mg/kg streptozotocin. All experimental groups received herbal extracts orally and individually at a dose of 0.1g/kg/day for 5 weeks. The body weight and fasting blood glucose level of all rats were measured before and after 5 weeks of treatment. In addition, HBA1c, serum insulin, lipid profile, and cardiac antioxidants as well as lipid and protein oxidation were evaluated. Results After a period of 5 weeks, the body weight of diabetic rats was significantly (p Conclusion Our data indicate that experimental diabetes led to alteration in the atherogenic parameters, with an increasing incidence of oxidative stress in the heart, and the effects of the extract might be attributed to the hypoglycaemic and antioxidative potential of flavonoids, the major components of the plant extract. These results provide the first evidence for the efficacy of ZS, MA or OE in restoring lipid profile in the diabetic rats, the mechanism of which may associate with the alleviation of oxidative stress. Consequently, we suggest that these extracts could be used as antidiabetic complement in case of DM. In future, more studies would be urgently required in order to confirm these results in human and to adjust the correct bio-available dose for better therapeutic effects.

Pharmacokinetic Profile of Lesogaberan (AZD3355) in Healthy Subjects

Objective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan.Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study.Participants: Ten healthy male subjects took part in the study.Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days.Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan.Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study.Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.

Pharmacokinetic Profile of Lesogaberan (AZD3355) in Healthy Subjects

Objective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan. Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study. Participants: Ten healthy male subjects took part in the study. Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days. Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan. Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study. Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.

Clinical updates on carvedilol: a first choice β-blocker in the treatment of cardiovascular diseases

Importance of the field: Carvedilol, a non-selective β-blocker, has recently drawn attention because of its therapeutic benefits over other prescribed analogues for the treatment of cardiovascular diseases (CVDs).Areas covered in this review: The present review attempts to present the clinical efficacy of carvedilol in comparison to other available β-blockers. The literature search was carried out in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) without time constraints to ensure maximum literature coverage.What the reader will gain: A relatively large number of comparative studies have revealed that carvedilol has advantage over traditional β-blockers with respect to hemodynamic and metabolic effects, due to its unique non-selective α-/β-adrenoceptor affinity. Such results indicate its safe and effective therapeutic application particularly in patients with complicated CVDs, even in pediatric and geriatric patients.Take home message: The therapeutic profile of carvedilol indicates its suitability for treatment of complicated CVDs than other non-selective β-blockers. However, there is a limitation in terms of its dose due to its low bioavailability (∼ 25%). Therefore, there is still need for bioavailability enhancement and dose reduction to further improve the therapeutic efficacy of the drug.