Effect Of Single Oral Dose Research Articles

Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

BackgroundKeverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. AimsTo evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. MethodsIn the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n = 8), lansoprazole (LSZ) 30 mg (n = 2) or placebo (n = 2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n = 7) or fed-fasting (n = 7) groups for evaluating the food effect of keverprazan. ResultsTwenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25–1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00–7.17 h, 88.8–198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5–60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). ConclusionKeverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.

Antinociceptive effect, acute toxicity and chemical analysis of cold mechanically extracted N. Sativa seed oil

Nigella sativa L. (Ranunculaceae), seed oil is traditionally used for pain, stiffness in the joints and eczema. The N. sativa seed oil (NSSO) contains an abundance of monoterpenes and essential fatty acids of various pharmacological actions. The objective of this study is to investigate the antinociceptive effect of single oral dose of NSSO on acetic acid-induced writhing and hot plate induced algesia in mice. Further, the study also, aims to characterize the chemical constituents of NSSO by using GC/MS. Swiss albino mice were divided into two sets of three groups consisting of six animals per group for the assessment of analgesic effect by hot plate and by acetic acid induced writhing methods. Group I, received distilled water (10 ml/kg, p.o.); group II, received diclofenac sodium (2.5 mg/100g, p.o.); and group III, received NSSO (0.5 ml/100g, p.o.). After NSSO administration the animals were placed on the hot plate and their response was noted down at different time interval. Further, another set of animals of other three groups were subjected to acetic acid induced writhing test after 30 minutes of drug administration. The results of the study showed that NSSO significantly (p<0.05) increased the latency to thermal stimulus, and also, there was significant (p<0.01) reduction in the number of writhes induced by 0.07% acetic acid. The GC/MS chromatogram of NSSO showed a total of 50 compounds. The LD50 of NSSO was greater than 5 g/kg. Thus in conclusion, NSSO (0.5ml/100g, p.o.) showed a significant analgesic effect against acetic acid induced writhing and also in hot plate model in mice. The phytochemical analysis of NSSO showed the presence of several active principles, primarily linoleic acid and thymoquinone. The presence of linoleic acid and thymoquinone in NSSO, possibly contributed to its analgesic effect that needs further investigation in other animal models of algesia.

Acrocomia crispa fruits lipid extract prevents LPS-induced acute lung injury in mice

The aim of this study was to evaluate the effects of single oral doses of D-005 (a lipid extract obtained from the fruit oil of Acrocomia crispa) on LPS-induced acute lung injury (ALI) in mice. D-005 batch composition was: lauric (35.8%), oleic (28.4%), myristic (14.2%), palmitic (8.9%), stearic (3.3%), capric (1.9%), caprylic (1.2%), and palmitoleic (0.05%) acids, for a total content of fatty acids of 93.7%. D-005 (200 mg/kg) significantly reduced lung edema (LE) (≈ 28% inhibition) and Lung Weight/Body Weight ratio (LW/BW) (75.8% inhibition). D-005 (25, 50, 100 and 200 mg/kg) produced a significant reduction of Histological score (59.9, 56.1, 53.5 and 73.3% inhibition, respectively). Dexamethasone, as the reference drug, was effective in this experimental model. In conclusion, pretreatment with single oral doses of D-005 significantly prevented the LPS-induced ALI in mice.

Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200mg, pregabalin 150mg, duloxetine 60mg, lacosamide 100mg or placebo) in a Williams design, with CO2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6h postdose from all three skin types. In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68μV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73μV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2μV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54μV; 95% CI -6.21, -2.87) and pregabalin (-3.72μV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78μV; 95% CI -5.31, -2.25) and duloxetine (-2.32μV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

Effects of single oral doses of trichothecene mycotoxins on young common carp (Cyprinus carpio L.)

Effects of single oral doses of trichothecene mycotoxins on young common carp (Cyprinus carpio L.)

Effect of single oral dose of tramadol on gastric secretions pH.

Background:Tramadol is an atypical analgesic agent. It has been shown that intramuscular or intravenous injection tramadol is able to inhibit M3 muscarinic receptors. Tramadol is able to mediate smooth muscles contraction and glandular secretions. We have evaluated the effects of single oral dose of tramadol given preoperatively on gastric juices pH in patients electively scheduled for laparoscopic cholecystectomy.Materials and Methods:Sixty adult, American Society of Anesthesiologist I and II patients scheduled for laparoscopic cholecystectomy were included in the study. Patients were randomly assigned to receive either placebo (n = 30) or oral tramadol 50 mg (n = 30). General anesthesia was induced using propofol, fentanyl and cisatracurium. After induction of anesthesia 5 ml of gastric fluid was aspirated through orogastric tube. The gastric fluid pH was measured using pH meter.Result:There was no significant difference in the pH between the groups. Gastric pH of the placebo and tramadol groups was 1.97 versus 1.98 (P = 0.092) respectively.Conclusion:Preoperatively single oral dose of tramadol was unable to elevate the desired level of gastric acid secretions pH (>2.5). This may be due to pharmacokinetic disparity between the analgesic and pH elevating properties of tramadol.

Cardioprotective effects of single oral dose of nicorandil before selective percutaneous coronary intervention.

Objective:Nicorandil, an opener of ATP-sensitive K+ channels, was used to treat angina in patients with coronary artery disease. In this study, we aim to investigate the cardioprotective effects of single oral dose of nicorandil in patients undergoing selective percutaneous coronary intervention (PCI).Methods:One hundred and thirty-eight patients with acute coronary syndrome undergoing PCI from July 2011 to October 2012 were randomly divided into control group (group 1, n=47), 10 mg oral nicorandil group (group 2, n=45), and 20 mg oral nicorandil group (group 3, n=46) about 2 hours before procedure, respectively. Cardiac troponin I (cTnI) levels were determined at 20 ~ 24 hours after PCI.Results:There was a significant difference in the rate of any cTnI elevation among the three groups (group 1: 36.17%, group 2: 20.00%, group 3: 15.22%, p=0.0176). With respect to the frequency of cTnI elevation ≥3 and 5×the upper limit of normal (ULN), there also had statistical difference among the three groups (17.02% in group 1, 8.89% in group 2, and 4.35% in group 3, respectively for cTnI elevation ≥3× ULN, p=0.0428; 12.77% in group 1, 6.67% in group 2, and 2.17% in group 3, respectively, for cTnI elevation ≥5× ULN, p=0.0487). Logistic regression analysis showed that LVEF (OR=0.915, 95% CI=0.853-0.981) and the use of nicorandil (OR=0.516, 95% CI=0.267-0.996) before PCI were independent protective factors of myocardial injury.Conclusion:Single oral dose of nicorandil (10 mg, 20 mg) 2 hours before the PCI procedure could decrease the incidence of peri-procedure myocardial injury and PCI-related myocardial infarction.

Antifertility effects of single oral doses of triptolide in male house rat (Rattus rattusL.)

The aim of present study was to evaluate the effect of single oral doses of triptolide on fertility of male house rat, Rattus rattus. Single oral administration of triptolide to male R. rattus resulted in 16.67 and 33.33% mortality in rats treated with 100 and 150 mg kg−1 b.wt. of triptolide, respectively, within 1–3 days of treatment. The LD50 value of triptolide against male R. rattus was found to be 182.81 mg kg−1 b.wt. Autopsy of rats surviving till day 45 after treatment revealed no significant effect on weights of reproductive organs. The sperm motility and viability in cauda epididymal fluid were reduced significantly in all the treated groups. Sperm concentration was significantly reduced only in rats treated with 100 mg kg−1 b.wt. of triptolide. Treatments significantly affected sperm morphology. The sperms with head tail separation ranged from 15.8 to 24.0% in all treated groups. The present study suggests the potential of triptolide in regulating fertility of male R. rattus.

Effect of single dose pretreatment analgesia with three different analgesics on postoperative endodontic pain: A randomized clinical trial.

Introduction:One of the aims of root canal treatment is to prevent or eliminate pain. Postoperative endodontic pain control continues to be a significant challenge.Aim:To compare and evaluate the effect of single oral dose of 100 mg of tapentadol, 400 mg of etodolac, or 10 mg of ketorolac as a pretreatment analgesic for the prevention and control of postoperative endodontic pain in patients with symptomatic irreversible pulpitis. The incidence of side effects was recorded as secondary outcome.Materials and Methods:Sixty emergency patients with moderate to severe pain, diagnosed with symptomatic irreversible pulpitis were randomly allocated (1:1:1) to any of the three groups; tapentadol, etodolac, or ketorolac. Medications were administered 30 min before beginning of the endodontic treatment. Patients recorded pain intensity on 10 cm visual analog scale (VAS) after treatment, for upto 24 h.Results:At 24 h, mean ±standard deviation (SD) of VAS scores (in cm) for tapentadol, etodolac, and ketorolac were 0.89 ± 0.83, 2.68 ± 2.29, and 0.42 ± 0.69, respectively. Kruskal-Wallis (K-W) test showed significant difference among the three groups (P = 0.001). Mann-Whitney test showed significantly lower VAS scores in tapentadol and ketorolac than etodolac group (P = 0.013 and 0.001, respectively).Conclusions:Single oral dose of 10 mg of ketorolac and 100mg of tapentadol as a pretreatment analgesic significantly reduced postoperative endodontic pain in patients with symptomatic irreversible pulpitis when compared to 400 mg of etodolac.

Effect of single oral dose of proanthocyanidin on postprandial hyperglycemia in healthy rats: A comparative study with sitagliptin.

Background:Many of flavonoid rich natural products found to have a significant influence on postprandial hyperglycemia, a major risk factor for diabetic complications. Enhancement of insulinotropic gut hormones by inhibition of dipeptidyl peptidase-IV (DPP-IV) are among the newest strategies for treatments of Type 2 diabetes which thought to be the underlying action through which flavonoid can reduce postprandial hyperglycemia.Aim:This study aim was designed to investigate the potential role of standardized grape seed proanthocyanidin in controlling postprandial hyperglycemia by enhancing the regulatory incretin effect of gut hormones in response to oral and intraperitoneal (I.P) glucose load in healthy rats.Materials and Methods:Five groups of animals each of six rats were used in this study, which was conducted in March 2013. Groups (II and V) treated with single oral dose of proanthocyanidin (50 mg/kg), Group III received single oral dose of sitagliptin (40 mg/kg) and Groups (I and IV) treated with vehicle serve as control groups. All treatments were given 30 min before oral or I.P glucose load. Blood glucose was estimated over 2 h duration at (0, 30, 60, 90, and 120) min from glucose load.Result:Both proanthocyanidin and sitagliptin significantly improve hyperglycemia induced by oral glucose load relative to control. While non-significant changes were achieved by proanthocyanidin after I.P glucose challenge compared to untreated control group.Conclusion:The result of this study indicated that proanthocyanidin may possess an enhancement of incretin effect of gut peptides, which could be responsible for some of its action on glucose homeostasis. This finding may provide an opportunity for further pharmacological studies using more specific models to clarify the possible action of proanthocyanidin as a natural DPP-IV inhibitor.

Effects of Single Oral Doses of Flavonoids on Absorption and Tissue Distribution of Orally Administered Doses of Trace Elements in Rats

Many flavonoids have the capacity to modulate the activity of drug metabolizing enzymes and transporters, thus raising the potential for alterations in the pharmacokinetics of drugs and other essential elements. The present study evaluates the effect of single supraphysiological orally administered doses of silibinin, epigallocatechin gallate (EGCG), quercetin and rutin on the absorption and tissue distribution of orally administered doses of the trace elements zinc copper and iron in rats. Thirty rats were allocated into 5 groups treated as follow: 1<SUP>st</SUP> group treated with olive oil, served as control; the other 4 groups were administered orally single doses of either silibinin, EPGC, quercetin or rutin, after 2 hr a solution contains sulphate salts of zinc, copper and iron was administered orally. The animals were sacrificed, blood samples, tissues of brain, kidney and liver were obtained for evaluation of the plasma and tissues concentrations of Zn, Cu and Fe using atomic absorption spectrometry. All four flavonoids decreased serum and tissues concentrations of the trace elements compared with control. In conclusion, concomitant administration of single doses of Zn, Cu and Fe with supra-physiological doses of the flavonoids silibinin, EGCG, quercetin and rutin significantly decreases serum and tissue levels of these trace elements.

Netazepide, a gastrin/CCK2 receptor antagonist, causes dose‐dependent, persistent inhibition of the responses to pentagastrin in healthy subjects

To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing. We did two studies in which we infused pentagastrin (0.6 μg kg(-1) h(-1) intravenously), aspirated gastric secretion and measured the volume, pH and H(+) secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100 mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100 mg) twice daily for 13 doses on the response to pentagastrin. Netazepide was well tolerated. After placebo, pentagastrin increased the volume and H(+) secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100 mg) abolished the response. After 13 doses, the reduction in volume and H(+) secretion rate persisted (P < 0.001), but the pH effect was mostly lost. Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.

Treatment of antipsychotic-induced hyperprolactinemia with bromocriptine: A case report

INTRODUCTION Previous literature has highlighted an increase in morbidity and mortality associated with antipsychotic use in persons with severe mental illnesses (SMI), which include schizophrenia and bipolar disorder. Drug-induced hyperprolactinemia is a function of dopamine blockade in the anterior pituitary. Elevated prolactin levels are often accompanied by symptoms of decreased libido and erectile dysfunction (ED) in men, and galactorrhea and amenorrhea in women. However, the extent to which antipsychotic (AP) use is associated with sexual dysfunction has not been extensively reported. Hyperprolactinemia may also increase the risk for osteopenia.

In vivo effect of single oral dose of artemether against early juvenile stages of Schistosoma mansoni Egyptian strain

The current treatment and control of schistosomiasis, rely on a single drug, praziquantel, although, it has minor activity against juvenile stages of the parasite. Studies have shown that artemether (ART) exhibits effects against juveniles of Schistosoma mansoni Liberian and Puerto Rican strains, Schistosoma japonicum and Schistosoma haematobium. Aiming to assess the in vivo activity of single oral dose of ART against early juvenile stages of S. mansoni Egyptian strain, this study was established. Mice were treated with ART (400mg/kg) at two time points evenly spaced over the period of larval development (7 and 21days post-infection; pi), and a third treatment point (day 49 pi) was included to elucidate when susceptibility decreases. Administration of ART on day 7 pi reduced the total worm burden by 85.94%. The greatest reductions were seen when treatment was given on day 21 pi, with total and female worm burden reductions of 91.52% and 90.57%, respectively, and cessation of oviposition. Similar dose given on day 49 pi reduced total worm burden by 55.17% and female worm burden by 66.51%. Moreover, it induced significant reduction in the tissue egg load and significant alterations in the oogram pattern with decreased immature eggs and increased dead eggs. Antipathological activities were evident in significant reductions in granulomata count and diameter. In conclusion, ART exhibits major in vivo schistosomicidal effects against the early larval migratory stages of S. mansoni Egyptian strain, mainly the 21-day old schistosomula, hence preventing disease progression and morbidity.

Pharmacokinetics and central nervous system effects of the novel dual NK1/NK3 receptor antagonist GSK1144814 in alcohol‐intoxicated volunteers

Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated. In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test. Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small. Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.

A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

BackgroundNon-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model.MethodsMale Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing.ResultsAt the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance.ConclusionThe presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

Effect of aprepitant on the pharmacokinetics of the cyclin-dependent kinase inhibitor dinaciclib in patients with advanced malignancies

Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib. As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m(2) dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone. Twelve patients completed the study; T (max) occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89-126 %) and 111 % (90 % CI 93-132 %) for dinaciclib C(max) and AUC([I]), respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant. Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.

Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men

The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aβ(1-38), Aβ(1-40) and Aβ(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aβ concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.

Oral administration of a nephrotoxic dose of potassium bromate, a food additive, alters renal redox and metabolic status and inhibits brush border membrane enzymes in rats

The time dependent effect of orally administered KBrO(3) on redox status and enzymes of brush border membrane (BBM) and carbohydrate metabolism has been studied in rat kidney. Animals were given a single oral dose of KBrO(3) (100mg/kg body weight) and sacrificed at different times after this treatment; control animals were not given KBrO(3). The administration of KBrO(3) resulted in nephrotoxicity, a decline in the specific activities of several BBM marker enzymes and also induced oxidative stress in kidney. The specific activities of enzymes of carbohydrate metabolism were also altered and suggest a shift in energy metabolism from the aerobic to anaerobic mode. The renal effects of single oral dose of KBrO(3) appeared to be reversible; maximum changes in all the parameters were 48 h after administration of KBrO(3) after which recovery took place, in many cases almost to control values, after 168 h. These results suggest that the administration of a single nephrotoxic dose of KBrO(3) inhibits brush border membrane enzymes, induces oxidative stress and alters energy metabolism of the renal system in a reversible manner.