Effect Of Single Oral Dose Research Articles

Pharmacokinetics and central nervous system effects of the novel dopamine D3receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state

GSK598809 is a novel selective dopamine D(3) receptor antagonist, currently in development for the treatment of substance abuse and addiction. In a blinded, randomized, placebo-controlled study, effects of single oral doses of 175 mg GSK598809 were evaluated in healthy volunteers. Pharmacokinetics, central nervous system (CNS) effects and potential for interactions with alcohol were evaluated, using an alcohol infusion paradigm and analysis of eye movements, adaptive tracking, visual analogue scales, body sway, serum prolactin and verbal visual learning test. Adverse effects of GSK598809 included headache, dizziness and somnolence. Plasma concentration of GSK598809 was maximal 2-3 hours postdose and decreased with a half-life of roughly 20 hours. CNS effects were limited to prolactin elevation and decreased adaptive tracking. Co-administration of GSK598809 and alcohol did not affect alcohol pharmacokinetics, but caused a 9% decrease of C (max) and a 15% increase of AUC of GSK598809. CNS effects of co-administration were mainly additive, except a small supra-additive increase in saccadic reaction time and decrease in delayed word recall. In conclusion, GSK598809 causes elevation of serum prolactin and a small decrease in adaptive tracking performance. After co-administration with alcohol, effects of GSK598809 are mainly additive and the combination is well tolerated in healthy volunteers.

P.4.a.005 Pharmacodynamic effects of single oral doses of the novel anxiolytic compound BNC210 in healthy male volunteers

P.4.a.005 Pharmacodynamic effects of single oral doses of the novel anxiolytic compound BNC210 in healthy male volunteers

Single Dose of 50 mg/kg Clofibrate in Jaundice of Healthy Term Neonates: Randomised Clinical Trial of Efficacy and Safety

To evaluate the effect of single oral dose of 50 mg/kg clofibrate in hyperbilirubinemia of term healthy neonates in Yazd, Iran. A parallel single- blinded randomized clinical trial, conducted on 60 healthy term neonates admitted between July and December 2007 to Shahid Sadoughi Hospital. Inclusion criteria were neonates with gestation age of 38-42 wk, birth weight of 2500-4000 g, product of normal vaginal delivery, breast-fed and total serum bilirubin (TSB) level of 17-29.9 mg/dL. Neonates with sepsis, anemia, severe asphyxia, hemolytic diseases, major congenital anomalies, indirect hyperbilirubinemia and underlying hepatic disorders were excluded. Selection of patients was based on random allocation via table of random numbers and the patients distributed into two groups. In group one, 30 neonates were treated with phototherapy alone and in 30 of other group treatment done with single dose of 50 mg/kg clofibrate and phototherapy. The primary endpoint with respect to efficacy in reducing of TSB was achieving TSB to less than 14 mg/dL as measured at the beginning, 12, 24 and 48 h after the start of phototherapy. Secondary outcomes were hospital stay days, duration of phototherapy and side effects of treatments during hospital stay and on the second day after discharge. No significant differences were seen from the viewpoint of rout of delivery, gender, gestational age, birth weight, hemoglobin and bilirubin level at time of admission and weight in discharge time in the two groups. After 48 h of intervention, 27 (90%) neonates in clofibrate group and 15 (56.7%) in control group had TSB of less than 14 mg/dL (p 0.02). Mean TSB 12 h after treatment (mean ± SD: 14.82 ± 1.7 mg/dL vs. 16.67 ± 1.77 mg/dL, P 0.001), 24 h after treatment (mean ± SD: 11.97 ± 2.92 mg/dL vs. 14.61 ± 2.52 mg/dL, P 0.001) and 48 h after treatment (mean ± SD: 7.91 ± 2.45 mg/dL vs. 12.74 ± 2.21 mg/dL, P 0.0001), mean of hospital stay days (mean ± SD: 1.7 ± 0.7 days vs. 3.2 ± 1.2 days, P 0.03) and duration of phototherapy (mean ± SD: 30.2 ± 13.99 h vs. 46.2 ± 15.58 h, P 0.001] were significantly lower in clofibrate group. Only loose stool was seen in two patients of clofibrate group and no significant difference was seen from view of safety of the treatments. A single dose of 50 mg/kg clofibrate in treatment of neonatal hyperbilirubinemia is effective, safe and cost effective in view of reducing hospital stay days.

Distribution, Elimination, and Renal Effects of Single Oral Doses of Europium in Rats

Single doses of europium (III) chloride hexahydrate were orally administered to several groups of rats. Cumulative urine samples were taken at 0-24 h, and blood samples were drawn after 24-h administration. The europium concentration was determined in these samples by inductively coupled plasma atomic emission spectroscopy. The volume, creatinine, ß-2-microglobulin, and N-acetyl-ß-D-glucosaminidase were measured in the urine samples to evaluate possible europium-induced renal effects. The blood samples showed low europium distribution, with an average of 77.5 μg/L for all groups. Although the urinary concentration and excretion showed dose-dependent increases, the percentage of europium excreted showed a dose-dependent decrease, with an average of 0.31% in all groups. The administration of europium resulted in a significant decrease of creatinine and a significant increase of urinary volume, N-acetyl-ß-D-glucosaminidase, and ß-2-microglobulin. Rare earth elements, including europium, are believed to form colloidal conjugates that deposit in the reticuloendothelial system and glomeruli. This specific reaction may contribute to low europium bioavailability and renal function disturbances. Despite low bioavailability, the high performance of the analytical method for determination of europium makes the blood and urine sampling suitable tools for monitoring of exposure to this element. The results presented in this study will be of great importance in future studies on the health impacts of rare earth elements.

A study to evaluate the effects of single oral doses of BMS-708163 in the cerebrospinal fluid of healthy young men

A study to evaluate the effects of single oral doses of BMS-708163 in the cerebrospinal fluid of healthy young men

Toxicokinetics and toxicological effects of single oral dose of fumonisin B1 containing Fusarium verticillioides culture material in weaned piglets

Toxicokinetics and the toxicological effects of culture material containing fumonisin B(1) (FB(1)) were studied in male weaned piglets by clinical, pathological, biochemical and sphingolipid analyses. The animals received a single oral dose of 5 mg FB(1)/kg of body weight, obtained from Fusarium verticillioides culture material. FB(1) was detected by HPLC in plasma collected at 1-h intervals up to 6h and at 12-h intervals up to 96 h. FB(1) eliminated in feces and urine was quantified over a 96-h period and in liver samples collected 96 h post-intoxication. Blood samples were obtained at the beginning and end of the experiment to determine serum enzyme activity, total bilirubin, cholesterol, sphinganine (Sa), sphingosine (So) and the Sa/So ratio. FB(1) was detected in plasma between 30 min and 36 h after administration. The highest concentration of FB(1) was observed after 2 h, with a mean concentration of 282 microg/ml. Only 0.93% of the total FB(1) was detected in urine between 75 min and 41 h after administration, the highest mean concentration (561 microg/ml) was observed during the interval after 8 at 24 h. Approximately 76.5% of FB(1) was detected in feces eliminated between 8 and 84 h after administration, with the highest levels observed between 8 and 24 h. Considering the biochemical parameters, a significant increase only occurred in cholesterol, alkaline phosphatase and aspartate aminotransferase activities. In plasma and urine, the highest Sa and Sa/So ratios were obtained at 12 and 48 h, respectively.

Zidovudine, diclofenac and ketoprofen pharmacokinetic interactions in rats.

Zidovudine (AZT) is widely used for the management of human immunodeficiency virus (HIV) infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for relief of non-specific fever and musculoskeletal pain in patients with HIV including those with AZT-induced myopathy. The effects of single oral doses of diclofenac and ketoprofen on AZT pharmacokinetics were studied in rats. The influence of AZT on the pharmacokinetics of diclofenac or ketoprofen was also investigated. The administration of diclofenac (3 mgkg(-1)) or ketoprofen (1 mgkg(-1)) did not significantly alter AZT (1.5 mgkg(-1)) pharmacokinetic parameters compared with administering AZT alone. There was no significant difference between the pharmacokinetics of ketoprofen given alone or in combination with AZT. However, the co-administration of AZT with diclofenac affected the pharmacokinetics of diclofenac. The Cmax of diclofenac was significantly (P < 0.05) increased by approximately threefold within a shorter time (0.6+/-0.2 h). The mean AUC value for diclofenac was increased from 2.29 to 5.04 microg mL(-1) h in the presence of AZT. AZT decreased the mean apparent clearance of diclofenac by 54%. The increase in diclofenac concentrations could be attributed to a decrease in its clearance or delay in its metabolite formation due to a competitive effect. The results show that diclofenac and AZT should be given with caution because of the possible increase of diclofenac toxicity, in anticipation of follow-up clinical studies to examine this finding in man. AZT and ketoprofen could be a safe combination since no pharmacokinetic interaction was detected.

Activity of Artemether and Mefloquine against Juvenile and Adult Schistosoma mansoni in Athymic and Immunocompetent NMRI Mice

Immune effector mechanisms can enhance the activity of antischistosomal drugs. We examined the in vivo effect of single oral doses of the antimalarials artemether (400 mg/kg) and mefloquine (200 mg/kg), recently described to have promising antischistosomal properties, against juvenile and adult Schistosoma mansoni in T cell-deficient and in comparably infected age- and sex-matched immunologically intact control mice. Artemether and mefloquine are equally effective in athymic and immunocompetent mice. Artemether treatment resulted in total and female worm burden reductions ranging between 71.1% and 85.3%, whereas mefloquine achieved total and female worm burden reductions of 80.4-97.8%. In conclusion, artemether and mefloquine act T-cell independently and no synergistic interaction with the immune response was involved.

Effects of a concomitant single oral dose of rifampicin on the pharmacokinetics of pravastatin in a two-phase, randomized, single-blind, placebo-controlled, crossover study in healthy Chinese male subjects

Background: Pravastatin is a potent cholesterol-lowering agent; ~34% of an oral dose of pravastatin is eliminated unchanged through biliary and urinary excretion. Rifampicin is an inducer of drug metabolism enzymes, and it affects the activities of transporters involved in pravastatin disposition. Drug-drug interaction between rifampicin and pravastatin is possible because of the effects of rifampicin on the activities of drug transporters. Objective: This study was designed to investigate the effects of a single oral dose of rifampicin on the pharmacokinetics of pravastatin. Methods: Healthy Chinese male volunteers were recruited for this 2-phase, single-blind, placebo-controlled, crossover study. The subjects were randomly divided into 2 groups to receive either rifam-picin or placebo concomitantly with pravastatin. All subjects received a 20-mg oral dose of pravastatin on days 1 and 9, separated by an 8-day washout period. Subjects in the rifampicin group received a single 600-mg oral dose of rifampicin on day 1 and placebo on day 9; those in the placebo group received placebo on day 1 and a single 600-mg oral dose of rifampicin on day 9. High-performance liquid chromatography-tandem mass spectrometry was used to determine plasma concentrations of pravastatin for up to 12 hours after administration. Results: Twelve volunteers participated in the study (6 per group). The mean (SD) age of the subjects was 20 (2) years (range, 18–25 years). The mean height of the subjects was 174 (4) cm (range, 168–180 cm), and the mean weight was 69.2 (3.7) kg (range, 65–77 kg). The mean pharmacokinetic parameters for pravastatin that changed significantly were as follows (rifampicin and placebo groups, respectively): C max (315.7 [227.2] and 115.8 [77.5] ng · mL −1 [ P = 0.009]); AUC 0–12 (604.8 [73.3] and 259.0 [133.4] ng · h · mL −1 [ P < 0.001]); AUC 0–∞) (623.3 [248.8] and 275.1 [58.5] ng · h · mL −1 [ P < 0.001]); and apparent oral clearance (CL/F) (0.52 [0.18] and 1.30 [0.58] L · h −1 · kg −1 [ P < 0.001]). No significant changes in the T max or t ½ of pravastatin were observed. All subjects tolerated pravastatin well during both phases of the study, with or without coadministration of rifampicin. None of the subjects withdrew from the study. Conclusion: Coadministration of a single oral dose of rifampicin significantly increased the plasma concentration of pravastatin in this group of healthy Chinese male subjects.

Effect of single oral dose of Nizatidine administered a night before surgery on the intragastric pH and volume in adult patients undergoing elective surgery” a triple blind placebo controlled clinical trial.

Effect of single oral dose of Nizatidine administered a night before surgery on the intragastric pH and volume in adult patients undergoing elective surgery” a triple blind placebo controlled clinical trial.

Effect of single oral dose of Famotidine administered a night before surgery on the intragastric pH and volume in adult patients undergoing elective surgery; a triple blind placebo controlled clinical trial

Objectives: To evaluate the effect of preanaesthetic administration of oral Nizatidine on pH and volume of gastric contents excluding samples contaminated with duodenogastric reflux.Design: Prospective, triple blind, randomized and placebo controlled clinical trial.Methods: The patients in Group C (Control) received Placebo while Group N (Nizatidine 300 mg) orally at 9.00 p.m., a night before elective surgery. Next day, gastric contents were aspirated with a large bore, multi-orifices gastric tube passed through an endotracheal tube placed blindly in esophagus after tracheal intubation and analyzed for the presence of bile salts, pH and volume.Results: Thirty five samples (29.66 %) out of 118 were contaminated with duodenal contents. One sample was contaminated with blood while one patient has no gastric contents. Duodenogastric reflux significantly affected pH and volume. Nizatidine, after excluding those samples contaminated either with duodenal fluid or blood, did not decrease significantly pH (p 0.0554), volume (p 0.5202) and the proportion of the patients (28.57% versus 24.39%) considered” at risk” compared with Placebo (p 0.8044) according to the criteria defined (pH ≤ 2.5 and volume ≥ 25 ml).Conclusion: Nizatidine 300 mg given orally, a night before surgery did not afford adequate prophylaxis for the acid aspiration syndrome excluding those samples contaminated with duodenogastric reflux.

Esomeprazole as a prophylactic agent for acid aspiration syndrome in adult patients undergoing elective surgery: A triple blind placebo controlled clinical trial

Background: To explore the effect of single oral dose of esomeprazole 20 mg, administered a night before surgery, on intragastric pH and volume in adult patients undergoing elective surgery by excluding cases contaminated with duodenogastric refluxate. Patients and Methods: This prospective, triple blind, randomised and placebo controlled clinical trial was conducted to explore the effect of single oral dose of esomeprazole 20 mg, administered a night before surgery, on intragastric pH and volume on 120 adult inpatients of either sex, American Society of Anaesthesiologist physical status I-II, and aged 15‐70 years. The patients in Group C (control) received placebo while Group E (Esomeprazole) received esomeprazole orally at 9.00 pm, the night before elective surgery. On the day of surgery, the gastric contents were aspirated with a large bore, multi-orifice gastric tube passed through an endotracheal tube placed blindly in the oesophagus after tracheal intubation and analysed for pH, volume and the presence of bile salts. Results: Thirty nine samples (33%) out of 117 were contaminated with duodenal contents. Duodenogastric reflux significantly affected pH and volume in Group C (p value 0.0003 and 0.0016) and E (p value 0.0401 and 25 ml/kg) at the time of induction of anaesthesia excluding samples contaminated with duodenogastric reflux.

Poster Abstract #7: Pharmacokinetic-Pharmacodynamic Interaction Between Nebicapone (BIA 3-202) and Controlled-release Levodopa/Benserazide (Madopar HBS 125)

Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity, and nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.

Pharmacokinetic-Pharmacodynamic Interaction between Nebicapone, a Novel Catechol-O-Methyltransferase Inhibitor, and Controlled-Release Levodopa/Carbidopa 200 mg/50 mg

Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16). This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods. There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated. Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.

Genetic Variation in the Renal Sodium Transporters NKCC2, NCC, and ENaC in Relation to the Effects of Loop Diuretic Drugs

There is little data on genetic predictors of loop diuretic efficacy in humans. Therefore, we investigated the diuretic effects of single oral doses of bumetanide, frusemide, and torsemide in a crossover study in 97 healthy Caucasians in relation to genetic variation in the renal sodium transporters NKCC2 (coded by SLC12A1), NCC (SLC12A3), and ENaC (three subunits coded by SCNN1A, SCNN1B, and SCNN1G). The NCC alanine 264 allele (Gly264Ala) and the most frequent SCNN1B haplotype were associated with stronger diuresis, indicating lower reabsorbing function of these alleles. The variant alleles of the tightly coupled polymorphisms rs5723 (Leu649Leu) and rs5729 in SCNN1G were associated with weaker diuresis, indicating higher activity. Extended haplotype homozygosity implied evolutionary selection of the NCC alanine 264 allele. In conclusion, acute diuretic effects of loop diuretics were affected by genetic variation in sodium transporters that, in the nephron, are located distally from NKCC2.

"Effect of single oral dose of Sodium Rabeprazole administered a night before surgery on the intragastric pH and volume in adult patients undergoing elective surgery" a triple blind placebo controlled clinical trial

Back Ground: Saliva, duodenogastric refluxate and blood due to gastric mucosal entrapment can affect both pH and volume of gastric contents while sampling from stomach. This issue has never been exposed while evaluating the effectiveness of drugs used for the prophylaxis of acid aspiration. We considered all these factors. Methods: This prospective, triple blind, randomized and placebo controlled clinical trial was conducted to explore the effect of single oral dose of Sodium Rabeprazole 20 mg on intragastric pH and volume in 100 adult inpatients of either sex, ASA I-III, and aged 15-70 years. The patients in Group S received (Sodium Rabeprazole 20 mg) while Group C received Placebo orally at 9.00 p.m., a night before elective surgery. Gastric contents were aspirated with a large bore, multi-orifices gastric tube passed through an endotracheal tube placed blindly in esophagus after tracheal intubation and analyzed for the presence of bile salts, pH and volume. Results: Fifteen cases (15.15%) were contaminated with duodenal contents and one with blood (1%). The proportion of the patients considered at risk according to the criteria defined (pH ≤ 2.5 and volume ≥ 25 ml) was statistical significant in Group S compared with Placebo (p value 0.0005). Conclusion: Oral Sodium Rabeprazole 20 mg administered a night before elective surgery does improve the gastric environment at the time of induction of anesthesia, should the aspiration of gastric contents occur.

Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes

In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. The study was conducted at six investigational sites. The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics. Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events. In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.

Benzo(a)pyrene‐induced acute neurotoxicity in the F‐344 rat: role of oxidative stress

Given the link between neurotoxicity and exposure to pollutants, the potential behavioral neurotoxicity of benzo(a)pyrene [B(a)P] was investigated. Studies have established that B(a)P requires metabolic activation to highly reactive species to elicit many of its adverse effects. This study investigated the perturbation of nervous system function by correlating behavioral changes with the metabolism of B(a)P, antioxidant enzyme levels and lipid peroxidation in selected brain regions. The neurobehavioral effects of single oral doses of B(a)P (25-200 mg kg(-1) body weight) on motor activity were examined in male F-344 rats at 2, 4, 6, 12, 24, 48, 72 and 96 h post treatment. Parent B(a)P and metabolites were measured at the above mentioned time points by reverse phase HPLC. The activity of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) and levels of malondialdehyde were determined at 6 and 96 h in both the striatum and hippocampus of B(a)P exposed rats. Suppression of motor activity (up to 70%) reached a maximum at 6 h, but was reversible at 96 h in all dose groups. The kinetics of disposition data show a strong link between B(a)P metabolism and the onset and duration of behavioral effects. Benzo(a)pyrene caused a 15-70% inhibition in the activity of superoxide dismutase and glutathione peroxidase and an enhancement in catalase and lipid peroxidation (up to 68%) in the striatum and hippocampus at 6 and 96 h post treatment, respectively. These findings suggest that B(a)P-induced acute neurobehavioral toxicity may occur through oxidative stress due to inhibition of the brain antioxidant scavenging system.

The influence of the novel 5‐HT1A agonist R137696 on the proximal stomach function in healthy volunteers

As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.

Evaluation of tetrahydrobiopterin (BH4) as a potential therapeutic agent to treat erectile dysfunction

Nitric oxide (NO)-mediated smooth muscle relaxation causes penile erections. The endothelial NO synthase (eNOS) coenzyme tetrahydrobiopterin (BH4) converts eNOS-mediated catalytic activity from oxygen radical to NO production, improving endothelial function and vascular smooth muscle relaxation. Using quantitative immunohistochemistry, 8-isoprostane and nitrotyrosine concentrations were compared in cavernosal tissue from 17 potent and 7 impotent men, and the effect of single oral doses of BH4 on penile rigidity and tumescence was investigated. The pharmacodynamic effect of single oral doses of BH4 on penile rigidity and tumescence was investigated in a randomized, placebo-controlled, double-blind cross-over fashion in 18 patients with erectile dysfunction (ED) while receiving visual sexual stimulation. 8-Isoprostane content in endothelium and smooth muscle was significantly higher in impotent patient samples; the level of nitrotyrosine was unchanged in ED patients. Relative to placebo, a single dose of 200 mg BH4 led to a mean increase in duration of > 60% penile rigidity (33.5 min [95% confidence interval (CI): 13.1-49.3] at base and 29.4 min [95% CI: 8.9-42.2] at tip). A 500-mg dose increased the relative duration of > 60% penile rigidity by 36.1 min (95% CI: 16.3-51.8) at the base and 33.7 min (95% CI: 11.4-43.9) at the tip. Treatments were well tolerated. BH4 treatment is suggested to switch eNOS catalytic activity from super-oxide to NO formation, leading to a reduced formation of free radical reaction product 8-isoprostane without alteration of nitrotyrosine. The observed results make BH4 a suitable candidate as an ED treatment through reconstitution of altered catalytic activity of the eNOS.