Sensitivity of repeated interdigital web pinching to detect antinociceptive effects of ibuprofen.

AIMS: The aim of the current study was to assess the viability of the interdigital web pinch model as a test for analgesic activity in volunteer-based early phase drug development. METHODS: Pain thresholds and sensitization to a series of four sessions of interdigital web pinching (12 Newtons force) were measured in 26 male volunteers before and 1 and 3 h after oral dosing with ibuprofen (800 mg) or placebo to ibuprofen. Within each time point, the pain thresholds were measured by calculating the average visual analogue scores (VAS) for the first session of pinching (VAS-1). Sensitization to pinching was assessed by calculating the average changes in these scores for the three subsequent sessions of pinching (VAS-2). Moreover, the difference between the VAS score after the first session of pinching and that obtained at the end of the fourth session of pinching was calculated as a secondary endpoint (VAS-3). RESULTS: Treatment with ibuprofen had no significant effect on VAS-1 at either 1 or 3 h after dosing. However, the mean values of VAS-2 and VAS-3, were significantly reduced (P < 0.05) following treatment with ibuprofen. CONCLUSIONS: This model has been able to detect an antinociceptive effect with ibuprofen. However, large numbers of subjects were required in order to demonstrate this effect and this feature would restrict the model's utility in early phase clinical trials where small numbers of subjects are normally employed.

Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers.

Two open-label, two-way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen or ibuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once-daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of > or = 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single-agent medication (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log-transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded if the 90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R-(-)- and S-(+)-ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 micrograms/mL vs. 14.1 micrograms/mL; 17.3 micrograms/mL vs. 16.7 micrograms/mL; 19.4 micrograms/mL vs. 19.5 micrograms/mL, respectively), and values for R-(-)- as well as S-(+)-ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R-(-)- and S-(+)-ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single-agent medications were all well tolerated. In conclusion, the long half-life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once-daily dosing of telmisartan can be maintained, which may help to optimize patient compliance, and patients may self-administer concomitant acetaminophen or ibuprofen.

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form.

OBJECTIVE: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. METHODS: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. RESULTS: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. CONCLUSION: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

Optimizing the absorption of valspodar, a P-glycoprotein modulator, Part II: Quantifying its pharmacokinetic variability and refining the bioavailability estimate.

A randomized, sequential, bioreplication study was performed with 24 healthy volunteers to assess the pharmacokinetic variability of oral and intravenous administrations of valspodar, a multidrug resistance modulator for use as a chemotherapy adjunct. Subjects received 200 mg as a 2-hour intravenous infusion and 400 mg orally as microemulsion soft gelatin capsules each given on two separate occasions. Following replicate intravenous administrations, reproducibility in peak concentration and area-under-the-curve was demonstrated by interoccasion equivalence testing. Low to moderate inter- and intra-subject pharmacokinetic variability were observed with coefficients of variation ranged from 9% to 19%. Absolute bioavailability from the microemulsion formulation was 60%. Replicate oral administrations demonstrated uniform and repeatable absorption with interoccasion equivalence in peak concentration, time to reach the peak concentration, and area-under-the-curve. Coefficients of inter- and intra-subject variation for these parameters ranged from 10% to 20% indicating low to moderate pharmacokinetic variability. When variabilities were compared between the two routes of administration, the absence of differences indicated that the rate and extent of drug absorption from the microemulsion formulation was as uniform and repeatable as by intravenous infusion.

Tolerance to subchronic, high-dose ingestion of erythritol in human volunteers.

Erythritol is a sugar alcohol (polyol) which is absorbed from the small intestine in substantial amounts, not metabolized in the human body, and therefore excreted in the urine. Erythritol holds promise as a low-calorie sugar substitute. Human tolerance to repeated oral doses of erythritol was examined in a double-blind, two-way crossover study in 12 healthy, male volunteers. The participants consumed erythritol and, for comparison, sucrose for a duration of 7 days each. The daily dose of the test compounds ingested was 0.3 g/kg on Day 1, 0.6 g/kg on Day 2, and 1.0 g/kg on subsequent days. The daily dose was consumed under supervision in five portions, i.e., with the three main meals, a midmorning snack, and during the afternoon. The test compounds were incorporated into yoghurt, cookies, soft drinks, and chocolate. On each treatment day, body weight and blood pressure were measured and the participants were interviewed about side effects and their perception of stool and urine production. During the last 96 hr of each treatment period, urine was collected at 3-hr intervals during the day and for a 9-hr interval overnight for analysis of erythritol and different urinary parameters. On Days 3 to 7 of each treatment period, the participants were institutionalized. Body weights and blood pressure remained stable during the entire study. Signs of gastrointestinal intolerance were not seen and stool frequency and appearance were not different between the two treatments. The intake of liquids, which were provided ad libitum, was generally rather high (32.8 g/kg body wt/day on average) but not different between erythritol and sucrose consumption. Urine output also was high during both treatment periods. About 78% of ingested erythritol was excreted in the urine which led to a higher urinary osmolality but did not influence the 24-hr output of creatinine, citrate, urea, or electrolytes (Na+, K+, Cl-, Pi). The excretion of calcium was slightly higher during the erythritol test period but in absolute terms this increase was small. The urinary excretions of albumin, beta 2-microglobulin, and N-acetyl-glucosaminidase were slightly elevated during the erythritol test period but they were still well within the physiological range. None of the observed urinary changes became more pronounced with increasing duration of the erythritol treatment. In conclusion, the results of the present study demonstrate that the repeated ingestion of erythritol at daily doses of 1 g/kg body wt was well tolerated by humans.

A clinical study to evaluate the efficacy of the antihistamine doxylamine succinate in the relief of runny nose and sneezing associated with upper respiratory tract infection.

Antihistamines are widely used in common cold medications, although the role of histamine in the development of common cold symptoms is unclear and the use of antihistamines for the treatment of common cold is controversial. It is clear that antihistamines do not offer a cure for common cold but they may alleviate symptoms of sneezing and runny nose. The present study was designed to investigate the efficacy of an antihistamine, doxylamine, on the symptoms of runny nose and sneezing associated with common cold. We conducted a randomized double-blind study in cold sufferers. One thousand and one volunteers with cold symptoms were screened in four centres (UK, Denmark, Belgium, Germany) and 688 satisfied the entry criteria of the study. The main reasons for excluding subjects were a low nasal secretion weight (secretion weight < 0.2g, 72%) and a low subjective rhinorrhoea score (24%). Volunteers were randomized to receive either doxylamine succinate 7.5 mg by mouth four times a day up to nine doses (n = 345) or placebo (n = 343). The principal measurements were prospectively defined as runny nose and sneezing symptom scores. Data were analysed on an intention-to-treat basis, using Cochran-Mantel-Haenszel statistics controlling for baseline symptom scores. A between-group comparison showed that doxylamine-treated volunteers benefited from a significantly greater reduction in runny nose scores (P < 0.01) and sneezing scores (P < 0.001), than those volunteers in the placebo group. Doxylamine therapy was well tolerated; the incidence of unexpected side-effects was comparable with placebo. Of the expected side-effects, 13.3% of doxylamine-treated patients reported drowsiness. The incidence of sedative effects was lower than has been reported for other commonly used first-generation antihistamines.

Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus.

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation.

The inter- and intraindividual variability of cyclosporine pharmacokinetics from a microemulsion formulation were compared with the currently marketed formulation in a sequential bioreplication study. Twenty-four healthy male volunteers were randomized to receive each formulation on two separate occasions; the reference treatment was a single oral dose of 300 mg of Sandimmune and the test treatment was a single oral dose of 180 mg of Sandimmune Neoral, both given as soft gelatin capsules. Serial venous blood samples were obtained over a period of 48 h after each administration, and cyclosporine concentrations were measured in whole blood by a specific monoclonal RIA method. Between- and within-subject variabilities were quantified from the appropriate sums of squares from analysis of variance and statistically compared between formulations. Both inter- and intraindividual variation for the peak concentration, time to reach the peak, area under the curve, and terminal half-life of the test formulation were significantly reduced (p < 0.05) with two exceptions. For area under the curve between subjects (p < 0.2) and peak concentration within subjects (p < 0.1), trends toward reduced variability for the test formulation were evident. These results were further reflected in the inter- and intraindividual coefficients of variation of the pharmacokinetic parameters that ranged from 3 to 22% for the test formulation compared with 19 to 41% for the reference formulation. In comparison with the currently marketed formulation, reduced variability in the pharmacokinetics of cyclosporine following oral administration of Sandimmune Neoral provides a more predictable and consistent concentration-time profile.

Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation.

The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) were compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neoral at all dose levels investigated. The area under the curve for Sandimmune increased in a less than proportional manner with respect to dose, whereas that for Sandimmune Neoral was consistent with linear pharmacokinetics. Because of this difference, no global assessment of relative bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compared to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after administration as Sandimmune Neoral should facilitate more accurate dosage titration in the clinical setting.

Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers.

Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM-CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.

[Bioequivalence and bioavailability after single administration of effervescent ranitidine tablets]. / Bioäquivalenz und Bioverfügbarkeit nach Einmalgabe von löslichen Ranitidin-Tabletten.

An open two-way cross-over study in 12 healthy male volunteers was performed in order to determine the relative bioavailability of a 150 mg ranitidine (Zantic, CAS 66357-35-5) effervescent tablet sweetened with saccharine in comparison to the 150 mg standard ranitidine dispersible tablet (Trinkette). On two occasions separated by a wash-out period of 1 week volunteers received a single oral dose of both formulations. On each administration day blood samples were collected at predetermined time points in order to investigate the pharmacokinetic parameters. Single oral doses of ranitidine were very well tolerated by healthy male volunteers. The non-parametric 95% confidence intervals for AUC and Cmax were 87 to 116% and 84 to 107%, respectively. The relative bioavailability of the ranitidine effervescent tablet was 99% compared to the dispersible tablet. The mean of the Cmax ratio was 95%. The ranitidine effervescent tablet could thus be claimed to be bioequivalent to the dispersible tablet.