Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers

Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. Objective: This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. Methods: An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. Results: The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. Conclusions: Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.     

Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers.

1. Losartan (DuP 753, MK-954) is a novel, potent and highly selective AT1 angiotensin II receptor antagonist. The effect of multiple oral doses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2. In a double-blind and randomized fashion, subjects received 50 mg losartan or placebo once daily for 15 days in each period. At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively. 3. Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the study, no laboratory abnormalities were noted. 4. Multiple oral doses of losartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0.48h) of immunoreactive digoxin during losartan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml-1 h during placebo; not significant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 vs 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5. Multiple oral doses of losartan did not affect the pharmacokinetic parameters of oral digoxin AUC(0.48 h) during losartan 23.6 +/- 3.7 ng ml-1 h vs 22.4 +/- 2.6 ng ml-1 h during placebo; not significant, Cmax 3.5 +/- 0.7 ng ml-1 with vs 3.1 +/- 0.5 ng ml-1 without losartan; not significant and tmax 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 51.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6. We conclude that multiple oral doses of losartan (50 mg daily) do not alter the pharmacokinetics of immunoreactive digoxin, following either intravenous or oral digoxin. Furthermore, the co-administration of digoxin with losartan is well tolerated by healthy male volunteers.     

Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers

The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.     

Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.     

Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene CysLT1 receptor antagonist

Urinary tract infections may induce severe inflammation, transient impairment in renal function and scar formation, ranging in severity from acute symptomatic pyelonephritis to chronic pyelonephritis, which have a potential to lead to renal failure and death. The present study aimed to investigate the possible protective effect of montelukast, a selective antagonist of cysteinyl leukotriene receptor 1 (leukotriene CysLT1), against Escherichia coli-induced oxidative injury and scarring in renal tissue. Wistar rats were injected 0.1 ml of E. coli (ATCC 25922 10(10) cfu/ml) or saline into left renal medullae. Six rats were assigned as the sham group and were given 0.1 ml 0.9% NaCl. Pyelonephritic rats were treated with either saline or montelukast immediately after surgery and at daily intervals. Twenty-four hours or one week after E. coli injection, rats were decapitated and the kidney samples were taken for histological examination or determination of renal malondialdehyde, glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen contents. Formation of reactive oxygen species in renal tissue samples was monitored by using chemiluminescence technique with luminol and lucigenin probes. Creatinine, blood urea nitrogen and lactate dehydrogenase (LDH) activity were measured in the serum samples. E. coli inoculation caused significant increases in malondialdehyde level, MPO activity, chemiluminescence levels and collagen content, while GSH level was decreased in the renal tissues (p<0.05-0.001). On the other hand, serum TNF-alpha, LDH, blood urea nitrogen and serum creatinine levels were elevated in the pyelonephritic rats as compared to control group. Leukotriene CysLT1 receptor antagonist montelukast reversed all these biochemical indices, as well as histopathological alterations, that were induced by acute pyelonephritis. It seems likely that montelukast protects kidney tissue by inhibiting neutrophil infiltration, balancing oxidant-antioxidant status, and regulating the generation of inflammatory mediators suggesting a future role for leukotriene CysLT1 receptor antagonists in the treatment of pyelonephritis.     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers.

This study was designed to determine the safety, tolerability, pharmacokinetics and effects on cognitive function of GTS-21 in healthy, male volunteers. A total of 18 subjects were randomized to GTS-21 (25, 75 and 150 mg) or placebo administered three times daily (first 4 days, once on Day 5) for three, 5-day sessions. GTS-21 was well tolerated up to doses of 450 mg/day, with no clinically significant safety findings. C(max) and the area under the plasma concentration of GTS-21 and the metabolite 4-OH-GTS-21 increased in a dose-related fashion; although considerable intersubject variability occurred, it decreased with continued dosing. GTS-21 showed statistically significant enhancement of three measures of cognitive function (attention, working memory, episodic secondary memory) compared to placebo. A relationship between exposure to GTS-21 and the magnitude of the cognitive response was apparent, with maximal effect approached for doses between 75 and 150 mg three times a day. These data indicate that GTS-21 may represent a novel treatment for dementia.     

No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers

The effect of rosuvastatin on the pharmacokinetics of digoxin was assessed in 18 healthy male volunteers in this double-blind, randomized, two-way crossover trial. Volunteers were dosed with rosuvastatin (40 mg once daily) or placebo to steady state before being given a single dose of digoxin 0.5 mg. Blood and urine samples for the measurement of serum and urine digoxin concentrations were collected up to 96 hours following dosing. The effect of rosuvastatin was assessed by constructing 90% confidence intervals (CIs) around the treatment ratios (rosuvastatin + digoxin/placebo + digoxin) for digoxin exposure. The geometric least square mean AUC(0-t) and Cmax of digoxin were only 4% higher when the drug was coadministered with rosuvastatin compared to placebo. The 90% CIs for both treatment ratios (AUC(0-t) = 0.88-1.24; Cmax = 0.89-1.22) fell within the prespecified margin of 0.74 to 1.35; therefore, no significant pharmacokinetic interaction occurred between rosuvastatin and digoxin. The geometric mean amount of digoxin excreted into the urine and its renal clearance were similar with rosuvastatin and placebo. These results demonstrate that rosuvastatin has no effect on the pharmacokinetics of digoxin. Coadministration of rosuvastatin and digoxin was well tolerated.     

Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers.

The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending-dose, double-blind, placebo-controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double-blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24-hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.     

Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients

OBJECTIVE: To describe the factors affecting pharmacokinetics of telmisartan, an angiotensin II receptor antagonist, a population pharmacokinetic (PPK) model has been developed based upon the data collected from healthy volunteers and hypertensive patients. METHODS: A total of 1566 plasma samples were collected from 20 healthy volunteers and 129 hypertensive patients, together with the demographic background. The data were analyzed by the NONMEM program using two-compartment model with first-order absorption. The robustness of the obtained PPK model was validated by the bootstrapping resampling method. RESULTS: The oral clearance (CL/F) was found to be associated with age, dose and alcohol consumption, but neither related to serum creatinine nor smoking history. The volume of distribution for the central compartment was related to age and dose, and the volume of distribution for the peripheral compartment was related to body weight and gender. The absorption rate constant (Ka) and the absorption lag time were described as function of dose. The CL/F decreased with advanced age. The CL/F decreased and Ka increased with higher dose, reflecting the super-proportional increase in the plasma levels of telmisartan. The AUC and C(max) values predicted by the present PPK model were well consistent with the observed values. The means of parameter estimates obtained with 200 bootstrap replicates were within 95-111% of the final parameter estimates from the original data set. CONCLUSION: A PPK model for telmisartan developed here well described the individual variability and exposure, and robustness of the model has been validated by the bootstrapping method.     

Safety of multiple doses of ofloxacin in healthy volunteers.

A safety profile of ofloxacin, a new fluoroquinolone antibiotic, was assessed in twelve healthy male volunteers. Ofloxacin was dosed at 400 mg twice daily over a 10-day course of treatment. This evaluation included chemistry and haematologic profiles, neurologic evaluations, ophthalmologic examinations, audiometric testing, and electrocardiogram before, during and the end of the study. In addition, plasma samples were analysed for ofloxacin prior to each morning dose and a complete plasma concentration profile was performed on day 6. Gastrointestinal complaints such as nausea, diarrhoea and upset were the most frequent side effects reported. The only other adverse event that occurred in more than one volunteer was headache. None of the subjects in this study developed a serious side effect and no physical or psychological changes were observed. Laboratory values remained in their normal ranges with the exception of one volunteer who developed a 3-fold rise in one liver function test at the end of the study. The subject was asymptomatic and this aberration resolved without sequelae. In summary, a 10-day course of ofloxacin was found to be safe and have a low potential for toxicity. The side effects observed in this study were mild and similar to those observed with other fluoroquinolones.     

Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans

AIMS: To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. METHODS: A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo or 10 mg montelukast daily for 6 days, 4 mg rosiglitazone was administered and plasma samples were obtained for 24 h and analyzed for rosiglitazone and N-desmethylrosiglitazone using high-performance liquid chromatography with fluorescence detection. RESULTS: During the montelukast phase, the total area under the time-concentration curve (AUC) and peak plasma concentration of rosiglitazone were 102% (90% CI 98, 107%) and 98% (90% CI 92, 103%) of the corresponding values during the placebo phase, respectively. Multiple dosing with montelukast did not affect the oral clearance of rosiglitazone significantly (90% CI 94, 105%; P = 0.50). The AUC ratio and plasma concentration ratios of N-desmethylrosiglitazone : rosiglitazone were not changed by multiple dosing with montelukast (90% CI 90, 103%; P = 0.14). CONCLUSIONS: Multiple doses of montelukast do not inhibit CYP2C8-mediated rosiglitazone metabolism in vivo despite in vitro findings indicating that montelukast is a selective CYP2C8 inhibitor.     

Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed. The decrease observed in ethambutol urinary excretion may be accounted for by taking into consideration the variability of the urinary excretion of ethambutol reported in the literature. However, a slight, likely not clinically relevant, induction or activation of kidney alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out at present. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.     

Multiple-dose pharmacokinetics of the new H1-receptor antagonist tazifylline in healthy volunteers

The multiple-dose pharmacokinetics of the new H1-receptor antagonist, tazifylline, were investigated in healthy volunteers. From single-dose data, tazifylline appeared to be rapidly absorbed (median tmax of 0.6 h) and eliminated (t1/2 = 1.0 +/- 0.2 h). However, plasma levels measured on days 3 and 8 of the multiple-dose regimen (10 mg b.i.d. for 8 days) indicated moderate accumulation. A two-compartment model best described multiple-dose data with a terminal half-life of 15.6 +/- 7.6 h consistent with twice-daily dosing of tazifylline.     

Glyceryl-1-nitrate pharmacokinetics in healthy volunteers.

The plasma kinetics and urinary excretion of glyceryl-1-nitrate (G-1-N), a metabolite of glyceryl trinitrate with antianginal potential, were investigated in 10 healthy male volunteers, after intravenous infusion and oral administration of 20 mg G-1-N. The apparent volume of G-1-N distribution was 601 corresponding to 0.761 kg-1 body weight, on average. It is suggested that total body water is the principal biological correlate of the hydrophilic drug. Mean intravenous clearance was 283 ml min-1 or 3.61 ml min-1 kg-1. The average of elimination half-lives were 2.50 +/- 0.36 (s.d.) h after the intravenous and 2.54 +/- 0.40 (s.d.) h after the oral dose. Inter-subject variances of pharmacokinetic parameters were low compared to variances reported for glyceryl trinitrate. The coefficient of intra-subject variation of the elimination half-lives was 8.8%. 5.5% (i.v.) and 5.4% (p.o.) of the administered dose were excreted into urine up to 48 h after the administration. 1% (i.v.) and 1.5% (p.o.) were in the conjugated form. The oral dose was rapidly and almost completely absorbed. The oral bioavailability on the basis of areas under the curve amounted to 88.6% on the average. For clinical use, owing to its high oral bioavailability, long residence in the body, inactivation by metabolic conversion, and good predictability of kinetic parameters, G-1-N offers advantage over glyceryl trinitrate.     

Gastric emptying in healthy volunteers after multiple doses of levodopa.

1. Oral levodopa frequently produces an episodic delay in gastric emptying which leads to multiple peak concentrations of the drug in plasma. We have studied the effects of multiple dosing of levodopa on gastric emptying and levodopa absorption in eight healthy young volunteers in a randomised two-way cross-over study. 2. The plasma concentration-time curves for levodopa were measured after three oral doses of 125 mg given at 2 h intervals and compared with the concentration-time curve for levodopa following administration of two doses of placebo and a single oral dose of 125 mg. 3. A low incidence of multiple peak plasma concentrations of levodopa was detected after all doses of levodopa. The area under the plasma concentration-time curves (AUC) for the final dose of levodopa (150.8 +/- 22.0 micrograms ml-1 min) was lower than for the two preceding doses (205.7 +/- 41.8 and 199.5 +/- 51.8 micrograms ml-1 min) but not different from that of the single dose given at the same time of day (141.7 +/- 29.1 micrograms ml-1 min). This indicates that the lower AUC of the final dose of levodopa was related to the time of administration and not a result of the two preceding doses. 4. The absence of any significant effects of preceding doses of levodopa on gastric emptying was confirmed a) by co-administration of soluble paracetamol, as a marker of gastric emptying, with the second dose of levodopa or placebo and b) by co-administration of radiolabelled DTPA and gamma-camera imaging with the final dose of levodopa on the multiple dosing day and the single dose of levodopa on the placebo day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological profile of MEN91507, a new CysLT(1) receptor antagonist

MEN91507 (8-[2-(E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran sodium salt)) potently displaced [3H]leukotriene D(4) binding from guinea-pig lung and dimethylsulphoxide-differentiated U937 (dU937) cell membranes (K(i) 0.50 +/- 0.16 and 0.65 +/- 0.29 nM, respectively). On the other hand, MEN91507 did not display significant binding affinity for a series of receptors or channels. In functional studies on dU937 cells, MEN91507 behaved as insurmountable antagonist of leukotriene D(4)-induced calcium transients, with an apparent pK(B) of 10.25 +/- 0.15. In anaesthetized guinea-pigs, MEN91507 antagonized in a dose-dependent manner leukotriene D(4)-induced bronchoconstriction following i.v. or oral administration: the ED(50s) were 3.0 +/- 0.3 and 140 +/- 90 nmol/kg, respectively. The inhibition of leukotriene D(4)-induced bronchoconstriction by MEN91507 was long-lasting, since a dose of 0.6 micromol/kg produced 74% reduction of the response after 8 h from administration. Likewise, leukotriene D(4)-induced microvascular leakage was antagonized by MEN91507 either following i.v. or oral administration: a significant inhibitory effect was still evident at 16 h from oral administration of a dose of 6 micromol/kg. It is concluded that MEN91507 is a potent and selective antagonist of both guinea-pig and human CysLT(1) receptors; in addition, in vivo studies on guinea-pigs indicate that MEN91507 is an orally available and long-lasting antagonist of the bronchomotor and pro-inflammatory effects induced by leukotriene D(4) through the stimulation of CysLT(1) receptors.     

Effect of the low-affinity,noncompetitive N-methyl-d-aspartate receptor antagonist dextromethorphan on visceral perception in healthy volunteers

BACKGROUND: The use of N-methyl-d-aspartate (NMDA) receptor antagonists may hold promise for the treatment of pain of visceral origin, in particular in conditions characterized by visceral hypersensitivity. AIM: To study the effect of dextromethorphan, a low affinity, non-competitive NMDA receptor antagonist, on visceral perception in healthy volunteers. METHODS: Nine healthy volunteers (5 female, median age 22 years) underwent a gastric barostat study after oral administration of placebo, dextromethorphan 10 mg or dextromethorphan 30 mg, on three separate days in a double-blind, randomised order. Sensations induced by step-wise isobaric gastric distension (2 mmHg/2 min) were studied during fasting and 30 min after a meal. In addition, proximal gastric tone was measured during fasting and postprandially. RESULTS: Compared to placebo, dextromethorphan 30 mg significantly increased the distension-evoked sensation scores for nausea (P=0.004) and satiation (P=0.004) during fasting; and for bloating (P= 0.001), nausea (P=0.000) and satiation (P=0.01) 30 min postprandially. Dextromethorphan did not alter pain scores, proximal gastric tone or gastric compliance. CONCLUSIONS: Dextromethorphan increases the perception of non-painful sensations during gastric distension, without altering the perception of pain. Therefore, application of dextromethorphan as a visceral analgesic is questionable. Future studies with more specific NMDA receptor antagonist are warranted.     

瑞格列奈对匹伐他汀药代动力学的影响

目的:研究健康志愿者服用瑞格列奈后对匹伐他汀药代动力学的影响。方法:用自身前后对照、随机交叉的试验方法,筛选出12例健康受试者,随机分为2组:一组口服匹伐他汀钙片和安慰剂(n=6);另一组同时口服瑞格列奈和匹伐他汀钙片(n=6)。洗脱2周后,两组交叉服用药物。用液相色谱-质谱联用(LC-MS)法测定血浆匹伐他汀的浓度,用DAS 2.1软件计算药代动力学参数。结果:联用瑞格列奈和匹伐他汀钙片与单用匹伐他汀钙片的主要药代动力学参数:AUC0～48分别为(182.37±70.37)和(94.62±7.55)ng.h.L-1;Cmax分别为(41.96±6.77)和(24.98±4.36)ng.L-1;Tmax分别为(0.75±0.00)和(0.75±0.20)h,t1/2分别为(9.91±2.28)和(8.68±3.00)h;CL分别为(0.010±0.00)和(0.02±0.00)L.h-1。结论:在健康受试者体内,瑞格列奈对匹伐他汀的主要药代动力学参数有显著性影响。