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The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2-4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX-1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern. [ABSTRACT FROM AUTHOR]

BACKGROUND: Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4. OBJECTIVE: This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan. A secondary objective was to assess the safety and tolerability of combining these agents. METHODS: This was an open-label, randomized, 2-way crossover study in healthy volunteers. During treatment period 1, subjects received either a single oral dose of sumatriptan 50 mg (sumatriptan alone) or clarithromycin 500 mg orally every 12 hours on days 1 to 3 and a single oral dose of sumatriptan 50 mg plus a single oral dose of clarithromycin 500 mg on the morning of day 4 (combination treatment). During treatment period 2, they received the alternative regimen. Equivalence between sumatriptan alone and combination treatment was concluded if the 90% CI for the ratio of reference to test means of loge-transformed data for area under the plasma concentration-time curve extrapolated to infinity (AUC(infinity)) and maximum plasma concentration (Cmax) fell within the interval from 0.8 to 1.25. RESULTS: In the 24 evaluable subjects (12 men, 12 women) included in the pharmacokinetic analysis, mean sumatriptan AUC(infinity) and Cmax values after administration of combination treatment were 9% and 14% higher, respectively, than the corresponding values after administration of sumatriptan alone. The 90% CI for the ratio of reference to test means for AUC(infinity) was 1.03 to 1.15. The 90% CI for the ratio of reference to test means for Cmax was 1.03 to 1.26, above the traditional bioequivalence criterion. All other pharmacokinetic parameters tested, including nonparametric analysis of the time to Cmax, met the criterion for equivalence between treatments. Both treatments were well tolerated in the 27 subjects (13 men, 14 women) included in the safety analysis. CONCLUSIONS: The extent of absorption of sumatriptan was similar after oral administration alone and in combination with clarithromycin dosed to steady state. These data are consistent with previous reports that sumatriptan is unaffected by coadministration with the potent CYP3A4 inhibitor clarithromycin, supporting concomitant administration of these agents without the need for dose adjustment of sumatriptan in the acute treatment of migraine. [ABSTRACT FROM AUTHOR]

The objectives of this randomized, open-label, three-period, incomplete block design study were to evaluate the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) delivered by the contraceptive patch, Ortho Evra/Evra, and to evaluate patch adhesion under conditions of heat, humidity, and exercise. During each treatment period, 30 healthy women wore Ortho Evra on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool water immersion, or a combination of activities). Blood samples were collected before and several times to 240 hours after patch application. Mean serum concentrations of NGMN and EE generally remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the 7-day wearperiodfor all activities. Only 1 (1.1%) of 87 patches completely detached spontaneously. Peel force measurements were comparable for all activities. Ortho Evra was well tolerated. In conclusion, Ortho Evra delivers efficacious concentrations of NGMN and EE and maintains adhesive reliability through 7 days of wear even under conditions of heat, humidity, and exercise. [ABSTRACT FROM AUTHOR]

The primary objective of this open-label study was to determine the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE)following two consecutive applications of a contraceptive patch (ORTHO EVRA/EVRA). Twelve healthy women wore the first patch on their abdomen for 7 days and, after removal at 168 hours (day 7), wore a second patch for 10 days (i.e., 3 days beyond the intended 7-day wear period). Blood samples were collected before and at various times up to 456 hours (day 19) after application of the first patch for analysis of NGMN and EE. Mean serum concentrations of NGMN and EE remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the entire 7-day wear period after application of the first patch and for 10 days after application of the second patch; reference ranges are based on studies with ORTHO-CYCLEN/ Cilest. No patch detached spontaneously. No subject discontinued or experienced a serious adverse event. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effect of age and gender on the pharmacokinetics (PK) of the ghrelin receptor agonist anamorelin., Methods: Three demographic cohorts of healthy subjects were enrolled in this single-center, open-label study. Subjects received a single oral dose (25 mg) of anamorelin HCl. Serial blood samples were collected over 24 hours to assess anamorelin PK and circulating growth hormone (GH) levels. Data were compared with a reference cohort., Results: Anamorelin was rapidly absorbed in all cohorts; peak concentrations were observed 30-45 minutes and 2-4 hours post-dose, which declined biexponentially with mean terminal half-lives of 6-7 hours. An age effect on C max and AUC ∞ was not apparent; however, mean AUC ∞ values were approximately 1.8-1.9-fold higher in the female cohorts than in the reference male cohort. GH increase was rapid and virtually identical in both sexes, though attenuated in elderly subjects. No clinically significant safety or tolerability findings were observed., Conclusions: While PK parameters do suggest higher exposure in females, this effect is considered to be modest given the variability of the 6-8 subjects per cohort. Moreover, no such effect was observed in the pharmacodynamic responses, thus, dose adjustment for age and gender is considered unnecessary.

Background and Objective: Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655)., Methods: Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics., Results: Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated., Conclusion: Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.

Background: Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin, like all retinoids, is teratogenic, and women of child-bearing potential must strictly adhere to pregnancy-prevention measures., Aim: To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive., Methods: In total, 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol, 17-deacetyl norgestimate, alitretinoin and its main metabolite 4-oxo-alitretinoin were assessed alone and in combination., Results: The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with alitretinoin, and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly, the influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate., Conclusions: There was no clinically relevant influence of alitretinoin on the PK of ethinyl estradiol/norgestimate, and no influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin. Consequently, oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during alitretinoin treatment for women of childbearing potential., (© 2011 The Author(s). Clinical and Experimental Dermatology © 2011 British Association of Dermatologists.)

Purpose: Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain., Methods: A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs)., Results: Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions., Discussion: The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis. We describe the piecewise development of a three-compartment pharmacokinetic model with both linear and Michaelis-Menten eliminations, and an indirect pharmacodynamic response model to describe the pharmacokinetics and pharmacodynamics, respectively, of the fusion protein, Fc-osteoprotegerin (Fc-OPG), in healthy postmenopausal women. Subsequently, model verification was performed and used to address study design questions via simulation. The model was developed using data from eight cohorts (n = 13 subjects/cohort; Fc-OPG:placebo = 10:3) classified by dose level (0.1, 0.3, 1.0, or 3.0 mg/kg) and route of administration (intravenous [IV] or subcutaneous [SC]). Fc-OPG serum concentrations and urinary N-telopeptide/creatinine ratios (NTX) following both IV and SC administration were available. The model provided an adequate fit to the observed data and physiologically plausible parameter estimates. Model robustness was tested via a posterior predictive check with the model performing well in most cases. Subsequent clinical trial simulations demonstrated that a single 3.0-mg/kg SC dose of Fc-OPG would be expected to produce, at 14 days post-dose, a median NTX percentage change from baseline of -45% (with a 95% prediction interval ranging from -34% to -60%). Lastly, model ruggedness was evaluated using local and global sensitivity analysis methods. In conclusion, the model selection and simulation strategies we applied were rigorous, useful, and easily generalizable.

P2Y(12) receptors participate in ADP-induced activation and aggregation of human platelets. INS50589, a selective P2Y(12) receptor antagonist, is being developed for use where controlled, reversible modulation of the platelet hemostatic function is needed. The tolerability, pharmacokinetics, and pharmacodynamics of INS50589 were tested in healthy human volunteers. Thirty-six subjects received intravenous infusions of placebo or INS50589 at 0.1-3 mg/kg/h for four hours. Platelet function, clotting parameters, bleeding time, safety assessments, and plasma concentrations of INS50589 and its major metabolite were monitored for 24 hours. Near-steady state plasma concentrations of INS50589 and effects on platelet function were achieved rapidly. The average maximal plasma concentration of INS50589 was linearly related to the dose administered. Intravenous INS50589 produced dose-dependent inhibition of platelet activation and aggregation in response to ADP in vitro until nearly full inhibition was achieved at the higher doses. Bleeding time was correspondingly increased, without any effect on activated clotting time, prothrombin time, or activated partial thromboplastin time. Platelet response to ADP had returned to at least 75% of the baseline value within 0.25-4 h after cessation of the intravenous infusion of INS50589, depending upon the dose and ADP challenge concentration. Infusions were well tolerated up to the highest dose tested. There was no evidence that the principal metabolite (INS51088) contributed to these effects. INS50589 is a well-tolerated, reversible, competitive antagonist of ADP at the P2Y(12) human platelet receptor, and its potential therapeutic utility in various cardiovascular settings is discussed.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of approximately 12 mm Hg and approximately 7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

Background: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential., Methods: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericia's correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured., Results: Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were <0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values >445 msec with duloxetine, and the change in QT Fridericia's correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method., Conclusions: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

This clinical delivery system bridging study evaluated the performance of a single-use disposable, commercial prototype device (designated ND 5.5) for particle-mediated epidermal delivery (PMED) of a nucleic acid vaccine against Hepatitis B virus (HBV). Healthy adults, previously immunized with licensed HBV vaccine, received a single boost vaccination of HBV nucleic acid vaccine administered by ND 5.5 or XR-1, the clinical research device used in previous clinical trials. Similar increases in anti-HBV surface antigen serum antibody titers and cell-mediated immune responses were produced by ND 5.5 and XR-1 when delivering comparable effective doses of the vaccine. The overall intensity of the immune response was lower in those subjects vaccinated with two, rather than 4 administrations of vaccine delivered by ND 5.5. Skin reactions at sites of vaccine administration were equivalent with both devices. This is the first clinical demonstration of the safe and effective PMED of a nucleic acid vaccine with the ND 5.5 device.

Background: Vaccinia immune globulin (VIG) administered via the intramuscular route has historically been used for the treatment of complications of smallpox vaccination. Intravenous formulations of VIG are required to improve tolerability and pharmacokinetic profile., Methods: We conducted 2 separate studies to evaluate the feasibility of administration of an intravenous formulation of antivaccinia immune globulin (VIGIV). The first study assessed the pharmacokinetics and safety of a newly manufactured lyophilized VIG product for intravenous administration (VIGIV-lyo). Seventy-eight healthy volunteers received an intravenous infusion of VIGIV-lyo at doses of 100 mg/kg, 200 mg/kg, or 500 mg/kg. In the second study, we evaluated the safety of a liquid product of VIGIV (VIGIV-liq) in 33 healthy volunteers receiving an intravenous infusion of 100 mg/kg VIGIV-liq., Results: The geometric mean titer of VIG at the target dose (100 mg/kg) after intravenous administration is 2.5 times higher than the predicted geometric mean titer after intramuscular injection (P<.001). The pharmacokinetics of VIGIV-lyo are linear for doses from 100 mg/kg through 500 mg/kg. Administration of the 200-mg/kg and 500-mg/kg doses of VIGIV-lyo does not result in markedly higher adverse event rates. The adverse event rates observed with the liquid product are comparable to those seen with the lyophilized product., Conclusions: These 2 studies suggest that intravenous administration of VIG is well tolerated and results in a more favorable pharmacokinetic profile than does VIG administered intramuscularly.

Unlabelled: The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis., Introduction: RANKL is an essential osteoclastic differentiation and activation factor., Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers., Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of -81% in the 3.0 mg/kg AMG 162 group compared with -10% in the placebo group; serum NTX changes were -56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to approximately 3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.

The platelet effects of a supratherapeutic dose of the new cyclooxygenase (COX)-2 specific inhibitor, valdecoxib (40 mg twice a day), naproxen 500 mg twice a day, diclofenac 75 mg twice a day, and placebo were compared in 62 healthy adult subjects in this 7(1/2) day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B(2) (TxB(2)) concentrations were measured at baseline and at regular intervals on days 1 and 8. Valdecoxib had no effect on platelet function. Naproxen and diclofenac significantly reduced the platelet aggregation response to AA and to a lesser extent collagen and ADP at most assessments compared with placebo. Naproxen significantly lowered serum TxB(2) levels. In contrast to standard doses of 2 nonsteroidal antiinflammatory drugs (NSAIDs), a supratherapeutic valdecoxib dosage does not impair platelet function (COX-1). Valdecoxib may be a safer analgesic option than conventional NSAIDs in patients for whom bleeding complications are a concern. (Am J Emerg Med 2002;20:275-281., (Copyright 2002, Elsevier Science (USA). All rights reserved.))

This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. The range of AUA and Amax values in the study population overlapped that of historical control normal-weight subjects (<100 kg), indicating that weight-adjusted tinzaparin dosing yields a predictable response regardless of body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.

Osteoprotegerin (OPG), a tumor necrosis factor (TNF) receptor family member, is a critical regulator of bone resorption. It is an important inhibitor of the terminal differentiation and activation of osteoclasts. This randomized, double-blind, placebo-controlled, sequential dose escalation study was conducted in postmenopausal women to determine the effect of a single subcutaneous (s.c.) dose of OPG on bone resorption as indicated by the biochemical markers, urinary N-telopeptide (NTX) and deoxypyridinoline (DPD), which are stable collagen degradation products. NTX levels decreased within 12 h after OPG administration. At the highest dose administered (3.0 mg/kg), a mean percent decrease in NTX of approximately 80% was observed 4 days after dosing. Six weeks after dosing a mean decrease of 14% in NTX was observed. The levels of bone-specific alkaline phosphatase (BSAP), a marker of bone formation, did not change for approximately 3 weeks after dosing. Thereafter, a modest decrease, reaching approximately 30% at 6 weeks, was observed in the 3.0-mg/kg dose group. The rapid decrease from baseline in NTX and delayed decrease in BSAP indicated that OPG acted primarily on osteoclasts to decrease bone resorption. OPG injections are well tolerated. This study, for the first time, indicates that a single s.c. injection of OPG is effective in rapidly and profoundly reducing bone turnover for a sustained period and that OPG therefore may be effective in treatment of bone diseases characterized by increased bone resorption such as osteoporosis.

Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function). The Phase I studies described in this report were parallel, randomized, double-blinded, placebo-controlled studies conducted in 48 healthy volunteers (n = 24 per study) with perflubron emulsion (Oxygent; Alliance Pharmaceutical Corp., San Diego, CA). Because of the decreased platelet counts observed with previous PFC emulsions and the intended use of perflubron emulsion in surgical patients, these studies assessed postdosing coagulation responses and hemostasis. PFC pharmacokinetic variables were also evaluated. The primary endpoint for examination of coagulation effects was prospectively defined as bleeding time. Subjects received either saline (3 mL/kg) control, or perflubron emulsion at 1.2 g PFC/kg or 1.8 g PFC/kg, and were evaluated for a 14-day period. No postinfusion changes in bleeding time or differences in ex vivo agonist-induced platelet aggregation were observed. A 17% reduction in platelet count was observed 3 days after dosing in the 1.8-g PFC/kg group; levels recovered to baseline by Day 7. The intravascular half-life of perflubron for the first 24 h was dose dependent: 9.4+/-2.2 h and 6.1+/-1.9 h in the 1.8- and 1.2-g PFC/kg groups, respectively. Results indicate that this perflubron emulsion did not affect coagulation function in healthy volunteers.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study). The study described herein focuses on safety concerning immune function. The primary endpoint was defined prospectively as delayed hypersensitivity skin test responses with lymphocyte proliferative responses to mitogenic stimulation providing a secondary measure for changes in cell-mediated immunity. Subjects received either perflubron emulsion IV (1.2 g PFC/kg or 1.8 g PFC/kg) or saline (3 mL/kg) control. Perflubron emulsion had no effect on delayed hypersensitivity skin reactions, lymphocyte proliferative potential, circulating immunoglobulins, complement activation, or plasma levels of the inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta. Perflubron emulsion was generally well tolerated, although there was a dose-dependent increase in minor flu-like symptoms in the perflubron treatment groups at 24 h after dosing. Increased serum levels of interleukin-6 were observed in those subjects exhibiting febrile responses. The clinical safety profile of perflubron emulsion supports its continued investigation as a temporary oxygen carrier in surgical patients to reduce exposure to allogeneic blood transfusion.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 [a thromboxane A2 receptor agonist]), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.

To characterize the plasma concentration-effect relationship of flumazenil in the presence of a predefined midazolam level, a double-blind, placebo-controlled, randomized two-way crossover study was conducted in nine healthy male subjects. After reaching a criterion level of midazolam-induced depression of the Digit Symbol Substitution Test (DSST), volunteers received a dose of flumazenil (1.0 mg) or placebo over 1 minute, with the infusion of midazolam continued. Blood samples were collected, simultaneously with the DSST assessment, at predetermined intervals and were assayed for flumazenil and/or midazolam plasma concentrations. Pharmacokinetic-pharmacodynamic modeling techniques were used to estimate the equilibration rate constant (keo) between plasma concentration and effect for flumazenil; a sigmoidal maximum-effect model was used to relate the DSST score to the flumazenil plasma concentration. Flumazenil exhibited a rapid onset (the half-life of equilibration between drug concentration in the blood and drug effect was 3.3 minutes) and short duration of action (the flumazenil plasma concentration causing half-maximal effect was 7.4 ng/ml, which was reached about 1 hour after dosing). The results of this study also show the competitive nature of flumazenil as a midazolam antagonist.

A double-blind, placebo-controlled trial was undertaken to assess the safety and efficacy of once daily cetirizine in alleviating the symptoms of perennial allergic rhinitis. Subjects were adults with perennial allergic rhinitis, characterized by nasal congestion, postnasal discharge, sneezing, rhinorrhea, nasal itching, lacrimation, ocular itching, and itching of the roof of the mouth, and a total pretreatment symptom severity score of greater than or equal to 8. Patients were randomized to treatment with 10 mg cetirizine, 20 mg cetirizine, or placebo for 4 weeks. Efficacy was assessed in 215 patients and safety in 216. Cetirizine in once daily dosages of 10 or 20 mg proved to be effective in relieving the overall symptoms of perennial allergic rhinitis and particularly postnasal discharge and sneezing. The 10-mg dose afforded optimal symptomatic relief, and the 20-mg dose provided little or no additional benefit. Cetirizine was well tolerated, and the frequency of somnolence was not significantly greater in patients receiving this drug than in those given placebo.

Twenty adult male volunteers were studied in an unblinded, ascending-dose study to evaluate the safety, tolerance, and pharmacokinetics of intravenously administered nonionic gadodiamide injection. Dosages administered were 0.05, 0.1, 0.2, and 0.3 mmol/kg. Subjects were monitored from 36 hours before, through 72 hours after administration. There were no clinically relevant changes in vital signs or electrocardiograms. No clinically significant changes occurred in blood or urine laboratory parameters, although a tendency for minor, transient elevations in serum iron levels 8 to 48 hours after administration was noted. These changes were not dose-related. Nine of 20 subjects reported at least one adverse event; all events were transient and of mild intensity, the most common being dizziness/lightheadedness and perversion of taste or smell. One subject reported discomfort consisting of mild stinging at the injection site during administration. Gadodiamide was excreted unmetabolized in the urine with greater than 95% recovery at 72 hours after administration. The serum elimination half-life was approximately 70 minutes.

The efficacy and safety of cetirizine were evaluated in 419 patients with seasonal allergic rhinitis. Using a 4-way, double-blind randomization schedule, patients were given a 1-week course of once daily cetirizine (5, 10, or 20 mg) or placebo. Patient and physician efficacy ratings corresponded, indicating superiority of cetirizine to placebo (P less than .05) in reducing symptom severity scores for sneezing, rhinorrhea, ocular pruritus, nasal pruritus, watering of the eyes, and redness of the eyes. All cetirizine doses achieved higher efficacy ratings (72.7%, 79.2%, and 75.7%, respectively) than placebo (52.9%; P less than .05) by the physician's global assessment. Cetirizine was well tolerated, with sedation being the most common adverse experience, increasing in frequency at higher doses. A dose-response relationship was evident for selected symptoms, and the once daily 5-mg dose was found to be an effective minimum dose.

The first human MR imaging results for the hepatobiliary contrast agent manganese(II)N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis(phosphate) (MnDPDP) are reported. MnDPDP is a paramagnetic contrast agent specific for hepatobiliary imaging. An imaging study was performed to investigate the presence of contrast enhancement or facilitated visualization of normal structures. Twelve healthy subjects receiving MnDPDP at doses of 3, 10, or 15 mumol/kg were imaged after injection for approximately 30 minutes at 1-5-minute intervals. Transaxial abdominal images were obtained at 1.5 T in a single breath-hold interval of 21 seconds with use of a spin-echo pulse sequence (repetition time = 150 msec, echo time = 20 msec). Liver parenchyma enhancement was observed 1 minute after injection and persisted for at least 30 minutes. Clearance into the gallbladder was visualized within 15 minutes. Enhancement was dose-dependent; a dose of 10 mumol/kg produced a 75%-100% signal enhancement of the liver at 10 minutes after injection.

Four double-blind, Latin-square studies were conducted to compare the pharmacokinetics and pharmacodynamic bioavailability of metoprolol OROS (oral osmotic) and the conventional tablet (CT) of metoprolol. Metoprolol OROS (7/95 mg or 14/190 mg) was administered once daily in doses equivalent to 100 mg of metoprolol CT given once, twice, thrice, and four times a day. In all four studies, lower peak plasma concentrations and longer times to peak were observed after metoprolol OROS than after metoprolol CT, indicating a controlled-release profile for metoprolol OROS. beta-Adrenergic blockade, as measured by reductions in exercise heart rate, was lower after metoprolol OROS than after metoprolol CT, but metoprolol OROS provided a smoother and more sustained beta-blockade. All four doses of metoprolol OROS at steady state produced relative pharmacodynamic bioavailability that ranged from 87% to 104% of that produced by equivalent doses of metoprolol CT.

T Cell Modulatory Peptide (TCMP-80), L-lysine-L-serine, is a synthetic dipeptide structurally related to a selected amino acid sequence in human immunoglobulin G. Based on in vitro and preclinical in vivo testing, TCMP-80 has immunomodulatory properties. This report describes the first administration of TCMP-80 to man in a randomized, double-blind, placebo-controlled, single rising-dose tolerability trial. Healthy male volunteers received TCMP-80 or placebo as a 10-minute intravenous infusion. At weekly intervals, two of four subjects were given TCMP-80; the remaining two received placebo. Each subject could receive only one dose during the study. Dosing started at 0.01 mg/kg and was increased to 0.03, 0.1, 0.3, 1, 3, 6.5, and 10 mg/kg. CBCs, blood chemistries, urinalyses, and lymphocyte subset populations were monitored predose and postdose on Days 1, 5, and 14. Three placebo and three TCMP-80 subjects reported adverse events. Adverse events reported after TCMP-80 administration were mild in nature (headache, dizziness, hematoma at injection site), appeared to be independent of dose, and resolved without medical intervention. No clinically significant alterations in vital signs, physical examination parameters, or clinical laboratory values were observed. Based on the results of this study, TCMP-80 is safe and well-tolerated within the dose range studied when administered as single intravenous infusions. Additionally, this study design represents an approach to assess the safety of an investigational immunomodulatory drug.

A significant reduction in symptoms scores was observed in those patients who elected to continue their immunotherapy after achieving maintenance. All of those patients developed allergen specific IgG4 within a year of post-maintenance injections. These findings suggest that a reduction of allergic symptoms is accompanied by a rise in specific IgG4 antibody against the offending allergen(s). These specific IgG4 antibodies can be induced by appropriate immunotherapy. Lastly, allergen specific IgG4 antibodies were rapidly and accurately determined using the 3M IgG4 FAST test.

The preclinical and clinical trial experience with ferrioxamine (S-FDF; Salutar, Inc.) as a contrast agent for magnetic resonance imaging (MRI) is summarized. The results in 44 patients or subjects show that the drug is safe and well tolerated when given intravenously. In certain conditions, early results show that the use of this contrast agent provides more information than can be obtained with MRI alone.

The pharmacokinetics of leucovorin was evaluated after intravenous, intramuscular, and oral administration in a randomized crossover study of 37 healthy men. A single 25-mg dose of leucovorin calcium was administered intravenously, intramuscularly, or orally to the subjects. Blood samples were obtained immediately before and at 13 time points up to 24 hours after the leucovorin dose. The three treatment phases were separated by one-week intervals. Bioavailability was assessed by measuring over 24 hours the blood concentrations of total folates, the parent compound 5-formyltetrahydrofolate, and the metabolite 5-methyltetrahydrofolate, using differential microbiologic assays with Lactobacillus casei and Streptococcus faecalis. Both intravenous and intramuscular administration produced rapid increases in serum concentrations of biologically active folates; these rises were sustained over time and were still detectable at 24 hours after drug administration. The bioavailability of intravenous and intramuscular doses was comparable based on area under the serum concentration-time curve, although for intramuscular administration, the peak concentration was lower and the time to peak concentration was longer. The initial rise in serum folate with intravenous and intramuscular dosing represented 5-formyltetrahydrofolate; this fell concomitantly with the appearance of 5-methyltetrahydrofolate. Oral leucovorin was 92% bioavailable compared with intravenous administration and produced a predictably different pattern of circulating folates, 5-methyltetrahydrofolate being the predominant form. Terminal elimination half-life, apparent volume of distribution, and clearance of total folate were not significantly different among the three treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Injections of iohexol in two series of volunteers, 20 in 1980 and 16 in 1982 are briefly reported. Intravenous injections of iohexol in doses from 125 to 1500 mg I/kg body weight were well tolerated. Iohexol was completely excreted in unchanged form. The results indicate that iohexol may safely be used in clinical trials.

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of theophylline was investigated in 10 male volunteers. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of theophylline elixir (5 mg/kg) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 h following the administration of theophylline. Plasma theophylline levels were analysed by HPLC. Theophylline was rapidly absorbed following oral administration of the theophylline elixir to both the placebo and etintidine treatment groups. Comparison of the pharmacokinetic parameters of theophylline between the etintidine and the placebo groups indicates that while etintidine did not significantly (p greater than 0.05) affect the apparent Cmax (11.1 vs 10.0 micrograms ml-1) and Tmax (1.7 vs 1.4 h) values of theophylline, etintidine significantly reduced the oral clearance (0.0200 vs 0.0564 l kg-1 h-1, p = 0.000006) and prolonged the elimination half-life (16.8 vs 6.0 h) of theophylline. The data indicate that etintidine, like cimetidine, extended the elimination of theophylline in humans.

The bioavailability of a new sustained-release potassium chloride (KCl) tablet, designed for once-a-day dosing, was compared to a KCl elixir using urinary excretion data. The study utilized 25 male volunteers dosed in a crossover design in a dietary/activity-controlled environment. The regimens consisted of a total of 80 mEq of potassium in three equally divided doses of elixir every 6 hr and a single 80-mEq dose using four 20-mEq sustained-release (SR) tablets. The mean time to maximum rate of potassium urinary excretion was 2.2 hr for the first elixir dose and 5.5 hr after the SR tablet (P less than 0.01), thereby supporting the prolonged-release properties of this formulation. After correction for baseline urinary potassium excretion, the mean total 24-hr urinary potassium excretion was 42.18 mEq for the elixir and 40.41 mEq for the SR tablet. The results indicate that the absorption pattern from the SR tablet is equal to three doses of KCl elixir dosed 6 hr apart.

The effect of cetamolol (an investigational cardioselective beta blocker with intrinsic sympathomimetic activity) on the hypokalemic response to epinephrine infusions in normal subjects was evaluated and compared with placebo and two other beta-adrenergic blocking drugs. After two daily doses of cetamolol 15 mg, atenolol (a cardioselective beta blocker) 50 mg; a long-acting propranolol preparation (a nonselective beta blocker) 80 mg; or placebo, 12 men (mean age, 26.7 years) were infused with epinephrine. The resulting average plasma epinephrine level was 1123 pg/mL, whereas average baseline serum potassium levels for the four treatment groups ranged from 3.94 to 4.07 mEq/L. Epinephrine-induced hypokalemia occurred in the placebo group (maximum potassium decrease of 1.00 mEq/L) and in the atenolol group (maximum potassium decrease of 0.59 mEq/L); potassium levels did not decrease but rose slightly in subjects receiving cetamolol or propranolol. Subjects treated with placebo or atenolol also demonstrated statistically significant prolongation of the QTc interval (0.039 seconds with placebo; 0.023 seconds with atenolol) and frequently developed T-wave flattening and U-wave appearance. After pretreatment with cetamolol or propranolol, however, the QTc interval was unaffected, T-wave abnormalities did not occur, and U waves appeared only rarely. The results of this study indicate that cetamolol blocks epinephrine-induced hypokalemia and associated electrocardiographic changes.