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Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2-106.8) and hydroxy pioglitazone (90.9; 78.6-105.1), an increase in pioglitazone AUC (117.8; 108.4-128.0), a decrease in hydroxy pioglitazone AUC(0-t) (89.7; 78.9-101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4-12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.

Cachexia occurs in up to 80% of patients with advanced cancer and is characterized by involuntary weight loss, frequently accompanied by anorexia and altered metabolism.1–5 It is associated with poorer survival, a decline in physical functioning and quality of life, increased risk of treatment failure and toxicity, and a greater symptom burden.2,6,7 Despite the negative impact of cachexia on cancer patients, the syndrome is under-recognized and often left untreated.8 Cancer cachexia is a complex syndrome that is not fully understood, but the underlying mechanisms are thought to include the metabolic, endocrine and central nervous systems.3,7 Treatments for cancer cachexia are unfortunately lacking. With no standard effective therapies available worldwide, cachexia remains a critically unmet need in cancer supportive care.9,10 Ghrelin and ghrelin receptor agonists are being explored for their potential impact on clinical conditions such as anorexia and cancer cachexia. These compounds have been found to have clinical attributes which make them well-suited for the treatment of cachexia. Ghrelin plays an important role in stimulating appetite and encouraging food intake. Activation of the ghrelin receptor (otherwise called the growth hormone [GH] secretagogue receptor) increases lean body mass and fat mass through the secretion of GH.11,12 Anamorelin (RC-1291) is an orally-active ghrelin receptor agonist which may assist in the treatment of cancer cachexia through its appetite-enhancing, anabolic effects.13–16 It is rapidly absorbed whilst experiments with radio-labeled (14C) anamorelin have shown that it is primarily eliminated in the feces (92%; urine 8%).13,17 In a phase I study in healthy volunteers, 5–6 days treatment with anamorelin HCl, hereafter referred to as anamorelin, led to dose-related increases in body weight with no dose-limiting adverse effects; 25 and 50 mg anamorelin also produced a significant increase in appetite (VAS–Hunger scores) at virtually every pre-prandial timepoint assessed. Food intake at the 4-hour timepoint was increased on average by 18.4% compared to placebo (P

Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state.Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure.Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

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((R))) 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. (c) 2011 The Author(s). Clinical and Experimental Dermatology (c) 2011 British Association of Dermatologists.

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.

The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential.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.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 were0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values445 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.Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

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.

Summary Laparoscopic adjustable gastric banding (LAGB) is gaining popularity as a technique for achieving effective weight loss in the severely obese population. It is a minimally invasive procedure and the reported early morbidity is low. However, we have observed at our institution that occasional patients complain of central chest pain, mimicking angina (verbal pain score of > 7 out of 10), within 2 h after the procedure. This is a worrying symptom because obesity is known to be a major risk factor for developing cardiovascular complications. We have now performed 250 LAGB operations at our hospital. The following four case reports document our patients who presented with early chest pain postoperatively. Common characteristics of male gender, morbid obesity and some degree of obstructive sleep apnoea were identified among the cases. The aetiology of the chest pain is uncertain; nevertheless, close monitoring is vital to exclude pathological events such as acute coronary syndrome.

Laparoscopic adjustable gastric banding (LAGB) in patients with a sliding hiatus hernia has become an accepted procedure. However, LAGB in patients with less common types of diaphragmatic hernia is rarely described. We report a super-super-obese woman with a para-hiatal hernia (non-hiatal, diaphragmatic hernia) where LAGB was performed. The para-hiatal hernia was successfully repaired laparoscopically at the same time that the LAGB was performed. A para-hiatal hernia is not a contraindication to LAGB and can be repaired at the same operation.

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.

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 7½ day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B2 (TxB2) 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 TxB2 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.)

SummaryThis 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 (

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). 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. 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. 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.

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.

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.

To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A receptor antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders. Phase I, randomised, placebo-controlled, double-blind, single-and multiple-dose study of orally administered atrasentan. Single daily oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of atrasentan or placebo were administered to healthy male volunteers (n = 72; six active and three placebo per drug administration group) on study day 1 and days 3 to 9. Atrasentan plasma concentration-time profiles for day 1 and day 9 were used to assess atrasentan pharmacokinetics. Except for the 1mg group, atrasentan plasma concentrations increased rapidly after single and multiple administration, declining thereafter biexponentially with a study-wide harmonic mean (pseudo-SD) half-life of 21 (12) hours and mean (SD) apparent total body clearance (CL/F) of 28 (9.8) L/h. For the 1mg group, there was no apparent distribution phase and the absorption was slower. Drug administration in the 40mg group was discontinued prematurely because of adverse events. Except for lower-than-predicted maximum plasma concentration (Cmax) values for the 1mg group, drug exposure (Cmax, trough concentration and area under the concentration-time curve) increased linearly with dose, and CL/F values were similar across groups, after single- and multiple-dose administration. Steady state was reached within 4 days of drug administration. The pharmacokinetics of atrasentan are dose- and time-independent after single-and multiple-dose administration over the range of 1 to 30 mg/day.

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.

Paraesophageal herniation can cause massive bleeding, strangulation or perforation. This study reviews the experience with 24 patients (74.6 years, range 63-89 years, 20 males, 4 females) with a total or near-total intrathoracic stomach, managed at the Royal Lancaster Infirmary. All patients were symptomatic with 3/24 patients presenting as emergencies. Twenty-three of 24 patients underwent surgery: gastropexy alone-5, gastropexy and hiatal repair-17, gastropexy, hiatal repair and fundoplication 1. One of the emergency patients died prior to surgery. Median operative time was 50 min (range 35-65 min) and median hospital stay was 7 days (range 5 days-3 weeks). A splenectomy was necessary in 1/23 (4.4%) patients. Postoperative morbidity included: recurrent hernia requiring surgery-1, pleural effusion requiring chest tube-1, empyema-1, dysphagia requiring dilatation-1, reflux with stricturing-1. Elderly patients with a total or a near-total intrathoracic stomach can be managed by gastropexy and hiatal repair, with acceptable morbidity.

Alitretinoin is an endogenous retinoid related to vitamin A. Studies have shown that oral alitretinoin is effective and well tolerated in the treatment of severe chronic hand eczema. This review summarizes the clinical pharmacokinetic and pharmacodynamic data from a number of studies involving alitretinoin. These include the effect of food on the pharmacokinetics of alitretinoin, interactions between alitretinoin and ketoconazole, simvastatin or cyclosporin A, the effect of alitretinoin on the pharmacokinetics of a combined oral contraceptive, alitretinoin in seminal fluid after repeated dosing, and the pharmacokinetics of alitretinoin and its metabolites in a clinical setting.

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. Clinical Pharmacology and Therapeutics (1994) 56, 530–536; doi:10.1038/clpt.1994.174

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.To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive.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.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.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.

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.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).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.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.

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.

The purpose of this prospective study was to determine the clinicopathological significance of necrotic areas demonstrated by rapid-bolus contrast-enhanced computed tomography (CT) in patients with biochemically predicted severe pancreatitis. Although CT necrosis occurred significantly more frequently in patients with clinically severe (ten of 12) compared with mild (seven of 20) pancreatitis (P < 0.025), seven of 17 (41 per cent) patients with CT necrosis developed clinically mild pancreatitis and six of ten (60 per cent) patients with clinically severe pancreatitis and CT necrosis recovered with conservative management. The site and extent of CT necrosis did not correlate with disease severity. Fine-needle aspiration cytology, operative and post-mortem findings and endoscopic retrograde cholangiopancreatography examinations all strongly suggested that CT necrosis represents true pancreatic necrosis. We conclude that the finding of CT necrosis is not in itself an indication for operative intervention, but that rapid-bolus contrast-enhanced dynamic CT greatly facilitates the planning and execution of surgical therapy.

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.

The Bioenteric Intragastric Balloon (BIB, Inamed Health, Santa Barbara, CA, USA) is an endoscopic method for achieving restriction of gastric intake in obese patients. It is less invasive and cheaper than bariatric surgery, but can only be left in the stomach for six months. We report our experience with the BIB in Singapore.Since its introduction to our hospital in 2004, a prospective database has been kept of all patients undergoing BIB insertion. This database was used to retrieve the information for this study.20 patients have undergone BIB insertion. Mean patient age was 40 (range, 28-52) years and 85 percent were female. Mean body weight was 79.6 (range, 67.6- 103.7) kg. Mean body mass index (BMI) was 31.5 (range, 27.8-38.8) kilogramme per square metre. Mean excess weight was 21.2 (range, 11.9-37.6) kg. The BIBs were inserted under conscious sedation. BIB intolerance was a major problem and four patients (20 percent) required early BIB removal due to refractive nausea and epigastric discomfort. All remaining BIBs were removed after six months under conscious sedation. The mean maximum weight loss during the six months was 5.9 (range, 1.4-13.4) kg. The mean maximum percentage of excess weight lost was 32.4 (range, 6.7-87). Weight loss was reasonably preserved at the end of the sixmonth period, but by one year, when all the patients had been without BIBs for at least six months, the mean weight loss for the group compared to pre-BIB weight was only 1.5 kg (range, weight gain 5.3 kg to weight loss 9 kg). The mean percentage excess weight loss at one year was 10.9 (range, 15.1 percent weight gain to 31.3 percent weight loss). Only four patients (20 percent) regarded their experience with the BIB as a success.The BIB is poorly tolerated by Asian patients, even when lower volumes are inserted into the balloon to compensate for the smaller Asian stature. Although temporary weight loss can be achieved, mandatory removal of the BIB at six months results in regain of the lost weight in the majority of patients. Eligible patients (BMI 32.5 and above) should be encouraged to undergo bariatric surgery rather than BIB to achieve long-term reliable weight loss. Patients who are ineligible for bariatric surgery may benefit from BIB, especially if they have severe comorbidities and have failed to lose weight by any other means in a validated weight management programme, but the chance of long-term success is poor.

Severe obesity is an increasing problem in Singapore. Laparoscopic adjustable gastric banding (LAGB) was introduced at our hospital in 2001 as part of a comprehensive weight management programme. To assess the effectiveness of this procedure, our results to date have been reviewed.A prospective database was kept of all patients undergoing LAGB and this was used to retrieve the information.256 consecutive patients underwent LAGB from January 2001 up to December 2005. There were 163 females and 93 males, with a median age of 36 years (range 18-63 years). Median preoperative weight was 112.7 kg (range 71.5-204 kg) and median body mass index (BMI) was 41.9 (range 32-73). Three patients were converted from laparoscopic to open laparotomy (1.2 percent). 91 percent of patients were discharged home on the first postoperative day. There were seven hospital morbidities (2.7 percent) with one mortality (0.4 percent). During follow-up, 20 patients (7.8 percent) developed late complications requiring revision surgery. Ten were band complications, requiring revision or removal of the band. The other ten were minor access port or tubing complications. Median weight loss at one year was 27.6 kg (range 5.6-71.2 kg) and median excess weight loss, using a BMI of 23 as a baseline, was 51.7 percent (range 9-117.5 percent). Easily measurable comorbidities such as diabetes mellitus and hypertension improved or resolved in 85.4 percent of patients.There is a clear demand for LAGB in Singapore. This has increased since the BMI thresholds for severe obesity were reduced in Asian patients. The surgery provides effective, lasting weight loss with improvement or resolution of comorbidity for most patients. LAGB has the advantages of allowing controlled weight loss and life-long treatment while being easily reversible. When compared to other bariatric surgical procedures, low hospital morbidity has to be offset against the closer follow-up required and the need for secondary surgical procedures in some patients.

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.

In most parts of the world, acute parotid abscess is a rare pathology. It occurs mainly in elderly debilitated patients and patients with oral sepsis. In Singapore, this lesion appears to be more common.We retrospectively reviewed all patients admitted to our hospital over a three-year period with parotid abscess.Ten patients were treated for parotid abscess. Only two of these patients were elderly and debilitated. The remaining patients were atypical in that they were relatively young and fit with no history of oral sepsis. All the abscesses responded to simple drainage and antibiotic therapy without the need to resort to the radical drainage techniques reported historically.Parotid abscess is seen in an unusually young cohort of patients in Singapore. The cause for this is unclear but it may be a result of chronic oral dehydration as a consequence of our climate.

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.

The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162. a human monoclonal antibody to RANKI,, 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:l 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 mgkg 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 -3-fold after 4 days in the 3.0 mgkg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >lo% 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. J Bone Miner Res 2004:19:1059-1066. Puhlished online on March I. 2004: doi: 10.13S9/JBMR.04030S

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.

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.

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 log e -transformed data for area under the plasma concentration-time curve extrapolated to infinity (AUC ∞ ) and maximum plasma concentration (C max ) 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 ∞ and C max 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 ∞ was 1.03 to 1.15. The 90% CI for the ratio of reference to test means for C max was 1.03 to 1.26, above the traditional bioequivalence criterion. All other pharmacokinetic parameters tested, including nonparametric analysis of the time to C max , 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.

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.

Aim: AZD9291 is a selective, 3rd generation EGFR-TKI, effective against EGFR-TKI-sensitising and resistance T790M mutations preclinically. In a Phase I study of AZD9291 in pts with EGFRm+ NSCLC (NCT01802632) performed in the West and Asia, all dose levels (20–240 mg daily) resulted in tumour shrinkage. This study also provided capsule PK data at all doses and tablet PK at 80 mg. A relative bioavailability study in HV (NCT01951599) has provided single 20 mg dose data for capsule, solution and tablet formulations and will provide initial fed/fasted data. Methods: In pts, plasma concentrations of AZD9291 (and potentially active metabolites AZ5104 and AZ7550) were determined up to 168 h following single dose and after 8 or 22 days of once daily dosing fasted. 197 pts received the capsule and 12 received the tablet. In HV, single dose PK were determined up to 504 h in a 3-period cross-over study. The impact of a high fat meal on PK will be investigated in a separate cohort. PK parameters were calculated using non-compartmental methods and nominal sample times. Results: AZD9291 was slowly absorbed with a median (range) tmax of 6 (3–24) h across doses. Exposure was dose proportional across the 20–240 mg dose range. AZD9291 steady state appeared to be achieved by 22 days of dosing. The geomean accumulation of AZD9291 in plasma in pts was ∼4.5-fold, consistent with the dosing frequency and observed mean (range) half-life of 55 (30–145) h. AZD9291 PK appeared to be time independent. Initial assessment of key demographic factors (body weight, Asian/Caucasian ethnicity, sex and age) indicated no relationship between any demographic factor and PK. The tablet produced similar exposure to the capsule. Exposures of AZ5104 and AZ7550 were ∼10-fold lower than AZD9291. The PK in pts and HV were consistent. Conclusions: PK results support once daily dosing, the same dose for all ethnic populations and switching from capsule to tablet in future studies. Plasma concentrations are sustained through the dosing period, which is considered optimal for efficacy and is supported by the tumour responses observed. Updated information will be provided. Disclosure: D. Planchard: Advisory boards: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, BMS; P.A. Dickinson, K.H. Brown and M. Cantarini: Employment and stock ownership: AstraZeneca; E. Felip: Advisory boards: Boehringer Ingelheim, Novartis, Roche, BMS, Lilly; P. Leese: Employment: Quintiles (the CRO contracted to do the study); M. Ranson: Advisory board: AstraZeneca. All other authors have declared no conflicts of interest.

Laparoscopic cholecystectomy is a safe and effective procedure in specialist centres, but its wider application will depend on the ability of general surgeons to become skilled in this technique. 180 patients underwent elective laparoscopic cholecystectomy during a nine-month period at a single district general hospital. All patients who would have been eligible for elective open cholecystectomy were offered the laparoscopic alternative. Laparoscopic cholecystectomy was abandoned in favour of an open procedure in 10 (6%) patients. Median operating time was 55 min. 2 patients had serious morbidity (right hepatic duct injury and a duodenal fistula) and there were no deaths. 3 patients required subsequent treatment for retained common duct stones. 90% of patients were discharged within 48 h of the operation and the median time to resume full activity after discharge was 12 days. Laparoscopic cholecystectomy is a safe and cost-effective technique in a district general hospital.

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.

Endotoxaemia and circulating tumour necrosis factor are important prognostic factors in severe sepsis and are implicated in the pathogenesis of septic shock. Because clinical and pathological features in acute pancreatitis are similar to septic shock this study sought to determine whether endotoxin and tumour necrosis factor were prognostic factors in 38 patients with prognostically severe acute pancreatitis. Endotoxaemia, present in 19/37 (51%) patients on day 1, was more common in nonsurvivors than survivors (10/11, 91% v 9/26, 35%, p = 0.003). Day 1 serum endotoxin concentrations were higher in patients with a severe outcome (median (interquartile range) 314 (173-563) pg/ml v 0 (0-185) pg/ml, p

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.

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.