摘要:

PurposeTo investigate the bioavailability and bioequivalence of three different formulations of eslicarbazepine acetate (BIA 2-093): 50 mg/mL oral suspension (test 1), 200mg tablets (test 2) and 800mg tablets (reference).Design, subjects and methodsSingle-centre, open-label, randomised, three-way crossover study in 18 healthy subjects. The study consisted of three consecutive periods separated by a washout period of 7 days or more. Each subject received a single dose of eslicarbazepine acetate 800mg on three different occasions: 16mL of oral 50 mg/mL suspension, four 200mg tablets or one 800mg tablet.ResultsEslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC∞) were, respectively (arithmetic mean ± SD), 18.0 ± 4.6 µg/mL and 325.7 ± 64.9 μg · h/mL for test 1, 16.0 ± 4.0 µg/mL and 304.2 ± 66.0 μg · h/mL for test 2, and 17.0 ± 4.1 µg/mL and 301.1 ± 60.0 μg · h/mL for the reference formulation. Point estimate (PE) and 90% confidence intervals (CIs) for AUC∞test 1/reference geometric mean ratio were 1.09 and 1.01, 1.15; for Cmaxratio, PE and 90% CI were 1.07 and 0.97, 1.15. When test 2 and the reference formulations were compared, the PE and 90% CI were 0.99 and 0.94, 1.07 for the AUC∞ratio, and 0.94 and 0.86, 1.02 for the Cmaxratio. Bioequivalence of test versus reference formulations is thus accepted for both AUC∞and Cmaxbecause the 90% CIs lie within the acceptance range of 0.80–1.25.ConclusionThe pharmacokinetic profiles of eslicarbazepine acetate oral 50 mg/mL suspension, 200mg tablet and 800mg tablet formulations were essentially similar, and the formulations can be considered bioequivalent.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and aimBecausein vitrostudies have shown that nimesulide not only preferentially inhibits COX-2 but also reduces the action/release of pro-inflammatory cytokines, down-regulates the synthesis and/or activity of collagenase(s), and releases reactive oxygen species and other toxic substances from neutrophils, this study investigated whether nimesulide and ibuprofen could affect levels of biochemical markers of joint inflammation and collagen catabolism in patients with flare-up of knee or hip osteoarthritis.MethodsNinety patients were included in this randomised, prospective, single- blind study. They received either nimesulide (n = 45) or ibuprofen (n = 45) for a 4-week treatment period. The following parameters were analysed by ELISA: urinary levels of C-terminal cross-linking telopeptide of type II collagen (CTX-II), a marker of type II collagen breakdown; serum levels of hyaluronan (HA), a marker of synovial inflammation and hyperplasia; and circulating levels of stromelysin-1 (matrix metalloproteinase-3 [MMP-3]), collagenase-1 (MMP-1) and collagenase-3 (MMP-13). Statistical analysis used was ANOVA.ResultsAt the end of the treatment period, nimesulide but not ibuprofen markedly reduced the urinary levels of CTX-II (p < 0.001) and the serum levels of HA (p < 0.05), two markers known to prognosticate poor outcome of the osteoarthritis disease process. Nimesulide also reduced the serum levels of both MMP-3 (p < 0.05) and MMP-13 (p < 0.001). Furthermore, in the nimesulide group, the decrease in levels of CTX-II correlated significantly with the decrease in levels of HA and MMP-13.ConclusionAlthough nonsteroidal anti-inflammatory drugs are effective in improving pain and disability in OA patients, to date it has been unclear to what extent these drugs could affect joint metabolism and hence joint structure. Patients with flare-up of their osteoarthritis disease process exhibit enhanced levels of markers of joint inflammation and cartilage collagen breakdown, which were markedly decreased by nimesulide but not by ibuprofen.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveBile acid-sequestering resins are known to be potent hypocholesterolaemic drugs, and a feeling of abdominal fullness has been reported as the most frequent adverse effect associated with their use. However, this unique adverse effect of colestilan, abdominal fullness, may have the potential to reduce total food intake. The aim of this study was to investigate the effect of colestilan, a new bile acid-sequestering resin, on the bodyweight of postmenopausal women who had previously dieted unsuccessfully.MethodsForty postmenopausal women who failed to diet successfully over a 4-week period were enrolled in this randomised, open-label, controlled study. Subjects were randomised to two groups: the colestilan group received four colestilan tablets administered in divided doses with three glasses of water before dinner and bedtime for 12 weeks; the control group received three glasses of water before dinner and bedtime for 12 weeks. All patients were monitored and were given the same diet instructions.ResultsTwelve weeks’ administration of colestilan in addition to diet instruction significantly reduced bodyweight and body mass index from 62.9 ± 5.7kg to 58.0 ± 5.4kg (mean ± SD) and from 26.1 ± 2.0 kg/m2to 23.9 ± 2.0 kg/m2, respectively. There were no significant differences in bodyweight before and after 12 weeks of treatment in the control group.ConclusionColestilan may be useful for appetite control and exerts anti-obesity effects when used in conjunction with a weight-management programme.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundBenign prostatic hyperplasia (BPH) is the non-malignant, uncontrolled growth of glandular and stromal elements of the prostate gland. Lipid extracts from Saw palmetto(Arecaceae)fruits are widely used to treat BPH. The Cuban royal palm (Roystonea regia) is a member of the same family. Previous studies have found that D-004, a lipid extract from theR.regiafruit, administered orally at 200–800 mg/day for 14 days, prevented testosterone- but not dihydrotestosterone-induced prostate hyperplasia in rats.ObjectiveTo determine whether D-004 can inhibit noradrenaline (NA) [norepinephrine]- and acetylcholine (ACh)-induced smooth muscle contraction in rat vas deferens and to investigate thein vivoeffects of D-004 on NA pressure-elevating effects in rats, an effect mediated by vascular α1-adrenoceptors.MethodsIn vitroeffects were investigated by adding D-004 (125–500 μg/mL) to preparations of rat vas deferens suspended in an organ bath containing Tyrode’s solution, in whichin vitrocontractions were induced by NA or ACh. Negative and positive controls containing Tyrode’s solution alone or with Saw palmetto extracts (125–500 μg/mL), respectively, were included. To assess thein vivoeffects of D-004 on arterial blood pressure, rats were randomly distributed to one of five groups (ten rats/group): these consisted of a negative control group receiving the vehicle, two groups treated with D-004 (400 and 800 mg/kg) and two other groups treated with Saw palmetto (400 and 800 mg/kg). All treatments were orally administered. Rats were anaesthetised with sodium thiopental. Heart rate and blood pressure were registered in baseline conditions. Immediately afterwards, rats were injected intravenously over 5 seconds with successive doses of NA (1, 2 and 4 μg/kg) [0.1mL/100g], with 5 minutes’ interval between doses.ResultsD-004 and Saw palmetto (125–500 μg/mL) significantly (p < 0.05) and dose dependently inhibited contractions induced by NA in rat vas deferens versus control. D-004 was more effective in inhibiting NA-induced contractions than Saw palmetto. The contractions induced by NA in preparations with D-004 (500 μg/mL) were weaker (p < 0.05) than in preparations containing Saw palmetto (500 μg/mL). At 125 μg/mL, D-004 inhibited the contractions induced by NA 1 and 32 × 10−6mol/L by 70.8% and 28.5%, respectively, and Saw palmetto by 56.2% and 10.7%, respectively. At 500 μg/mL, D-004 inhibited these contractions by 100.0% and 71.3%, and Saw palmetto by 80.0% and 42.7%, respectively. The inhibitory concentrations of 50% (IC50) for NA contractions were 148.34 (D-004) and 188.38 (Saw palmetto) μg/mL. D-004 and Saw palmetto significantly (p < 0.05) and to a similar extent inhibited ACh-induced contractions, but less effectively than contractions induced by NA, since at 125 μg/mL they were ineffective. At a dose of 800 mg/kg, but not at 400 mg/kg, D-004 and Saw palmetto inhibited the pressure-elevating effects induced with low (1 μg/kg) but not with high doses (2 and 4 μg/kg) of NA.ConclusionsD-004 and Saw palmetto extracts inhibitedin vitrothe contractile responses to NA and ACh in rat vas deferens, and were more effective in inhibiting NA than ACh contractions. Thein vivoeffects of D-004 and Saw palmetto on the hypertensive response induced by NA were significant but modest. These results are preliminary as the relevance of the effects of D-004 on α1-adrenoceptors deserves further investigation, including comparative studies versus specific defined α1-adrenoceptor antagonists.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveOral mucositis is a major complication of cytotoxic chemotherapy and radiotherapy associated with significant morbidity, pain, odynophagia, dysgeusia and subsequent dehydration and malnutrition, and effective prophylaxis and/or treatment of this condition is essential. The currently available palliative treatment shows improvement only in patients with mild to moderate mucositis. The primary aim of this study was to compare the clinical efficacy of MF 5232 (Mucotrol™), a concentrated oral polyherbal gel wafer formulation, with placebo in the management of chemoradiation-induced mucositis in cancer patients.Patients anddesign:In this randomised, double-blind, pilot study a total of 30 patients of either sex with chemoradiation-induced oral mucositis were randomised to receive MF 5232 (n = 15) or a matching placebo (n = 15) after food three times a day for 7–10 days. Patients were evaluated using validated and standardised scoring systems at baseline and after 7–10 days of treatment.ResultsThere were 11 evaluable patients in each treatment group. There was a significant reduction in mean mucositis scores with MF 5232 as follows: WHO (from 3.0 to 1.8), Radiation Therapy Oncology Group (gross score: from 2.8 to 1.8; functional score: from 2.9 to 1.0), and Objective Scoring System (ulceration score: from 7.4 to 4.4; erythema score: from 13.7 to 7.0). There were no significant changes in scores for placebo recipients. The treatments were well tolerated, with the exception of two patients in the treatment group who reported a burning sensation in the mouth after dissolving the wafer.ConclusionThis pilot study provided positive evidence for the efficacy of MF 5232 therapy in chemoradiation-induced mucositis. This was probably a result of its local analgesic, antioxidant and immunomodulatory activity and wound-healing properties. Further in-depth analysis in a larger number of patients is required to confirm these positive results.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Dapoxetine [LY 210448], a selective serotonin reuptake inhibitor (SSRI), is structurally related to fluoxetine with antidepressant activity. Dapoxetine is the D-enantiomer of LY 243917 and is 3.5 times more potent as a serotonin reuptake inhibitor than the L-enantiomer.[1]Dapoxetine was in phase I clinical trials in the US with Eli Lilly as an antidepressant, but no recent development has been reported for this indication. However, development is underway for the treatment of premature ejaculation, with phase III trials for this indication being completed in the US.The phase II trial for the treatment of premature ejaculation was conducted by PPD GenuPro, a subsidiary of PPD, which was established from a collaboration between Eli Lilly and PPD for the development of drugs to treat genitourinary disorders. Both Lilly and PPD had an option to re-license dapoxetine upon completion of phase II trials, but neither company exercised its option, and the rights remained with PPD GenuPro.In December 2003, PPD Inc. acquired from Eli Lilly and Co. the patents for dapoxetine for development in the field of genitourinary disorders. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine.[2]In December 2000, PPD GenuPro granted an exclusive, worldwide license for dapoxetine to ALZA Corporation, a wholly owned subsidiary of Johnson & Johnson. ALZA will be responsible for development, manufacturing and commercialisation of dapoxetine for urological indications, including premature ejaculation. It will make initial, milestone and royalty payments to PPD GenuPro, a portion of which will be paid to originator Eli Lilly.PPD Inc. received a milestone payment relating to the ongoing development of dapoxetine for premature ejaculation in July 2003.In December 2003, PPD and ALZA amended the dapoxetine license to allow PPD to receive a fixed-sum cash payment apon NDA approval. In return for this, ALZA will not have to make sales-based payments for a period of time following the approval of dapoxetine.[3]If dapoxetine is approved by the US FDA for premature ejaculation, the drug will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc.[4]In December 2004, ALZA Corporation submitted a new drug application to the FDA for dapoxetine hydrochloride in the treatment of premature ejaculation. If approved by the FDA, dapoxetine hydrochloride will be marketed in the US by Ortho-McNeil Pharmaceutical, Inc.[4]Johnson & Johnson plans to support the launch of dapoxetine for premature ejaculation with a ‘responsible’ direct-to-consumer advertising campaign.In May 2005, Johnson & Johnson presented data from two phase III trials involving dapoxetine for the treatment of premature ejaculation, during the 100th Annual Scientific Meeting of the American Urological Association (AUA-2005). Results on drug interactions and pharmacodynamics of dapoxetine were also presented during this meeting.[5]Dapoxetine also appears to be a useful adjunct to morphine, lowering the threshold for analgesia, although the compound itself has negligible analgesic activity.In December 2003, PPD, Inc. acquired from Eli Lilly and Company the patents for dapoxetine for development in the field of genitourinary disorders. Under the terms of the agreement with Lilly, PPD will pay Lilly US$65 million in cash. PPD will also pay Lilly a royalty on net sales of dapoxetine in excess of a certain threshold of annual net sales. As part of the transaction, PPD and Lilly terminated their existing license agreement for dapoxetine.[2]

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Galsulfase [Aryplase™, arylsulfatase B, BM 102, Naglazyme™, rhASB, recombinant human N-acetylgalactosamine-4-sulfatase, recombinant human arylsulfatase B] is under development with BioMarin Pharmaceutical as an enzyme replacement therapy for the treatment of mucopolysaccharidosis (MPS) VI.MPS VI (also known as Maroteaux-Lamy syndrome) is a progressive, debilitating genetic disease resulting in early death. Patients with MPS VI have a deficiency in the arylsulfatase B (ASB) enzyme that is essential for the progressive breakdown of certain complex carbohydrates. The deficiency in ASB results in the build-up of carbohydrate residues in the lysosomes in all cells of the body. Patients are usually diagnosed at 6–24 months of age, and the symptoms include deceleration of growth, enlarged liver and spleen, skeletal and joint deformities, and upper airway obstruction. Patients do not survive past 20–30 years of age in the more severe cases, but may live longer with the milder cases, but with significant medical problems. While the symptoms of MPS VI are similar to those of MPS I, mental retardation associated with the severe forms of MPS I had not been reported for patients with MPS VI. For some patients, bone marrow transplantation is a treatment, albeit risky, option. MPS VI afflicts approximately 1100 patients in the world.In November 2004, BioMarin announced that it has filed a Biologics License Application (BLA) with the the US FDA for galsulfase for the treatment of MPS VI. The company has requested a priority review as part of the BLA submission, which, if granted, is expected to be completed within 6 months of submission.[1]The FDA accepted the filing of the BLA for galsulfase for MPS VI in February 2005, and granted it a 6-month priority review period. The FDA's decision is due on 31 May 2005.[2]The FDA has granted galsulfase orphan drug status and fast-track designation. Orphan drug status will provide BioMarin Pharmaceutical with 7 years of marketing exclusivity for galsulfase in the US providing that galsulfase is the first agent to gain approval in the US for MPS VI.BioMarin received an orphan drug designation from the EC for galsulfase for the treatment of MPS VI.Following positive safety and efficacy results from the phase I study with galsulfase, BioMarin Pharmaceutical commenced and successfully completed a phase II trial with rhASB in ten patients with MPS VI. This 24-week, open-label, multicentre trial was conducted at two sites, in the US and Australia (at the Lysosomal Diseases Research Unit, Women's and Children's Hospital, Adelaide, Australia, by Dr John Hopwood), and evaluated the safety, efficacy and pharmacokinetics of weekly intravenous infusions of galsulfase at a dose of 1.0 mg/kg.BioMarin Pharmaceutical completed a phase I/II clinical trial of galsulfase in six patients with MPS VI in the Children's Hospital, Oakland, CA, USA, with Dr Paul Harmatz as a principal investigator. This randomised, double-blind study evaluated the safety and efficacy of two doses of galsulfase administered by weekly intravenous infusions for 24 weeks. Five patients from the phase I study had completed the 24-week, open-label extension study. Data from this study confirmed safety and good tolerability of both doses of galsulfase with the 1.0 mg/kg dose producing greater sustained effects. The patients will continue receiving therapy in the future.Seven preclinical trials with galsulfase were conducted in a naturally occurring feline model of MPS VI disease at the Lysosomal Diseases Research Unit, Women's and Children's Hospital, Adelaide, Australia, by Dr John Hopwood.The company manufactures galsulfase at a GMP facility licensed from the State of California.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Metformin extended release [Glumetza™,metformin hydrochloride, metformin gastric retention, metformin GR™] is a proprietary once-a-day formulation of metformin hydrochloride under development with Depomed for the treatment of diabetes mellitus.In May 2002, Depomed licensed manufacturing and marketing rights for its proprietary formulation of metformin extended release (500mg dose) to Biovail Corporation for the US (including Puerto Rico) and Canada. Under the terms of the agreement, Biovail will pay DepoMed a $25 million milestone fee upon approval of the 500mg dosage and also customary royalties on the net sales in the US and Canada. Biovail also agreed to acquire approximately 2.4 million of additionally issued Depomed shares for $12.3 million.Biovail has subsequently developed a 1000mg dose of metformin extended release [metformin XR] using its proprietary Smartcoat delivery technology allowing a graduated release of the active drug from the tablet.In April 2004, Depomed and Biovail amended their original license agreement of May 2002. Under the terms of the amended agreement, Depomed will receive royalties on sales of Biovail's 1000mg tablet in the US and Canada. In turn, Biovail acquired access to Depomed's clinical data for the metformin 500mg tablet that will be used to accelerate regulatory filings for Biovail's 1000mg tablet and establish equivalence between the two dosages.[1]Biovail is seeking marketing partners for metformin extended release (Glumetza™) in the US. The company anticipates signing an agreement for the US during the second half of 2005.In Canada, Biovail Corporation will market Glumetza™ through its Canadian division, Bioval Pharmaceuticals Canada.[2]Depomed has an agreement with LG Life Sciences for the commercialisation and distribution of metformin extended release in Korea.[2]Metformin GR™ is available for partnership in Europe and Asia.Biovail Corporation and Depomed announced in June 2005 that the US FDA has approved metformin extended release (Glumetza™) 500mg and 1000mg tablets for the treatment of type 2 diabetes mellitus. Biovail plans launching the product in the fourth quarter of 2005.[3]In July 2005, Biovail paid Depomed a $25 million milestone payment following approval of metformin extended release in the US for type 2 diabetes.[4]In March 2005, Biovail Corporation and Depomed announced that they have received an approvable letter from the FDA for the once-daily, extended-release formulation of metformin extended release (Glumetza™) 500mg and 1000mg tablets. The letter specified an issue related to finalising one manufacturing specification. There were no clinical labeling issues identified in the letter.[2]Both companies filed a response to a specified issue at the FDA on 8 April 2005. The companies believed that the response will be classified as a Class I response with a 60-day review period.[5]The 500mg dosage was developed by Depomed using its patented drug delivery GR™ technology, while Biovail developed metformin 1000mg dose using its proprietary Smartcoat delivery technology.[1]Biovail's NDA for a once-daily, extended-release formulation of metformin HCl for the treatment of type II diabetes was filed in April 2004 and accepted for review in June 2004 by the FDA.[6]Depomed completed two double-blind, pivotal, phase III clinical trials with metformin extended release 500mg at 60 sites in the US in more than 1000 patients with type 2 diabetes. In three different dosing regimens, metformin extended release significantly decreased the glycosylated haemoglobin level similarly to that of metformin immediate-release. Biovail successfully compared metformin extended release 1000mg dose with Depomed's 500mg dose in multiple equivalence studies. In these studies, metformin extended release was well tolerated and demonstrated an excellent safety profile in terms of gastrointestinal adverse events.On 1 June 2005, Depomed and Biovail Comporation, the licensee, announced that the Therapeutic Products Directorate in Canada issued a Notice of Compliance for metformin extended release (Glumetza™) 500mg and 1000mg for the treatment of type 2 diabetes. Biovail Pharmaceuticals Canada plans to launch the product in the fourth quarter of 2005.[7] Biovail has submitted an application for metformin extended release with the Therapeutic Products Directorate in Canada.[8] and received notification of acceptance for review in August 2004.[9]Bristol-Myers Squibb is marketing a proprietary, once-daily extended-release formulation of metformin (Glucophage®XR).Several companies are developing controlled-release and extended-release formulations of metformin.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS