摘要:

ObjectiveTo assess the efficacy and tolerability of acetyl-L-carnitine (levacecarnine; LAC) versus placebo in the treatment of diabetic neuropathy, mainly by evaluating the effects of treatment on electrophysiological parameters and pain symptoms.DesignThis was a multicentre (n = 20), randomised, double-blind, placebo-controlled, parallel-group study.Patients: 333 patients meeting clinical and/or neurophysiological criteria for diabetic neuropathy were enrolled.InterventionsPatients were randomised to treatment with LAC or placebo. LAC (or placebo) was started intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the study (355 days).Main outcome parameters and resultsThe main efficacy parameter was the effect of treatment on 6- and 12-month changes from baseline in nerve conduction velocity (NCV) and amplitude in the sensory (ulnar, sural and median) and motor (median, ulnar and peroneal) nerves. The effect of treatment on pain was also evaluated by means of a visual analogue scale (VAS). Among the 294 patients with impaired electrophysiological parameters at baseline, those treated with LAC showed a statistically significant improvement in mean NCV and amplitude compared with placebo (p < 0.01). The greatest changes in NCV (at 12 months) were observed in the sensory sural nerve (+5.7 m/sec in the LAC groupvs+1.0 m/sec in the placebo group), sensory ulnar nerve (+2.9vs+0.1 m/sec, respectively) and motor peroneal nerve (+2.7vs−0.2 m/sec), whereas the greatest changes in amplitude were recorded in the motor peroneal nerve (+2.2vs+0.1mV). After 12 months of treatment, mean VAS scores for pain were significantly reduced from baseline by 39% in LAC-treated patients (p < 0.0vsbaseline) compared with 8% in placebo recipients. LAC was well tolerated over the study period.ConclusionsLAC was effective and well tolerated in improving neurophysiological parameters and in reducing pain over a 1-year period. LAC is, therefore, a promising treatment option in patients with diabetic neuropathy.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Fidarestat [SK 860, SNK 860] is an aldose reductase inhibitor that is being jointly developed by Sanwa Kagaku Kenkyusho and NK Curex (a joint venture between Japan Energy and Kaken Pharmaceutical, 51%/49%) for the treatment of diabetic neuropathy.1Fidarestat (as Aldos™) is awaiting registration in Japan for diabetic neuropathy as of 25 September 2000. Kaken Pharmaceutical will market Aldos™ in Japan. Sanwa Kagaku Kenkyusho and Sankyo agreed to jointly develop fidarestat with Sankyo obtaining exclusive sales and marketing rights for fidarestat worldwide except for Japan, China, South Korea and Taiwan. Apparently, Sanwa Kagaku Kenkyusho has applied for a tradename of Amoa™ for fidarestat in the USA.Figure. Fidarestat

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Zenarestat [FK 366, FR 74366, FR 901366] is an orally active quinazoline derivative aldose reductase inhibitor under development with Fujisawa for the treatment of diabetic complications (neuropathy, retinopathy and cataracts).1It was licensed to Parke-Davis (formerly a division of Warner-Lambert, now Pfizer) for development and marketing for the treatment of diabetic neuropathy in the USA, Europe and all other world markets except the Asian markets of China, Taiwan, Japan and South Korea. In June 2000, the parent company of Parke-Davis, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development.Phase III clinical trials are in progress in Japan. However, in October 2000, Pfizer suspended US and European development after evaluation of results from early Phase III trials showed zenarestat therapy to be linked with renal toxicity in a small number of patients. The renal toxicity appeared to be dose-related as the majority of cases were seen in the highest dose level of 1200 mg/day. The efficacy of zenarestat in the treatment of diabetic neuropathy was confirmed in an interim efficacy analysis of one of these Phase III trials.[1] Fujisawa is continuing with the Phase III trial in Japan as the higher dose level is not being tested in this trial (only 600 mg/day is being studied). Fujisawa is developing an eyedrop formulation of zenarestat specifically for the treatment of diabetic retinopathy.Figure. Zenarestat

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

IntroductionDespite the fact that congestive heart failure (CHF) remains the most common disease in the developed world and has been extensively studied, there is little known about the molecular and cellular mechanisms of cardiac dysfunction. Angiotensin has been implicated as a mediator of cardiac injury; however, the mechanisms of its action have not been delineated. The objective of this study was to examine the relationship between the haemodynamic and molecular events during cardiac dysfunction and the role of the angiotensin system.Study designWe examined the effects of the angiotensin receptor blocker, valsartan, on changes in the haemodynamic and gene expression patterns in a post-myocardial infarction model in the rat.MethodsMyocardial infarction (MI) was induced in rats by coronary artery ligation. Cardiac haemodynamics were monitored using echocardiography. Gene expression profiles after myocardial infarction were identified using Affymetrix Genechip®oligonucleotide arrays.ResultsMyocardial contractility, as assessed by cardiac output and left ventricle (LV) fraction of shortening, was reduced in untreated animals by week 3 after MI (p < 0.05 versus baseline), and preserved with valsartan treatment as observed by the nonsignificant changes versus baseline. LV dilatation, as demonstrated by increases in LV systolic and diastolic diameters, developed by week 3 in untreated animals (p < 0.05 versus baseline) while valsartan-treated animals were protected and showed no significant increases in diameter size compared with baseline. LV hypertrophy, as shown by LV posterior wall thickness, was more profound in untreated animals (p < 0.05 versus baseline) than in those treated with valsartan at weeks 3 and 4. Changes in gene expression at 4 weeks after MI included those encoding muscle-specific genes, fibrous tissue proliferation, immune response and various others. Treatment with valsartan reversed these changes in 67% of overexpressed genes and 83% of underexpressed genes.ConclusionAngiotensin receptor blockade with valsartan was found to protect cardiac function, and this beneficial effect was accompanied by a reversal of changes in gene expression induced by MI.

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Telmisartan [BIBR 277, Micardis, Pritor] is an orally effective non-peptide angiotensin II (AT1) antagonist being developed as an antihypertensive.1Boehringer Ingelheim launched telmisartan (as Micardis®) in the USA (its first market) in November 1998 for use as a once daily treatment of hypertension, either alone or in combination with other antihypertensive agents. Telmisartan will be available in a tablet form, at a daily dose of 40 or 80mg. As per Annual Report 2001, telmisartan has now been launched in 47 countries. Telmisartan (as Micardis®/Pritor®) has been approved in the European Union via a centralised procedure in Brussels for once-daily treatment of essential hypertension. Boehringer Ingelheim has launched telmisartan (as Micardis®) in Germany, Italy, Greece, the United Kingdom and France for essential hypertension. Telmisartan has been launched in Spain by Boehringer Ingelheim (Micardis®) and Glaxo Wellcome (now GlaxoSmithKline) [Pritor®] for essential hypertension. Both Boehringer Ingelheim and Glaxo have launched telmisartan as Micardis®and Pritor®, respectively, in Australia for hypertension. Boehringer Ingelheim has also launched telmisartan (as Micardis®) in Canada, the Philippines, Mexico, Argentina, Brazil and South Africa for hypertension. In January 2002, Telmisartan/hydrochlorothiazide formulation (Micardis®Plus, HCT tablets) was launched in the Philippines. The agent has been registered in Latvia for hypertension. Nippon Boehringer Ingelheim has filed a regulatory application for telmisartan (Micardis®) in Japan for a once-daily treatment of hypertension. Telmisartan also appears to be under preclinical development in Japan for the treatment of myocardial ischaemia. Boehringer Ingelheim has initiated an open-label study assessing the effectiveness of telmisartan (Micardis®) on BP control and quality of life in patients with mild essential hypertension. This 6-week Micardis Community Access Trial (MICCAT) will enrol around 10 000 patients from 2200 centres across the USA. The purpose of the study is to compare community treatment with the results of clinical trials. The study will look at the change in DBP and SBP from the start to completion, the BP response in previously untreated patients compared with those exposed to a variety of medications and quality of life. Boehringer Ingelheim is initiating a 5-year ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) comparing Micardis®vsramipril (Aventis)vsthe combination of telmisartan and ramipril. The study will enrol 28 400 patients with increased cardiovascular risk at 793 study centres in 40 countries over 2 years. The end-points will be myocardial infarction, stroke and cardiovascular death. The programme is scheduled to be completed in 2007. In June 2001, Boehringer Ingelheim announced plans for the Telmisartan Randomised AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trial. The double-blind, parallel-group study will be initiated in 2001 in approximately 5000 patients worldwide and will be completed in approximately 5.5 years. TRANSCEND trial will run in parallel with ONTARGET trial and evaluate the objectives of the ONTARGET trial for treatment with telmisartan 80mgvsplacebo in patients who are intolerant to ACE inhibitors.In November 2001, Boehringer Ingelheim announced the company will be initiating the largest cardiovascular study programme in the company's history. Called the PROTECTION programme, it will build on the ONTARGET trial and investigate the effect of Micardis®on blood pressure control in special populations, such as the elderly and patients with diabetes. Ten studies under the PROTECTION programme will enrol about 6000 patients in North America, Europe and South Africa. This will be in addition to the 28 400 patients who will be enrolled in the ONTARGET study. The PROTECTION programme is set to begin in late 2002, and expected to be completed in early 2005, with interim results in 2003.The usual starting dose of telmisartan is 40 mg/day, which could be individually tailored within the 20-80 mg/day range, depending on the patient's BP response.[1]Formulations:Telmisartan/hydrochlorothiazide formulation (Micardis®Plus, HCT tablets) [fixed combination of 40 or 80mg/12.5mg] received US FDA approval as a once-daily treatment for hypertension. In May 2002, GlaxoSmithKline and Boehringer Ingelhein received approval for the telmisartan/hydrochlorothiazide (PritorPlus®) formulation by the European Medical Evaluations Agency (EMEA), for use in patients with essential hypertension. GlaxoSmithKline is also developing a telmisartan/lacidipine combination that is in Phase I clinical trials. Estimated MAA filing is in year 2003.Licensing agreements:Boehringer Ingelheim and Abbott Laboratories have entered into an 8-year co-promotional and co-marketing agreement for telmisartan in the USA. Abbott Laboratories joins Boehringer Ingelheim in promoting and selling telmisartan in April 1999. Boehringer Ingelheim has granted development and marketing rights for telmisartan outside the USA, Japan and ‘certain other countries’ to Glaxo Wellcome. Boehringer Ingelheim will market it in the USA. Under the agreement, both companies will conduct joint research and have marketing rights for two fixed combinations of telmisartan. Boehringer Ingelheim and Yamanouchi Pharmaceutical have signed a letter of intent on the co-promotion of telmisartan in Japan. Following approval in Japan, telmisartan will be manufactured by Nippon Boehringer Ingelheim, jointly marketed by both companies and distributed by Yamanouchi. Glaxo Wellcome is holding the US patent for telmisartan (expiry date - 2013). In December 2000, Glaxo Wellcome merged with SmithKline Beecham to form GlaxoSmithKline.Figure. Telmisartan

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Gemifloxacin [SB 265805, LB 20304, Factive™] is a fluoronaphthyridone with a novel oxime functionalised pyrrolidine.1It has displayed potency superior to other quinolones against methicillin-resistantStaphylococcus aureus(MRSA) and key respiratory tract pathogens such asHaemophilus influenzae, Moraxella catarrhalis andStreptococcus pneumoniaeand has the potential to become the once-daily drug of choice for the treatment of respiratory tract infection. Gemifloxacin is also highly effective against urinary tract pathogens includingEscherichia coliandProteus mirabilis. In addition, gemifloxacin has superior pharmacokinetic and toxicological profiles to ciprofloxacin.LG Chem Investments (formerly LG Chemical Ltd) has signed a worldwide development and commercialisation agreement for gemifloxacin with GlaxoSmithKline, but retains rights to the product in South Korea and has an option to co-promote the product in certain markets in Southeast Asia. In April 2001, LG Chemical split into three corporations − LG Chem Investments Ltd (LGCI), LG Chem Ltd and LG Household & Healthcare Ltd. Following a review of GlaxoSmithKline and LGCI’s joint development programme in April 2002, LGCI announced that it will regain full worldwide rights to future commercialisation of the product, including regulatory activities.[1] During a transition period, GlaxoSmithKline will assist LGCI in seeking marketing approval for gemifloxacin.GlaxoSmithKline has completed Phase III trials for oral gemifloxacin for the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, urinary tract infections and acute sinusitis. The company filed for approval for these indications in the European Union in February 2000. An NDA filing was submitted for the same indications in the USA in December 1999. However, in December 2000, GlaxoSmithKline announced that the FDA had issued a non-approvable letter for gemifloxacin. The company plans to work closely with the FDA to address the issues raised in the non-approvable letter. The latter may involve additional steps ranging from further discussions of the clinical data to the initiation of additional trials.[2]GlaxoSmithKline is also developing an IV formulation of gemifloxacin for the treatment of respiratory and urinary tract infections. It is in Phase III trials. To date, gemifloxacin has not yet been launched in any known country, and little information has been publicised regarding the product’s status following the issuance of the FDA non-approvable letter.Figure. Gemifloxacin

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Ramoplanin [A 16686, A 16686A, MDL 62198], originated by Biosearch Italia, is a glycolipopeptide antibacterial agent derived fromActinoplanesspp. with bactericidal activity primarily against Gram-positive organisms.1Ramoplanin kills microbes by blocking bacterial cell wall synthesis at a site that is different from those targeted by the β-lactams such as penicillin and the glycopeptides such as vancomycin. To date, laboratory studies have not encountered bacterial resistance with ramoplanin and no cross-resistance has been observed between ramoplanin and the β-lactams or glycopeptides. An oral and a topical formulation of ramoplanin are being investigated.Ramoplanin has potential for use in the treatment of vancomycin-resistant enterococcal (VRE) infections, for which it has been granted fast-track status by the US FDA and given an Orphan Medicinal Product designation by the European Commission. Other potential clinical uses under investigation are selective gut decontamination and eradication ofClostridium difficilefrom the bowels of patients with pseudomembranous colitis and eradication of nasal carriage of methicillin-resistantStaphylococcus aureus(MRSA).Oral formulation:A placebo-controlled Phase II trial of oral ramoplanin in 150 patients with hospital-acquired vancomycin-resistantEnterococcus faecium(VREF) intestinal infections has been completed at eight centres in the USA. The study was terminated early after an independent Data Safety Monitoring Board (DSMB) determined there was sufficient evidence of effectiveness and safety to proceed with Phase III trials. Genome Therapeutics, Biosearch's North American licensing partner, is currently conducting an ongoing Phase III study in the USA of oral ramoplanin for the prevention of bloodstream infections caused by VRE infections. In March 2002, Genome Therapeutics reported that the trial was ongoing with one-third of its goal of 950 patients enrolled into the trial to date. In order to include more of the at-risk population, Genome announced an amendment to their study inclusion criteria in May 2002 to include patients with an anticipated period of chemotherapy-related neutropenia of at least 5 days (was originally at least 10 days). The company plans to file a New Drug Application with the US FDA in 2004. This study was intially started in mid-2000 by IntraBiotics. In October 2001, Genome Therapeutics licensed ramoplanin from BioSearch Italia.Topical formulation:A Phase II trial of ramoplanin ointment to prevent hospital-based infections caused byS. aureus, including MRSA, has been initiated. The goal of the phase II trial is to determine whether ramoplanin ointment can effectively eradicate nasal carriage ofS. aureusin human volunteers. Nine sites across the USA will enrol a total of 250 volunteers who carryS. aureusin their nose. All volunteers will receive ramoplanin or placebo for 4 days and will be monitored for 90 days to evaluate nasal carriage of MRSA.Agreements:In October 2001, Biosearch Italia licensed exclusive rights to oral ramoplanin in the USA and Canada to Genome Therapeutics. The latter will be responsible for development of the drug, including funding of clinical trials, and will make a $US2 million initial payment, followed by up to $US8 million in milestone payments. Genome will also purchase bulk material from Biosearch and pay royalties on product sales. USA and Canadian rights to oral ramoplanin were previously licensed to IntraBiotics. As a follow-on to the delay in successfully completing the Phase III trial of oral ramoplanin in VREF infections, Biosearch Italia renegotiated this licensing agreement. IntraBiotics relinquished North American rights for ramoplanin oral powder to BioSearch, but retained the rights to topical ramoplanin for this market. However, BioSearch Italia announced in May 2002 that they had reacquired all worldwide rights for topical ramoplanin from IntraBiotics at no cost after the company failed to commence clinical trials in North America by the March 2002 deadline.[1]During February 2001 Biosearch Italia signed an agreement with an Italian subsidiary of Aventis (Aventis Bulk SpA) for the manufacture of ramoplanin. The latter will manufacture sufficient quantities of the drug for clinical development and its eventual launch in the USA.Figure. Ramoplanin

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Benatoprazole [TU 199; tenatoprazole] is an imidazopyridine derivative and a proton pump inhibitor.1It is under development with Mitsubishi Pharma Corporation (Mitsubishi Chemical) and Hokuriku Seiyaku (BASF Pharma, now Abbott Laboratories) in Japan as an oral antiulcer agent and for the treatment of reflux oesophagitis and Zollinger-Ellison syndrome. An application for approval of benatoprazole (formerly tenatoprazole) has been registered in Japan.Originally benatoprazole was co-developed by Tokyo Tanabe and Hokuriku Seiyaku. However, on 1 October 1999, Tokyo Tanabe was acquired by Mitsubishi Chemical and became Mitsubishi-Tokyo Pharmaceuticals. Subsequently, on 1 October 2001, Mitsubishi-Tokyo Pharmaceuticals merged with Welfide Corporation to form Mitsubishi Pharma Corporation.Figure. Tenatoprazole

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Celgene has developed a chirally pure form of methylphenidate (Ritalin®), called dexmethylphenidate [d-methylphenidate, d-methylphenidate hydrochloride, d-MPH; Focalin™].1The drug has been launched in the USA and is undergoing registration in Canada for the treatment of children with attention-deficit hyperactivity disorder (ADHD). Dexmethylphenidate is the single isomer version of racemic methylphenidate (Ritalin®), which contains the activedisomer of Ritalin®. Dexmethylphenidate acts via the inhibition of reuptake of norepinephrine and dopamine. Research is ongoing to further clarify the mode of therapeutic action in ADHD. Dexmethylphenidate was developed with the aim of reducing drug load, adverse events and drug interactions. Dexmethylphenidate provides effective management of attention-deficit hyperactivity disorder at half the dose of Ritalin®.In April 2000, worldwide rights (excluding Canada) to dexmethylphenidate were granted to Novartis. Celgene has also granted Novartis rights to all related intellectual properties and patents. Novartis will fund all remaining development and marketing expenses required for regulatory approval and commercialisation of dexmethylphenidate. Crystaal Corporation, the marketing division of Biovail Corporation International, has exclusive Canadian marketing rights for all formulations of dexmethylphenidate.Novartis launched dexmethylphenidate (Focalin™) in the USA during Q1 2002. It is available as a D-shaped tablet (2.5, 5 and 10mg doses). Novartis had planned to use the tradename Ritadex, however the FDA recommended an alternative name due to potential prescribing errors with Ritalin®. The finalised tradename to be used is Focalin™. In July 2001, a new drug submission was filed with Canada's Therapeutic Products Programme for dexmethylphenidate in the treatment of attention-deficit disorder and attention-deficit hyperactivity disorder. Novartis is also developing an extended-release version of chirally pure dexmethylphenidate.Dexmethylphenidate has been found to be effective and well tolerated in clinical trials, involving a total of 684 children with ADHD and in 15 healthy adult volunteers.[1]Dexmethylphenidate is a schedule II drug.Figure. Dexmethylphenidate

ISSN:1174-5886    

出版商:ADIS    

年代:2002

数据来源: ADIS