摘要:

In the treatment of HIV-infected patients, an urgent need exists for more conveniently dosed and better tolerated regimens with improved virological and immunological efficacy. Based on preclinical studies, the combination of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was considered to fulfill this. Several clinical studies, however, have shown different results with regard to mechanism of action, pharmacokinetics, efficacy and toxicity of dual NNRTI regimens. Combinations of two NNRTIs have shown additive or synergistic inhibitory effects on the HIV-1 reverse transcriptase activity and the viral replication of HIV-1in vitro, although antagonistic effects have also been described. When nevirapine and efavirenz were administered in combination, the exposure to efavirenz was decreased due to induction of metabolism by nevirapine. When compared with single NNRTI regimens, dual NNRTI regimens showed similar but not superior results with regard to virological and immunological success in treatment-naive and pretreated HIV-1-infected patients. However, NNRTI-associated adverse events, such as clinical hepatitis, elevated liver enzymes, rash, central nervous system toxicity and psychiatric disorders, occurred more frequently when two NNRTIs were administered concomitantly.In conclusion, regimens with both nevirapine and efavirenz seem to result in similar antiviral and immunological efficacy with an increased incidence of adverse events compared with single NNRTI regimens. The combination of two NNRTIs is therefore less desirable than other available and effective treatment options.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveMicrofabricated particles with nanosized features may serve an important role in the next generation of drug delivery vehicles. Microfabrication (micro-electromechanical systems) technologies offer the promise of both structural elements (e.g. pores, reservoirs) and electromechanical features (e.g. timers, valves, actuators) built into a single particle. In order to serve as carriers to deliver drugs to systemic sites of action, such as tumours, the particles must be safe to administer intravenously. An acute safety study was performed in a mouse model, using intravenous injection of solid silicon dioxide particles created to simulate the size and shape of potential targeted drug delivery vehicles.DesignTwo-micron thick, square and circular, parallelepiped-shaped particles were produced with varying sizes of 2µm, 5µm and 10µm using microfabrication techniques and injected into groups of mice (six mice per group) over a range of doses. End-points included acute lethality, clinical signs of toxicity and weight loss. Sections of major organs were sampled for histological examination.ResultsAt dose levels of 1 × 108particles per mouse, circular particles of 2µm and 5µm showed no signs of acute toxicity. Similar results were obtained with the 2µm and 5µm square silicon dioxide particles; however, 14-day necropsy indicates fewer 5μm circular particles in the lung than 5μm square particles, indicating that the shape of the particles may impact on safety. Acute lethality was observed for 10µm particles; none of the mice injected with the 10µm particles survived except at very low dose levels of 6 × 105particles per mouse.ConclusionsSolid silicon particles greater than 5µm in their largest dimension are cleared in the lungs and are not safe for intravenous delivery. Particles of 2–5µm in size do not lodge predominantly in the lung and do not cause acute toxicity, but accumulate in organs such as the liver and spleen. Possible chronic toxicities associated with organ uptake of such non-biodegradable particles have yet to be addressed.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

AimOxidative stress caused by smoking has been implicated in many pulmonary diseases. Smoking causes reductions in plasma nitrate plus nitrite (NOx) concentrations and increases in plasma malondialdehyde (MDA) concentrations, which indicate oxidative stress and lipid peroxidation, respectively. In this study, we investigated the acute effects of smoking a single cigarette on the plasma concentrations of NOx and thiobarbituric acid reactive substances (TBARS) including MDA, and whether administration of erdosteine, a mucolytic and antioxidant agent, affects these parameters.MethodsThirty healthy smokers were included in the study. Subjects smoked a single cigarette in 10 minutes on the study day. For analysis of NOx, TBARS and cotinine, blood was drawn from each subject before and 5 and 30 minutes after smoking. The subjects were then randomly divided into two groups, one receiving placebo and the other erdosteine suspension 175mg/5mL twice daily for 1 month. After this treatment period, the same study protocol was carried out. Two subjects in the placebo and five subjects in the study group were excluded because of noncompliance.ResultsTwenty-three (14 female, 9 male) subjects completed the study. Their mean age was 32 ± 8 years and their smoking history was 14 ± 9 pack-years. Baseline NOx, TBARS and cotinine concentrations were similar between the groups. NOx concentrations decreased significantly after smoke exposure. At the end of the treatment period there were no significant differences in NOx, TBARS or cotinine concentrations between the groups. The concentration of TBARS after smoking decreased significantly in the erdosteine-treated group (at 5 minutes: 2.8 ± 0.5 µmol/L before treatment and 2.3 ± 0.3 µmol/L after treatment, p < 0.05; at 30 minutes: 2.8 ± 0.5 µmol/L before treatment and 1.8 ± 0.7 µmol/L after treatment, p < 0.05). Smoking history was significantly correlated with cotinine concentrations.ConclusionAcute smoke exposure decreased plasma NOx concentrations in healthy smokers, and this was not changed with erdosteine treatment. However, significant decreases were noted in TBARS concentrations after smoke exposure in the group that received erdosteine, suggesting that short-term erdosteine administration might help prevent smoking-induced lipid peroxidation.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

IntroductionOxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic μ-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers.Study designA randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women.MethodsA single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state.ResultsTwenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC∞] 4.5, 9.1 and 20.1 μg · h/L, respectively) and maximum plasma concentration ([Cmax] 1.1, 1.9 and 4.4 μg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and Cmaxof oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median tmax(time to reach Cmax) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t½) was approximately 7.3–9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted.DiscussionBecause successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.

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:

Eszopiclone [Lunesta™, Estorra™] is a short-acting hypnotic agent that is a stereoselective isomer of the agent zopiclone, which has been available in Europe since 1992. Eszopiclone is structurally unrelated to the benzodiazepines, and Sepracor (the originator of eszopiclone) has stated that the drug acts rapidly, with the duration of effect lasting up to 6 hours. This may result in improved sleep maintenance, with less nocturnal awakening.Originally, racemic zopiclone was developed and marketed by Rhône-Poulenc Rorer, which merged with Hoechst Marion Roussel to form Aventis.Sepracor anticipates that eszopiclone will have equivalent efficacy to the racemic version with potential for an improved side effect profile.In October 1999, Sepracor exclusively licensed Aventis Pharma's preclinical, clinical and postmarketing surveillance data package for zopiclone, its isomers and metabolites. The company intends to use this information in addition to data from Sepracor's own studies as part of the regulatory package to gain approval of eszopiclone in the US. In July 2004, Sepracor announced terms of an additional agreement with Aventis under which it would have the right to read and reference Aventis' regulatory filings related to zopiclone outside the US for the purpose of development and regulatory registration of eszopiclone outside the US. Additionally, Aventis would assign Sepracor the foreign counterparts to the US patent covering eszopiclone and its therapeutic use.[1]In August 2004, Paul Royalty Fund II, an affiliate of Paul Capital Partners, purchased from Sanofi-Aventis the royalty rights on US sales of eszopiclone. In exchange for the rights, Sanofi-Aventis will receive fixed and milestone payments totalling up to US$115 million.[2]In December 2004 the US FDA approved eszopiclone (Lunesta™) for the treatment of insomnia. It is indicated for patients who experience difficulty falling asleep as well as for patients who have sleep maintenance difficulty, and is approved for long-term treatment. The recommended dosing to improve sleep onset and/or maintenance is 2mg or 3mg for adult patients (aged 18–64 years) and 2mg for older adult patients (aged ≥65 years). The 1mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. The launch of eszopiclone in the US is expected to take place in the first quarter of 2005.[3,4]The approval follows an NDA submission in January 2003, an approvable letter in February 2004, and a resubmission of the NDA in June 2004. The NDA contained data from 24 clinical trials that included >2700 adult and elderly subjects, as well as data from >60 preclinical studies. Six phase III trials in adult and elderly patients with chronic or transient insomnias were also included in the data submission.[5-7]Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause.[8-10]Sepracor has been granted a US patent for eszopiclone [S-zopiclone, (+)-zopiclone, Lunesta™, Estorra™], a single isomer of zopiclone.US patents (Nos. 6,319,926 and 6,444,673) have been issued covering the use of eszopiclone for the treatment of insomnia, eszopiclone and pharmaceutical compositions comprising eszopiclone.

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Bausch & Lomb and Control Delivery Systems have developed an intravitreal implant that can deliver the corticosteroid fluocinolone acetonide [fluocinolone acetonide implant, Retisert™] to posterior eye tissue for up to 3 years. The implant uses Bausch & Lomb's Envision TD™ technology. This fluocinolone acetonide implant has been designed for the treatment of non-infectious uveitis affecting the posterior segment of the eye and other eye disorders, which benefit from local anti-inflammatory therapy.In July 2003, Bausch & Lomb assumed all responsibility for day-to-day clinical development and regulatory activities relating to fluocinolone acetonide implant development from Control Delivery Systems.In May 2002, Control Delivery systems and Bausch & Lomb formally amended their budget for their license and development agreement. Bausch & Lomb will increase its funding to support the development of agents for the treatment of diabetic macular oedema, posterior uveitis and wet age-related macular degeneration to $US206 million through to 2008.In January 2004, Bausch & Lomb decided to focus development of the fluocinolone acetonide implant in only one indication, non-infectious uveitis affecting the posterior segment of the eye. It had been in development for other indications, including macular oedema and age-related macular degeneration. However, these will be targeted with later-generation implant technologies, different drugs, or combinations of both.The implant delivering fluocinolone acetonide 0.59mg or 2.1mg has completed enrolment in two pivotal 3-year phase IIb/III trials in the US, Canada, Australia and Asia for the treatment of posterior uveitis. Enrolment in these multicenter randomised, double-masked studies was closed in May 2003. Bausch & Lomb was expected to file an NDA with the US FDA for the use of the agent in the treatment of uveitis in mid-2003. However, in February 2003, the company reported that, after a review of various filing strategies, the date of filing for the treatment of non-infectious uveitis affecting the posterior segment of the eye would be held back until mid-2004, with possible commercialisation during 2005.Positive results based on 34-week data from the first phase III trial of fluocinolone acetonide implant, conducted in 26 US centres and one centre in Singapore, were reported in September 2003. Patients in this trial will be followed for an additional 2.5 years.[1]Thirty-four-week results from the second phase III trial, conducted in 239 patients at 19 centres in Canada, the US, Australia, India, the Philippines and Hong Kong, have confirmed results in the initial phase III study, and were presented at the 37th Annual Meeting of the Retina Society. Bausch & Lomb continues to target commercialisation for 2005.[2]In May 2000, the fluocinolone acetonide implant was granted fast-track status from the FDA and in July 2000 it received Orphan Drug designation from the FDA for posterior uveitis.In addition, enrolment was completed in a phase II trial of a fluocinolone acetonide 0.59mg implant for the treatment of predominantly occult subfoveal choroidal neovascularisation in patients with AMD in July 2002. However, development in this indication has been discontinued.[3]

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine®], for a number of metabolic and endocrine indications.In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds.The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature.Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis.Mecasermin rinfabate was developed by Celtrix using its proprietary recom- binant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000.Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate and its components will be carried out in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines at the capacity of up to 1000L.In April 2004, Insmed announced that it acquired a lease to operate the manufacturing facility formerly operated by Baxter for the commercial production of SomatoKine®in Boulder, CO, USA. With the two manufacturing facilities for SomatoKine®, Insmed plans to meet the development and commercial demands for the product over the next several years.[1]In its 2003 Form-10K, Insmed announced plans to conduct comparative studies with the previously used drug substance and the new substance produced by Avecia. The comparative data will be included in the regulatory filing for mecasermin rinfabate.Mecasermin rinfabate was originally licensed to Welfide for Japan. On 1 October 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical.In October 2004, Insmed announced that Tzamal Pharma has been granted exclusive distribution and marketing rights for mecasermin rinfabate in certain Middle Eastern territories including Israel. Tzamal Pharma also acquired exclusive rights to Insmed's named patient programme for the agent in these territories. Tzamal Pharma intends to begin the appropriate registration activities for mecasermin rinfabate in the treatment of children with growth hormone-insensitivity syndrome.[2]This pivotal, 12-month, multicentre, open-label trial in 30 children with GHIS was initiated in June 2003 and was designed to evaluate the safety and efficacy of the agent in prepubescent children with GHIS. The 6-month endpoint data analysis showed that mecasermin rinfabate given as a once-daily injection was safe and well tolerated. The agent demonstrated a significant increase in height velocity in children with GHIS similar to that observed by Pfizer in their pivotal study with twice-daily injections of rhIGF-I. The full results from the pivotal trial are expected in 2005.[3] In April 2003 Insmed initiated a named patient programme in Europe that will make available mecasermin rinfabate for the treatment of GHIS – Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Mecasermin rinfabate will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-I therapy. At precommercial scale quantities, the drug will be available on a limited basis.A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew's and the Royal London School of Medicine, London, UK. A single dose of mecasermin rinfabate delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. No adverse events were reported.Insmed has acquired an exclusive licence to Pharmacia's regulatory filings concerning yeast-derived insulin-like growth factor 1 (IGF-1). These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the IND application with the US FDA. Insmed believes that this licence will facilitate the development of mecasermin rinfabate for the treatment of children with GHIS.[4]In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of mecasermin rinfabate in adolescent patients with type 1 diabetes receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under supervision of Prof. D. Dunger.[5]The researchers from The Robarts Research Institute and the University of Western Ontario, Canada (leading investigator T.L. Delovitch, the Sheldon H. Weinstein scientist in Diabetes at the University of Western Ontario) have found that mecasermin rinfabate complex was significantly more effective than IGF-1 in reducing the severity of insulitis, beta cell destruction and delaying the onset of type 1 diabetes. The study was supported by grants from Canadian Institutes of Health and the Juvenile Diabetes Research Foundation.[6]Insmed plans to initiate large-scale phase II clinical studies in this indication.At the BIO 2004 Annual International Convention (BIO-2004) in June 2004, Insmed announced that it has received a grant from the US National Institutes of Health (NIH)/Muscular Dystrophy Association (MDA) worth $US6.5 million to investigate the efficacy of mecasermin rinfabate for the treatment of myotonic dystrophy.It has also been granted orphan drug status for the treatment of GHIS – Laron syndrome in the US and Europe.In December 2003, Insmed announced that mecasermin rinfabate was designated orphan drug status by the FDA for the treatment of extreme insulin resistance. This provides Insmed with 7 years of market exclusivity following approval of mecasermin rinfabate for this indication.[7]Insmed has received orphan drug designation for mecasermin rinfabate in the treatment of extreme insulin resistance in Europe (October 2004).[8]In November 2004, Insmed was granted the European patent EP1183042 entitled “Methods for Treating Diabetes”. This patent corresponds with the US patent US 6,040,292 also entitled “Methods for Treating Diabetes”. Both patents cover type 1 and type 2 diabetes mellitus and insulin resistant diabetes including type A insulin resistance (the least severe form of extreme insulin resistance syndromes).[9]In January 2004, Insmed obtained a non-exclusive licence to the patents for use of IGF-I for the treatment of extreme or severe insulin-resistant diabetes from Fujisawa Pharmaceutical. Insmed will have worldwide rights in territories (excluding Japan) with existing valid patent claims including the US and Europe.[10]Insmed holds 28 US issued or allowed patents for the composition, production, antibodies and methods of use of mecasermin rinfabate. These US patents expire at various times between the years 2010 and 2019.Insmed through their lawyers filed its defense and counterclaim to the alleged patent infringement brought by Tercica against Insmed in the London High Court of Justice. Insmed asserted that it did not infringe any valid patent claims as none of the claims of the patent were patentable because the subject matter was not new. Insmed also stated that the patent did not involve an inventive step, did not have capability of industrial application and had no clear description of the invention so that invention can be performed by the person skilled in the art. Insmed is seeking revocation of the patent on these grounds.[11]

ISSN:1174-5886    

出版商:ADIS    

年代:2005

数据来源: ADIS