GL-701 Genelabs

Genelabs is developing GL-701 (prasterone), oral dehydroepiandrosterone (DHEA), for the potential treatment of systemic lupus erythematosus (SLE) [154020]. In September 2000, the company completed submission of its rolling NDA, begun in May 2000 [340361], [355642], [361381], [380239], [383545]. In October 2000, the FDA granted the company's NDA Priority Review designation [387020]. Genelabs began its NDA submission for GL-701 in May 2000, by submitting the complete clinical, statistical and human pharmacokinetic sections to the FDA. This includes all the human efficacy and safety data for the NDA [368932]. In March 1999, Genelabs received Fast Track designation for GL-701 from the US FDA, allowing the development and review of an NDA to be expedited [319963]. Genelabs met with the US FDA in November 1999 to present the data from the two phase III trials in women and was advised by the FDA that its NDA proposal appeared adequatefor submission [348192], [361381]. Because of the public domain nature of DHEA, Genelabs was not certain that it would obtain patent protection. In the US it received Orphan Drug designation, providing seven years of exclusive marketing rights, and in October 1996, Genelabs received US-05567696, covering the use of GL-701 in lupus patients to reduce their dosage of concomitant corticosteroids [222741], [329646]. The US FDA has also granted Subpart E designation to GL-701, which permits expedited development [169754], [222741]. Genelabs licensed the product exclusively worldwide from Stanford University, which performed the early-stage clinical studies. The Asian marketing rights have been licensed to Genelabs Biotechnology Ltd (GBL), a joint investment with the government of Taiwan [229812]. In January 2001, analysts at UBS Warburg predicted that GL-701 would be launched in 2001, and reach sales of US $ 90 million by 2004 [398731].     

Bexarotene ligand pharmaceuticals

Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response target rates; side effects were primarily limited to local skin reactions [349982]. Ligand has worldwide rights to market bexarotene capsules, and will market the drug in the US, Canada and selected European markets. In Spain, Portugal, Greece and Central and South America, Ferrer Internacional will market and distribute the drug. As of December 1999, Ligand was seeking additional distribution partners for select European and Asian markets [351604]. In January 2000, Alfa Wassermann signed an agreement with Ligand to exclusively market and distribute Targretin gel and capsules in Italy. Alfa paid US $0.75 million on signing with additional amounts up to an aggregate total of US $1.0 million on achievement of certain registration milestones, which are expected to be met in 2000 [351882].     

Escitalopram H Lundbeck

Lundbeck and Forest have developed and launched escitalopram, the therapeutically active (S)-enantiomer of citalopram, as an improved follow-up compound for the potential treatment of depression. In December 2001, Lundbeck received Swedish approval for the treatment of depression and panic disorder [433058], and in January 2002, the product was approved in Switzerland for the treatment of depression [434736]. By May 2002 it had been approved in Belgium, Denmark, the UK, France, Iceland, Luxembourg, Norway and Austria, as a result of the European Mutual Recognition Procedure. Independently, regulatory authorities in Lithuania had also approved the drug for the treatment of depression. Launch in these countries will begin immediately after price and reimbursement negotiations are completed [450860]. By June 2002, it had been launched in Switzerland, Sweden and the UK [454488]. Based on the approvals in the EU, national applications are being submitted in several Central and Eastern European countries, where review and the first approvals were expected in the second half of 2002. At this time, the approval of escitalopram in Australia and Canada was expected in the second half of 2002 and the first half of 2003, respectively [450860]. It became evident in May 2002, that Portugal, Greece, Italy, Spain, Finland and Germany did not intend to approve escitalopram for marketing within the 90-day timeframe, and, at this time, Lundbeck, in accordance with the advice of the reference country, Sweden, chose to withdraw the registration applications from these six countries. At this time, the company still expected escitalopram to be approved in these countries [450860]. In the US, Forest submitted an NDA in March 2001 [402983] and in January 2002, Forest received an approvable letter from the FDA for escitalopram; at this time, US launch was expected in mid-2002 [437487], [444243]. By March 2002, Lundbeck had started to supply escitalopram to Forest [442326]. Lundbeck and Morchida entered a Japanese development and marketing agreement in May 2002, replacing a collaboration with Mitsui [453377].     

Treprostinil sodium Pharmacia

United Therapeutics Corp (UTC) is developing treprostinil sodium (Remodulin, UT-15), a stable structural analog of prostacyclin, for the potential treatment of primary pulmonary (arterial) hypertension (PAH), peripheral vascular disease (PVD) and other cardiovascular conditions [327593], including critical limb ischemia (CLI) [412483]. In August 2000, UTC submitted the initial, non-clinical sections of an NDA for the treatment of pulmonary hypertension [378906]. Treprostinil, which had previously been designated as an Orphan Drug, was also awarded Priority Review status by the US FDA in October 2000 [385864], [386271]. In December 2000, UTC agreed with the FDA that the NDA for treprostinil did not need to be presented to the Cardiovascular and Renal Drugs Advisory Committee, which was expected to allow UTC and the FDA to work towards the 6-month Priority Review timeline [393888]. On August 9, 2001, the advisory committee recommended approval of treprostinil and UTC refiled the NDA on the same day [418682]. In February 2002, the FDA issued an approvable letter for treprostinil injection for the treatment of PAH. The FDA proposed drug labeling for PAH consistent with the treatment of both primary and secondary pulmonary hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms. The approvable letter also stated that the FDA intended to approve treprostinil with a requirement that UTC subsequently conduct a post-marketing controlled clinical trial to verify and further describe the drug's clinical benefit [439278]. In February 2001, UTC submitted a marketing authorization application (MAA) in France for approval of treprostinil for the treatment of PAH. Upon approval of the MAA, UTC planned to file for Mutual Recognition in other European countries and was also preparing similar submissions to non-European countries [391986], [397958]. By early 2001, phase II trials of treprostinil for the treatment of CLI were underway [412483]. In March 2001, the company was planning a phase III pivotal study in late-stage PVD by the end of 2001 [424180]. In April 2000, UTC was issued US-06054486 for the method of treating PVD with treprostinil [364130]. In February 2000, UTC entered into an agreement with Paladin Labs for the exclusive Canadian distribution of treprostinil for the remainder of clinical trials and after regulatory approvals [357302]. In November 2000, UTC and Antigen Pharmaceuticals entered into a strategic alliance for the distribution of treprostinil in the UK and Ireland [390157]. In November 2000, Deutsche Banc Alex Brown predicted a sales potential of US $250 million to US $350 million [418736]. In August 2001, Merril Lynch predicted sales of US $10 million to $20 million in 2002 [420652].     

Moxifloxacin Bayer

Bayer has launched the fluorinated oxoquinolone, moxifloxacin, as a treatment for bacterial infection. It was launched in Germany for the treatment of respiratory tract infections in September 1999, and regulatory approval in the other EU member states was expected to be completed early in 2000, with marketing throughout the EU by the end of 2000 [336340,340358]. Moxifloxacin received FDA approval in December 1999 and it was launched in the same month [350407,350415,365913]. By July 2000, the drug had been launched in Japan [375976]. In February 1999, Lehman Brothers predicted 95% probabilities that moxifloxacin would reach the US and ex-US markets, and launch onto these market in 1999. Peak annual sales of US $500 million in 2005 (US) and US $800 million in 2007 (ex-US) are predicted [319225].     

Nystatin LF (Aronex/Abbott)

Nystatin LF (Nyotran) is a liposomal, intravenous nystatin formulation under development by Aronex, under license from the MD Anderson Cancer Research Center, as a systemic antifungal agent against strains including Aspergillus and Candida. Like amphotericin, nystatin is a polyene derivative that binds to ergosterol, a fungal cell membrane component, creating a pore in the membrane and thus killing the cell. Nystatin is an established antifungal agent, but is restricted to topical use as it is ineffective orally and severely toxic when administered iv [187583], [187589]. It has demonstrated good, broad in vitro antifungal activity against clinically relevant filamentous fungi [319465], including fungi resistant to fluconazole and amphotericin B products [264505], [2869821, [287790], 1289522]. The company is also conducting a phase III trial to evaluate its efficacy against cryptococcal meningitis [305531], [334156]. Aronex filed for approval of nystatin LF in Spain in December 1997 [272986] and expected to file an NDA in the US by the end of 1999 1311208], [342003]. However, in an effort to ensure that its US and European filings contained data from the phase III cryptococcal meningitis trial in its entirety, Aronex's marketing partner requested that all the 70-day data be gathered prior to unblinding this study. The filing had initially been based on interim data at the 14- and 21-day endpoint 1344887]. In September 2000, the company anticipated an NDA filing in the US in the fourth quarter of 2001 1382861], 1387947]. In December 1997, Aronex, together with Grupo Ferrer Internacional, filed an MAA in Spain seeking approval for Nyotran for the treatment of systemic fungal infections. Aronex intended to follow the filing with additional filings in other European countries 1272986]. In 1997, a commercialization agreement was signed with Ferrer for Spain and Portugal, with Aronex intending to form other such partnerships throughout Europe and Asia 1248346]. In November 1998, Aronex signed a licensing collaboration with Abbott Laboratories for the worldwide rights to nystatin LF [305531].     

Gamma-Hydroxybutyrate (orphan medical)

Orphan Medical is developing gamma-hydroxybutyrate (Xyrem) for the potential treatment of narcolepsy [183352]. In October 2000, an NDA was filed with the FDA [384422], [405504] and Xyrem received an FDA approvable letter in July 2001. Orphan Medical stated that it believed it could meet the requirements in the letter, including a trial in respiratory-compromised patients, by the end of 2001 [414461]. The FDA also requested follow-up safety data from patients in previous Xyrem trials. At that time, the drug was not expected to be launched until mid-2002 [415301], [416305]. In October 1999, the US House of Representatives passed the HR 2130 bill, allowing the medical use of gamma-hydroxybutyrate, which is classified as a Schedule I controlled substance in the US [343562]; the Senate approved this legislation in November 1999 [348206]. In February 2000, a congressional bill supporting the continued development of medically formulated gamma-hydroxybutyrate was passed, making medically formulated gamma-hydroxybutyrate products Schedule III substances [354108], [356597]. GHB occurs naturally in many human tissues. It has previously been used in the treatment of narcolepsy and is not patentable for that indication.     

Alibra (VIVUS)

VIVUS is developing a combination therapy for the potential treatment of impotence consisting of alprostadil and prazosin (an alpha-adrenoceptor blocker) for delivery via its transurethral MUSE system. The therapy is being developed as an alternative to MUSE-alprostadil, and the company believes the prazosin component has the ability to reduce the dose of alprostadil necessary, and hence reduce associated pain. In addition, the mechanism of action of prazosin may be more efficacious in some individuals [2730761. By October 1998, the combination was in phase III trials, which were completed by September 1999 [3015441, [338753]. VIVUS submitted an NDA to the US FDA in December 1999 [319367], [344214] and in May 2000, the company filed for marketing authorization in Europe 13687511. In October 2000, the company was still awaiting regulatory approval from the FDA and the EMEA 1384823]. The company subsequently withdrew its NDA in the US. VIVUS Inc have also now withdrawn their application to the FDA and the EMEA for the alprostadil/prazosin MUSE combination product 1394552]. The company is still in discussion with these authorities regarding the application. Abbott Laboratories has exclusive rights for MUSE-alprostadil and Alibra in select markets, including Europe, Japan, Australia, New Zealand, and South and Central America [371435].     

Lucinactant (Discovery Laboratories)

Discovery Laboratories Inc (formerly Acute Therapeutics Inc (ATI) is developing lucinactant, originally identified at the Scripps Research Institute and sublicensed from Johnson & Johnson, for the potential treatment of respiratory diseases [174059], [357077], [361765], [422819]. The company anticipated filing an NDA for lucinactant in 2002, and by March 2002, lucinactant was in two pivotal phase III international trials for respiratory distress syndrome (RDS) in premature infants, a phase III trial for meconium aspiration syndrome (MAS) in full-term infants, and a phase II trial for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in adults. The company expected to complete trials by late 2003 [400846], [445166]. In February 2002, lucinactant was awarded Orphan Drug product designation in Europe for the treatment of ALI, which incorporates ARDS [440083]. By April 2001, Orphan Drug status in the US had been granted for lucinactant for MAS [301112], RDS and ARDS [404160]. The FDA also designated the drug a Fast Track product for the treatment of MAS [302120] and ARDS [301562], [302176], [404160].     

Tobramycin (Cystic Fibrosis Foundation/PathoGenesis)

TOBI, the inhalant formulation of the antibiotic tobramycin, is a clear, sterile, preservative-free, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed-air driven nebulizer. It was launched in the US in January 1998 for use in cystic fibrosis (CF) patients with chronic pulmonary Pseudomonas aeruginosa infections [315294]. In March 1998, PathoGenesis filed for approval in Canada for this indication, and the Health Protection Branch granted TOBI a Priority Review [281940]. The compound was approved in both Canada and Argentina in February 1999 1312484], and launched in these countries in May 1999 [324276], [326053]. It was approved in Israel in January 2000 [351769] and in Australia in February 2000 [356941] and launched in the two countries in August 2000 [396142]. In March 2000, PathoGenesis and AeroGen Inc agreed to collaborate on developing the use of AeroGen's AeroDose inhaler for the delivery of tobramycin. The aim is to reduce the delivery time from 15 to 20 min to 5 to 10 min. Phase I trials with the inhaler were planned for the second quarter of 2000 [358125] and the product is expected to be in phase III trials by 2002 [396509]. TOBI is also under investigation for the treatment of non-CF patients with lung infection. In June 2000, PathoGenesis initiated a phase II trial of TOBI in bronchiectasis patients with Pseudomonas lung infections to assess whether TOBI improves symptoms associated with severe bronchiectasis [372767].     

Ziconotide (Elan Pharmaceuticals)

Elan Pharmaceuticals (formerly Neurex) is developing ziconotide, a neuron-specific N-type calcium channel blocker, for the potential treatment of severe pain and ischemia. A US NDA for the use of the compound in intractable pain is under review [351606,357600] and phase III trials for ischemia are ongoing [261455,292579]. Elan received an approvable letter from the FDA for pain in June 2000, and by October 2000, was responding to questions raised by the FDA in the letter [372580,386279]. In December 2000, DRAXIS filed an NDS for ziconotide with the Therapeutic Products Programme of Health Canada [393773]. The drug has Priority Review status in Canada [387218]. PAIN: In pivotal studies, ziconotide showed a significant reduction in pain compared to placebo. In the two trials, completed by December 1999, more than 700 patients received the drug for the treatment of intractable pain intrathecally. This included patients who had failed morphine therapy, or who had become intolerant of therapy due to side-effects. The drug was safe and well tolerated over periods as long as 3 years [351606]. ISCHEMIA: Elan and Pfizer (formerly Warner-Lambert) are also developing ziconotide for the treatment of ischemia associated with head trauma and stroke [292579]. In September 1997, Neurex and Warner-Lambert restarted a pivotal phase III head trauma study with no changes in the study design. In July 1997, patient enrollment had been halted pending analysis of clinical data from earlier studies to determine the relative risk/benefits of administering ziconotide with the current protocol [261455]. By April 1999, Parke-Davis (now Pfizer) was also working on the development of nonpeptide analogs of ziconotide, with the aim of developing an orally available agent for the treatment of chronic pain [325613,324954]. In July 2000, Merrill Lynch predicted FDA approval and launch in the third or fourth quarter of 2000 [375966], but in January 2001, the prediction of approval was revised to be in 2001 [395423].     

Perospirone (Sumitomo Pharmaceuticals)

Perospirone is a serotonin 5-HT2 antagonist and dopamine D2 antagonist developed by Sumitomo Pharmaceuticals for the potential treatment of schizophrenia and other psychoses [381769]. Its receptor binding profile and animal pharmacology resemble those of other atypical antipsychotic agents, in particular risperidone. In November 2000, CPAC's First Committee on Drugs recommended the approval of this product in Japan, [394007]; approval was granted in December 2000 [396121]. In January 2001, the NHI price was agreed by the Chuikyo [398222] and the drug was added to the NHI price list in February 2001 13982261. It was finally launched in Japan on February 8 2001 [399401]. In November 2000, Sumitomo and Welfide signed an agreement whereby Welfide's subsidiary Yoshitomi Yakuhin will copromote perospirone [394007]. Based on data from the Chuikyo, peak sales of perospirone are forecast to be yen9 billion in the sixth year following launch [398222], [398226]. In February 2001, Sumitomo predicted that perospirone would reach sales of yen10 billion within five to six years [399401].     

Role of fomepizole in the management of ethylene glycol toxicity

OBJECTIVE: To systematically review English-language articles on fomepizole administration in patients with ethylene glycol poisoning. DATA SOURCES: MEDLINE, EMBASE, Current Contents, and PubMed. Search terms were fomepizole, 4-methylpyrazole, and ethylene glycol. The search was supplemented with a bibliographic review of all relevant articles. STUDY SELECTION: All published reports of fomepizole administration in patients with ethylene glycol poisoning were reviewed, irrespective of study design. We identified one clinical trial and subsequent pharmacokinetic study, one case series, and 13 case reports. RESULTS: Fomepizole has been investigated in 70 patients in open, unblinded studies. Most patients received an intravenous loading dose, with subsequent variable maintenance doses every 12 hours until plasma ethylene glycol levels became undetectable. Additional hemodialysis treatment generally was administered when patients had renal insufficiency or ethylene glycol levels above 50 mg/dl. Many patients had detectable ethanol levels either because of coadministration or as a result of adjunctive treatment at a referring center. Poorer patient outcomes, such as death and renal insufficiency, were associated with later clinical presentation time after ingestion. At therapeutic fomepizole levels (> 8.6 mg/ml), the half-life of ethylene glycol was prolonged to over 19 hours. Fomepizole appeared to be well tolerated by most patients. CONCLUSION: Fomepizole is an effective alcohol dehydrogenase inhibitor that decreases production of ethylene glycol metabolites. Reduced mortality and morbidity are undetermined because of the small number of patients evaluated to date. Data on comparative efficacy of fomepizole versus ethanol and data on administration of fomepizole in children are limited.     

OvaRex (AltaRex)

AltaRex is developing OvaRex (B43.13), a monoclonal antibody vaccine, for the potential treatment of ovarian cancer. Additionally, immunotherapy may be possible in other cancers expressing the CA125 antigen, such as breast and lung cancers. AltaRex plans to file a BLA for OvaRex with the FDA in late 2001 and for Canadian and European regulatory submissions thereafter, with possible commercialization in 2002 [365081,377828,398528]. In December 2000, AltaRex engaged US Oncology to participate in the company's phase II trial for the 'watchful waiting' stage of ovarian cancer. The US Oncology relationship will bring over 20 satellite sites to the OvaRex study, in addition to 13 sites that had already begun enrolling patients [394604,384676,365081]. In 1997, AltaRex commenced a multicenter, placebo-controlled, double-blind, randomized phase IIb trial in the US for advanced ovarian cancer [230067,331744,344248]. In the following year, AltaRex submitted the IND to the FDA for this trial [303667]. Complete analysis of the data is expected by the first half of 2001 [291312,310071,344248]. If an NDA is filed before the end of 2001, approval by mid-2002 is possible [344248]. OvaRex has been awarded Fast Track designation for advanced ovarian cancer [310071] and Orphan Drug status in the US [230067].     

Vardenafil Bayer Yakuhin

Bayer is developing vardenafil, an orally active phosphodiesterase (PDE) 5 inhibitor for the potential treatment of erectile dysfunction (ED) [314382]. NDAs were filed in September 2001 in the US and Mexico [423096], and vardenafil was submitted for Canadian approval in October 2001. As of November 2001, Bayer was expecting a response from the FDA in the second half of 2002 [429499]; the EMEA accepted a filing in January 2002, following a December 2001 submission [438163]. By October 2000, phase III trials were underway in Japan [384751] and by December 2001, a Japanese NDA had been filed; at the same time an application was filed in South Africa [426526], [433060]. At this time Japanese launch was expected in 2003 [434758]. By February 2001, Bayer was also investigating a nasal formulation of vardenafil for the potential treatment of erectile dysfunction [397608]. In November 2001, Bayer and GlaxoSmithKline signed a worldwide copromotion agreement for vardenafil, under which Bayer was to be responsible for all regulatory work required to obtain approval [429499]. In February 1999, Lehman Brothers predicted a 10% probability that vardenafil would reach the market, with launch in 2002. Peak Japanese sales of US$600 million were predicted for 2014 [319225]. In May 2000, Bayer predicted peak sales of Euro900 million [397137]. In July 2001, Lehman Brothers predicted a 75% chance that vardenafil would reach the market, and forecast peak sales of US $0.85 billion worldwide; the analyst also speculated that Bayer would seek a comarketing partner [414766].     

Pazufloxacin Toyama Chemical Co

Toyama Chemical Co Ltd is developing pazufloxacin (T-3761), an orally active synthetic quinolone antibiotic, which is awaiting registration following successful clinical trials that demonstrated its pharmacological similarities to tosufloxacin (Toyama Chemical Co) with respect to clinical efficacy, adverse effects and overall safety [272136]. As of June 2000, the company had filed an NDA for marketing approval in Japan [373027]. The company is also developing an injectable formulation, pazufloxacin mesylate (T-3762), which has entered phase III trials in Japan [228819]. There is a licensing agreement with Welfide Corp (formerly Yoshitomi/The Green Cross Corp) in Japan [228819].     

Exisulind Cell Pathways

Cell Pathways has developed exisulind (Aptosyn), an oral apoptosis modulator and cGMP phosphodiesterase inhibitor, for the potential treatment of several oncologic indications including precancerous adenomatous polyposis coli (APC), also known as familial adenomatous polyposis (FAP), precancerous sporadic colonic polyps, cervical dysplasia and the prevention of tumor recurrence in prostate and breast cancer. An NDA filing for the treatment of precancerous APC, for which the US FDA designated exisulind a Fast Track product in July 1998, was initially expected in March 1999 [291313]. However, in January of the same year the company stated that it anticipated a delay in the NDA filing. The decision was based on unsatisfactory phase III data [308912], [313124]. In June 1999, the company completed analysis of the phase III trial data [328000] and the NDA was submitted in August 1999. An NDA was accepted for review by the FDA in October 1999 for the treatment of APC [328000], [338007], [344721], after data from three additional trials were submitted to the FDA in support of the NDA. At this time phase II/III trials were also ongoing for prostate and breast cancer recurrence [287250], [326795]. Approval for the indication of FAP had been expected by the end of 2000 [365737] but in September 2000 the FDA completed its initial review and advised Cell Pathways that exisulind will not be approved at this time. Cell Pathways has received a 'non-approvable' letter and intends to advise the FDA of its intent to amend the NDA and to request a meeting to address the deficiencies in the NDA [383249], [383560]. The first of the three additional trials submitted to the FDA in October 1999 was a 6-month, open-label trial involving 48 of the patients who completed a phase II/III study of exisulind in early 1999. After 6 months of treatment with exisulind, 25 patients who had previously been taking placebo experienced a 50% reduction in polyp formation. The patients continuing treatment with exisulind exhibited a further 50% reduction from their already reduced rate of polyp formation [344991]. The second study was an extension study of 11 patients who participated in a 6-month, open-label, phase I/II, dose-ranging, safety and efficacy trial. As of October 1999, these patients were still on therapy and had been receiving exisulind for between 36 and 50 months. They had all experienced statistically significant reductions in polyp formation rates [344991]. The third study was a double-blind, placebo-controlled safety study of 26 patients. All patients exhibited a trend of reduced new polyp formation when compared to placebo. Exisulind was generally well-tolerated by all patients during the course of the studies [344991]. In July 2000, Cell Pathways signed a marketing and distribution agreement for Canada with Paladin Labs, allowing Paladin exclusive rights to commercialize exisulind within Canada [376072]. Also in July 2000, Cell Pathways announced that patents covering methods of identifying compounds that selectively stimulate apoptosis have been allowed in Europe and Japan. The patents describe the mechanism of action of Cell Pathways' SAANDs, including exisulind, and use of that knowledge in screening for new drugs [374888]. In January 1999, the company received US-05858694 covering the mechanism of action of exisulind [311504].     

American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee.

Fomepizole (4-methylpyrazole, 4-MP, Antizol) is a potent inhibitor of alcohol dehydrogenase that was approved recently by the US Food and Drug Administration (FDA) for the treatment of ethylene glycol poisoning. Although ethanol is the traditional antidote for ethylene glycol poisoning, it has not been studied prospectively. Furthermore, the FDA has not approved the use of ethanol for this purpose. Case reports and a prospective case series indicate that the intravenous (i.v.) administration of fomepizole every 12 hours prevents renal damage and metabolic abnormalities associated with the conversion of ethylene glycol to toxic metabolites. Currently, there are insufficient data to define the relative role of fomepizole and ethanol in the treatment of ethylene glycol poisoning. Fomepizole has clear advantages over ethanol in terms of validated efficacy, predictable pharmacokinetics, ease of administration, and lack of adverse effects, whereas ethanol has clear advantages over fomepizole in terms of long-term clinical experience and acquisition cost. The overall comparative cost of medical treatment using each antidote requires further study.     

Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone—A Viable Therapeutic Option

Fomepizole is used to treat and prevent toxicity from ethylene glycol poisoning. Treatment with fomepizole without hemodialysis in massive ethylene glycol ingestion has been rarely reported in the literature; however, published literature and practice guidelines recommend considering dialysis for ethylene glycol levels >50 mg/dL. We report a case of massive ethylene glycol ingestion resulting in the highest serum ethylene glycol concentration in a patient without ethanol co-ingestion who was treated with fomepizole and was not hemodialyzed. A 48-year-old male presented to the emergency department after reportedly ingesting >1liter of antifreeze in an attempt at self-harm. He denied concomitant ethanol consumption. His initial presenting serum ethylene glycol level was 700 mg/dL, with normal renal function, and a metabolic acidosis with a high anion gap. One hour after presentation, he was started on intravenous fomepizole. Treatment with fomepizole continued until the patient's plasma ethylene glycol concentration was 16 mg/dL. His metabolic acidosis quickly resolved, he had no adverse reactions to the treatment, and his renal function remained normal. Ultimately, he was discharged to a psychiatric unit without sequelae. Published literature and practice guidelines suggests considering hemodialysis initiation in patients with an ethylene glycol level >50 mg/dL. This recommendation is anecdotally, rather than evidence, based. With the potential risks inherent in hemodialysis, our case provides evidence that treatment with fomepizole without hemodialysis appears to be a viable alternative option in patients with even extremely high plasma ethylene glycol concentrations as long as their renal function is intact.     

AN-1792 (Elan)

Elan is developing AN-1792 as a potential immunotherapy for Alzheimer's disease (AD). It is currently in phase I trials [350904]. Phase II/III trials, running in parallel in the US and UK, are expected to start by the end of 2001 [375061], [383226], [401966]. American Home Products (AHP) are collaborating with Elan on research and development of an immunotherapy directed towards the beta-amyloid peptide, including AN-1792 and other potential products [361702]. In September 2000, an agreement was established between Elan, AHP and Cambridge Antibody Technology (CAT), whereby CAT are investigating anti-beta-amyloid human antibodies [394844]. In July 2000, Merrill Lynch predicted a possible late-2001 entry into pivotal trials with a potential NDA filing in 2004 [375966]. The clinical program is expected to take approximately four years [339630]. In April 2001, ABN Amro Hoare Govett stated that, if data from the large phase II trial expected to start late in 2001 satisfied FDA requirements, then Elan might be able to file an NDA in 2003, with a potential launch in 2005 [407412].