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].

Common ground in therapy of substance abuse.

Literature concerning the treatment and basis of substance abuse includes large contributions from clinicians and psychologists. Reviews of pharmacotherapies for substance abuse usually classify therapies on a clinical or behavioral basis and this is often complicated by the variety of abused substances and the multiple uses to which individual therapies are put. In contrast, this review looks at products from a pharmacological perspective and identifies common ground evident in pharmacotherapies for all substance abuse. A simple working framework for classifying approaches to drug development is suggested, and four distinct pharmacological approaches applicable both to established and potential products are identified.

AD-5423 Dainippon Pharmaceutical Co Ltd.

AD-5423, a D(2)/5-HT2 antagonist, is in phase II clinical trials by Dainippon for the treatment of schizophrenia and other psychoses. In a phase I study of AD-5423 in eight healthy volunteers, it appeared to be well-tolerated and failed to induce extra pyramidal side effects, excessive sedation or hypotension [181465]. Analysts at Yamaichi estimate that AD-5423 will be launched in Japan in 1999 and annual sales will be less than five billion Yen [216018].

Glycine absorption from the small intestines of rats after secondary infections with Eimeria nieschulzi.

A second (challenge) infection of Eimeria nieschulzi in clinically immune rats did not produce weight gain depression but caused a decrease in the absorption of glycine from the ileum. The malabsorption due to challenge was equivalent to that caused by the primary infection which did cause weight loss.

Intestinal absorption studies with glycyl-proline, glycine and ethanol in rats infected with Eimeria nieschulzi.

The absorption of glycyl-proline, glycine, and ethanol through the intestinal wall was studied in vitro by an everted sac technique in rats infected with the coccidial parasite Eimeria nieschulzi which causes damage and atrophy to the intestinal villi. The absorption of the dipeptide and of the amino-acid was reduced through tissue from infected animals but the transport of ethanol was similar in both infected and uninfected rats. The replacement of sodium by potassium in the mucosal bathing fluid as well as the separate addition of the metabolic inhibitors, potassium cyanide and dinitrophenol, reduced the amount of amino-acids transferred in both the infected and uninfected tissue in a similar proportion. The results support the conclusion that infection by the parasite affects several different elements of transport across the ileal wall but does not selectively reduce any single one.

Absorption of glycine and proline from the small intestine of rats infected with Eimeria nieschulzi.

The absorption of glycine and proline through the jejunum and ileum of rats with an Eimeria nieschulzi infection was impaired when the amino acids were presented to the mucosal surface as either a mixture or the dipeptide, glycyl-proline.

Studies on the in vitro metabolism of dimethylnitrosamine by rat liver.

The biotransformation of dimethylnitrosamine (DMN) to formaldehyde, generally attributed to the mediation of a demethylase enzyme associated with the microsomal mixed function oxidase system, has been investigated in rat liver preparations. All of the enzyme activity was found in the postmitochondrial fraction and the microsomes contained approximately 50% of this activity. The restoration of total activity resulting from the addition of the cytosol to the microsomal fraction was found to be due to presence of diffusible, heat-labile constituents in the cytosol. Enzyme kinetic studies revealed that DMN was metabolized to formaldehyde by either a multistep or a multicomponent process. DMN demethylase was found to be relatively stable to storage in contrast to cytochrome P-450 and a number of mixed function oxidase enzyme activities. In spectral interaction studies DMN was found to form an atypical interaction spertrum with either control, phenobarbitone-pretreated or phospholipid-depted microsomal preparations. DMN had little effect on Type II spectral interaction of aniline, but noncompetitvely inhibited the Type I spectral interaction of benzphetamine and biphenyl. Whilst the mixed function oxidase enzyme inhibitors SKF 525A and metyrapone markedly reduced the metabolism of ethylmorphine and anailine, DMN demethylase was little affected by the former compound and appreciably enhanced by metyrapone. Moreover, DMN demethylase was strongly inhibited a number of hepatic mixed function oxidases, but significantly reduced anaerobic nitroreductase activity. The results of these studies reveal important differences between the properties of the enzymatic systems which metabolize DMN and mixed function oxidase substrates, and are consistent with the conclusion that the degradation of DMN to formaldehyde by rat liver preparations is a multicomponent system not rate limiting with respect to cytochrome P-450.