Time for a refrigerated drug to break down

[Middleway]

I have just gone back onto Nardil. It states it needs to be refrigerated between 2 and 6 degrees c. How long do you think it would take to begin to decompose? As a side note. Nardil never used to be refrigerated, it was only after they reformulated it a few years back (and according to many on the internet screwed up its effectiveness) that this has needed to be done. Any ideas on why a stable molacule could be made unstable?

 

[sunyata]

your question would better answered if your thread title was less ambiguous. Be specific like: "drug name + storage conditions?"

 

[vecktor]

This is speculation:
Nardil (phenelzine) is a alkyl hydrazine derivative and is in the form of a sulphate salt, in this form most hydrazines reasonably stable though they do oxidise slowly. I have seen 40+ year old hydrazinium sulfate stored at room temperature in a sealed bottle, still as good as new.

Freebase hydrazines are much less stable to air so the problem could possibly be that the new formulation allows the formation of small amounts of freebase or allows air into the formulation, there are reports of unpleasant smells developing on storage, which suggests that there is the formation of freebase.
Also the old formulation was protected from air oxidation by the coating the new one isn't.

So if the new formulation allows decomposition it is not a matter of how long before it decomposes rather how quickly and how much decomposes. At 5oC it decomposes 4 times more slowly than at room temperature.

Pfizer screwed up with Nardil, but now they cannot go back to the old formulation without admitting they screwed up with the new formulation and so open themselves to a class lawsuit. I would thinbk Pfizer wants this drug to disappear as it is hardly lucrative.

I guess Nardil works but hydrazines worry me and I wouldn't choose to ingest one.

 

[Middleway]

Why do they worry you? Hypertensive crisies?

 

[MurphyClox]

Why do they worry you? Hypertensive crisies?

I know that this question was directed to Vecktor, but let me answer anyway: Hydrazines are usually not the healthiest compounds. The parent, unsubstituted hydrazine itself, is highly toxic and carcinogenic. The carcinogenic properties were confirmed for single-substituted derivates as well, like monomethylhydrazine, and it is quite likely that a phenethyl wouldn't make such a big difference.
Also, the terminal nitrogen is quite a strong nucleophil and will react with a diversity of substrates, including enzymes of all kind. These reactions proceed (of course!) quite unselective. Another good reason to worry about.

Peace! Murphy

Edit: Here is an abstract with some more in-depth details about phenelzine:

"Effects of hydrazine, phenelzine, and hydralazine treatment on rat hepatic and renal drug-metabolizing enzyme expression."
Drug Metabolism and Disposition 1996, 24(7), p.734

Abstract

The hepatic and renal toxicity assocd. with hydrazine treatment has been linked to free radical damage resulting from oxidative metab. by cytochrome P 4502E1 (CYP2E1). Despite this assocn., there has been little characterization of the effects of hydrazine treatment on the expression of hepatic and renal CYP2E1 or glutathione-S-transferase-.alpha. (GST-.alpha.), an enzyme responsible for catalyzing the conjugation of free radicals with reduced glutathione. Therefore, the effects of treatment with hydrazine or one of the therapeutic hydrazines phenelzine and hydralazine on rat hepatic and renal CYP2E1 and GST-.alpha. expression were investigated. Adult male Sprague-Dawley rats were treated with 0.9% saline vehicle (1 dose i.p.), hydrazine (100 mg/kg i.p.), phenelzine (100 mg/kg i.p.), or hydralazine (25 mg/kg i.p.). CYP2E1 mRNA and protein levels were monitored by Northern and immunoblot analyses, resp., and GST-.alpha. Ya and Yc subunit levels were detd. by immunoblot anal. Hydralazine administration caused a significant (.apprx.159%) increase in renal GST-.alpha. Yc subunit expression. In addn., hydrazine and phenelzine treatment produced substantial elevations (.apprx.464% and 566%, resp.) in renal CYP2E1 protein, whereas hydralazine administration did not alter renal CYP2E1 expression. Changes in rat hepatic GST-.alpha. Ya or Yc subunit levels after treatment with hydrazine, phenelzine, or hydralazine were not statistically significant. Similarly, hepatic CYP2E1 levels were not significantly altered after treatment with hydrazine, phenelzine, or hydralazine. Northern-blot anal. revealed that the obsd. increases in renal CYP2E1 protein levels after treatment with hydrazine or phenelzine were not accompanied by concomitant increases in CYP2E1 mRNA. These results suggest that treatment with hydrazine or the therapeutic hydrazine phenelzine significantly increases the expression of rat renal CYP2E1 protein, and that the mol. mechanisms responsible for these effects are posttranscriptional in nature.

 

[Middleway]

I am not going to pretend to have a great grasp of biology but is there any reason why I should be more frightened of Hydrazines compared to say Nitrosamines which I also ingest daily in the form of smoked meat etc?
These studies say not. This is a massively life enriching drug for me despite all its shitty side effects, I would hate to give it up.
If it is genuinely a dangerous molacule are antioxidents enough to offset any risk?
Thanks BL'ers

Carcinogenicity has been observed in mouse studies but not in the rat. This is consistent with tumour and mutagenicity data reported for the MAO inhibitor, isoniazid.A group of 50 male and 50 female random-bred Swiss mice, 6 weeks of age, were given 0.015% phenelzine sulfate in the drinking water for their lifetime. An untreated group of 200 mice served as controls. Of the treated group, pulmonary tumours developed as follows: 38% adenomas, 7% adenomas and adenocarcinomas, and 1% adenocarcinomas). This compared to the pulmonary tumour incidence in the untreated group of 14% adenomas, 3% adenomas and adenocarcinomas, and 5% adenocarcinomas. Of the mice in the treated group 26% developed vascular tumours compared to 5% in the untreated group.An 87 week study of 26 male Sprague-Dawley rats, fed diets of phenelzine to evaluate carcinogenesis reported no significant difference in the incidence of both colonic and small intestinal adenocarcinomas between the phenelzine treated group (n=13) and matched controls (n=13).In the Salmonella typhimurium DNA reversion (Ames) test, phenelzine sulfate was a weak inducer of base-pair mutations in the absence of metabolic activation by rat liver homogenate. Results obtained in the pol A+/A- DNA reversion test in Escherichia coli report phenelzine sulfate as reactive against DNA. Similarly, phenelzine sulfate has been reported to inactivate Bacilus subtilis plasmid DNA.There is insufficient evidence to assess the carcinogenicity of phenelzine sulfate in humans

Action of hydrazine drugs in tumor-free and 1,2-dimethylhydrazine-treated male rats.Gershbein LL, Rao KC.
Biochemistry Section, John F. Kennedy Health Care Corporation, Chicago, IL 60634.

In order to evaluate possible carcinogenesis, young adult male Sprague-Dawley rats were fed diets of hydralazine, phenelzine, and isoniazid at levels of 0.020-0.035% for 87 weeks. Hydralazine and isoniazid were also tested by the subcutaneous (sc) route at weekly dosages of 17 and 83 mg/kg, respectively, in both intact and partially hepatectomized rats, but many succumbed after 7 to 49 weeks of treatment. Gastrointestinal lesions were absent and, of the miscellaneous changes, sc lesions occurred sporadically among the control and drug-treated groups. As a further criterion, male weanlings were placed on the diets and, starting on day 15, 1,2-dimethylhydrazine (DMH) was injected sc at 9.0 mg/kg once weekly for the first 7 weeks and twice per week for a total of 23 treatments. The rats were killed 22 weeks after the last injection, at which time colon adenocarcinomas were observed in over 80% per group, the total number being significantly greater for the isoniazid group due to heightened tumor occurrence at the distal colon. The tumor number in the descending colon for phenelzine was also increased but the overall score, as with the hydralazine group, was in the range of the DMH injected controls. Small intestinal adenocarcinomas were lower in number and involved fewer rats on the hydralazine and phenelzine diets as compared to the isoniazid and control groups. Based on the current data, it is concluded that on long term exposure of DMH treated rats to the monoamine oxidase inhibitors, hydralazine and phenelzine are not cocarcinogenic, whereas isoniazid enhances colon carcinogenicity.(ABSTRACT TRUNCATED AT 250 WORDS)

 

[Middleway]

Mod, could you please change title to reflect the change in discussion, Maybe " Possible carcinogenicity of nardil and time for decomposition at room temperature" thanks