Case reports from the WHO ADR database, including index cases involving four out of five PPIs, along with evidence of a possible mechanism, provide compelling evidence that there is a causal association between members of the PPI drug class and myopathy including polymyositis. Evidence was also obtained to support the view that PPI use may be associated with occurrence of other myopathies, including the serious reaction rhabdomyolysis.
The clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow - and possibly intermediate - acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes. Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable. If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy. Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype - especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fa
Our model suggests that both MTX and AZA may generate significant net cost savings and benefits for patients with IBD in New Zealand, with AZA likely to be more cost effective than MTX. Prospective testing for poor metabolisers of AZA may also be cost effective, with phenotype testing likely to be more cost effective than genotype testing.
Summary1. In newborn rats treated with 6-hydroxydopamine hydrobromide (6-OHDA) (50-150 mg/kg on 5-7 days) a widespread and long-lasting dose related sympathectomy was demonstrated. 2. When rats given 6-hydroxydopamine (100 mg/kg, seven treatments) in the neonatal period were killed at 10 weeks the concentration of noradrenaline (NA) in the heart, mesentery and vas deferens was significantly reduced. There was no alteration in the catecholamine content of the adrenal glands. 3. The amplitude of the responses of perfused mesenteric arteries from 6-hydroxydopamine treated rats to intra-arterial noradrenaline was not increased, compared with controls, but the duration of responses was increased. 4. 6-Hydroxydopamine given to newborn rats caused a long-lasting depletion of noradrenaline in three of the five regions of the central nervous system (cortex, cerebellum and spinal cord) studied. The concentration of noradrenaline in the pons-medulla was increased, but in the thalamic region was unchanged. The treated rats showed significantly lower exploratory activity. 5. Treatment of newborn rats with 6-hydroxydopamine thus has striking and long-lasting effects on peripheral and central adrenergic systems.
This study provides weak evidence to support the hypothesis of a link between SSRIs and precipitation of bleeding events at a population level. The 95% CI is consistent with a possible risk of bleeding associated with SSRI users versus non-psychiatric drug users in the first month. Fuller consideration of confounding would be possible using follow-up of identified cases in a nested case-control study.
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