Isoniazid release

Hsu Y-Y, Gresser JD, Stewart RR et al (1996) Mechanisms of isoniazid release frtnn poly (d, L-lactide-co-glycolide) matrices prepared by dry-mixing and low density polymeric foam methods. J Pharm Sci 85 706-713... 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

G. Raghupati Sarma, I. Chandra, S. Kailasam, A. S. L. Narayana, P. Venkatesan, Rifampin-Induced Release of Hydrazine from Isoniazid , Am. Rev. Respir. Dis. 1986,133, 1072-1075. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Stavudine NRTI1 Immediate release 30-40 mg bid, depending on weight3 Peripheral neuropathy, lipodystrophy, hyperlipidemia, rapidly progressive ascending neuromuscular weakness (rare), pancreatitis Avoid concurrent zidovudine and neuropathic drugs (eg, ddl, zalcitabine, isoniazid)... 

Figure 7.24 Metabolism of isoniazid. The acetylhydrazine released by the hydrolysis of acetylisoniazid is further metabolized to a reactive intermediate thought to be responsible for the hepatotoxicity.

Both of these wonder drugs boost the synaptic efficacy of norepinephrine and serotonin, but they do so in quite different ways. Isoniazid blocks the action of the amine degrading enzyme monoamine oxidase, allowing the released amines to stay longer in the synaptic cleft (because they are... 

The classical model of drug metabolism by acetylation is the tuberculostatic drug isoniacide (isonicotinic acid hy-drazide). The metabolism of isoniazide has two interesting aspects Firstly, non-enzymatic hydrolysis of the acetyl metabolite releases acetylhydrazine, which in turn is toxic. This, then, is an example of detrimental drug metabolism (Figure 2.30a, b). 

Peretti E, Karlaganis G, Lauterburg BH. Increased urinary excretion of toxic hydrazino metabolites of isoniazid by slow acetylators. Effect of a slow-release preparation of isoniazid. Eur J Clin Pharmacol 1987 33 283-6. 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

On her release from hospital, the patient is advised not to rely solely on oral contraceptives to avoid pregnancy since they may be less effective while she is being maintained on antimycobacterial drugs. The agent most likely to interfere with the action of oral contraceptives is (A) Ethambutol Isoniazid Pyrazinamide Rifampin Streptomycin... 

Isoniazid may increase the metabolism of enflurane, isoflurane or sevoflurane in some patients (probably related to isoniazid acetylator phenotype ) and so increase the release of fluoride ions that may cause nephrotoxicity. However, there do not appear to be any reports of a significant clinical effect on renal function. 

Figure 22 Drug-release profile of isoniazid from multiple emulsion based on imi/oligo/droplet internal phase. (From Ref 57.)...

Warrington and Olivier (1979) examined the release of lymphotoxin from the lymphocytes of the peripheral blood in patients with hepatitis after isoniazid. In five of six cases there was support of release of lymphotoxin after stimulation of these lymphocytes with isoniazid or isonicotinic acid conjugated with human serum albumin. Baker et al. (1974) had positive results from the macrophage migration inhibition test in only two of six patients after clinical hypersensitivity to isoniazid. 

Stronger than the polarity of the ether and the ketonic oxygen in PEO and PCL respectively, the H-bonds within PEO and PCL can be cleaved easily and the drugs can be released simply out of nanofibers. Results also demonstrate that clarithromycin and streptomycin show observable activity on M. avium confirmed by the formation of clear inhibition zones (Figure 11.12). For isoniazid, M. avium shows some resistance against it. The resistance against isoniazid is indicated by formation of bacterial colonies in the inhibition zone around the sample. Pyrazinamide showed no activity on M. avium either released from PEO or PCL matrix (this is discussed in the next section). 

Variations in drug concentration from 0.1 to I percent, and chitosan membrane thicknesses of 40 to 150 micron were used in the study of the permeabilities of isoniazid and amitriptyline hydrochloride. No changes in release rate (measured by ultraviolet spectrophotometric determination) into water were observed with either concentration or membrane thiekness, but rates for the two drugs were very different and were related to the respective molecular weights of the materials. 17 refs. BRAZIL... 

Blends of chitosan and PEG were prepared and characterised for controlled release of drugs. Structural studies of beads were performed using FTIR and SEM. The swelling behaviour, solubility, hydrolytic degradation and loading capacity of the beads for isoniazid were investigated. 25 refs. 

Kajjari, P. B., Manjeshwar, L. S., Aminabhavi, T. M. (2012). Novel pH-and temperature responsive blend hydrogel microspheres of sodium alginate and PNIPAAm-g-GG for controlled release of isoniazid, AAPS PharmSciTech, 13,1147-1157. 

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