Rifampicin inhibitors

Rifampicin has also shown antiviral activity but at levels 500—1000 times greater than required for antibacterial activity (130,140—142). Rifampicin shows promise in the treatment of leprosy (130,143). A large number of rifampicinlike derivatives are potent inhibitors of reverse transcriptase (123,144-148). 

Transcriptional inhibitors could be used simultaneously. Rifampicin blocks chloroplast and mitocondrian RNA synthesis [23, 24], while tagetitoxin is a very specific inhibitor of chloroplast RNA polymerase [25]. Treatment with these antibiotics does not inhibit Rubisco SSU synthesis since the promoter is part of the nuclear genome, while the cytosolic ribosomes are not affected by streptomycin. Therefore SSU promoters can be used to drive transgene expression and facilitate the accumulation of recombinant proteins. Expressed proteins are targeted to a suitable cellular compartment, such as the cytoplasm, apoplastic space or chloroplast, depending on the nature of the protein. 

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. 

Most ARVs available for adults are also available for children with specific child formulations including dosages that are based on either body surface area or weight. First-line treatment options for children include ZDV/3TC plus either a non-nucleoside (NVP or EFV) or ABC. EFV cannot be used in children under the age of 3 years due to lack of appropriate dosing information. However, EFV would be the non-nucleoside of choice in children on rifampicin, in case ARV needs to start before anti-tuberculous therapy is completed. Second-line therapy for children in the event of first-line regimen failure would include a change in nucleoside backbone (e.g., from ZDV + 3TC to d4T + ddl) plus a protease inhibitor. 

Protease inhibitors Use in combination with rifampicin Comments... 

Beta-blockers interact with a large number of other medications. The combination of beta-blockers with calcium antagonists should be avoided, given the risk for hypotension and cardiac arrhythmias. Cimetidine, hydralazine, and alcohol all increase blood levels of beta-blockers, whereas rifampicin decreases their concentrations. Beta-blockers may increase blood levels of phenothiazines and other neuroleptics, clonidine, phen-ytoin, anesthetics, lidocaine, epinephrine, monoamine oxidase inhibitors and other antidepressants, benzodiazepines, and thyroxine. Beta-blockers decrease the effects of insulin and oral hypoglycemic agents. Smoking, oral contraceptives, carbamazepine, and nonsteroidal anti-inflammatory analgesics decrease the effects of beta-blockers (Coffey, 1990). 

It is similar to rifampicin and shows significant activity against M. tuberculosis, M. avium complex and M. fortuitum. Rifabutin is both substrate and cytochrome 450 enzyme inducer. Because it is less potent inducer, rifabutin is used (in place of rifampicin) for the treatment of tuberculosis in HIV-infected patients, who are on concurrent antiretroviral therapy with a protease inhibitor. It is used alone or in combination with pyrazi-namide. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Bidstrup TB, Stilling N, Damkier P, Scharling B, Thomsen MS, Brpsen K. Rifampicin seems to act as both an inducer and inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 2004 60 109-14. 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

A high-throughput assay for bacterial RNA polymerase has been successfully developed and validated using a 96-well, automated format [70], The reaction mixture contained a DNA template, nucleotide substrates (NTPs), supplemented with a-33P-labeled CTP in Tris-acetate buffer (pH 6.8). The polymerase reaction was carried out at 34°C for 40 min (providing linear kinetics). The effect of dimethylsulfoxide (DMSO), the usual solvent for test compounds used in a screen, was taken into consideration. The radiolabeled RNA transcripts were allowed to bind diethyl aminoethyl (DEAE) beads, which were then separated via filtration, and radioactivity associated with the wells was quantitated to measure the RNA polymerase activity. The standard deviation of the measured activity was typically < 15% of the average. Use of this assay to screen for RNA polymerase inhibitors from chemical libraries and natural products led to the identification of DNA intercalators (known to inhibit RNA polymerase activity), rifampicin (a known inhibitors of RNA polymerase), and several derivatives of rifampicin from Actinomycetes extracts. Therefore this assay can be reliably utilized to detect novel inhibitors of bacterial RNA polymerase. 

First, the a subunit is needed for promoter binding and the formation of an open promoter complex. Subsequent to this, the /3 subunit (which will bind the inhibitor rifampicin) is essential for the formation of the first phosphodiester bond. 

The bacterial RNA polymerase inhibitors rifampicin and streptolydigin each bind to the same subunit of the enzyme, but their overall effect on the enzyme s activity is different. Why is this so ... 

Each of these inhibitors binds exclusively to the /3 subunit of RNA polymerase. This subunit is involved in both initiation and elongation of RNA chain growth. Rifampicin must bind to the subunit in a way that affects only the initiation step it has no effect on elongation. Streptolydigin, on the other hand, binds in a manner that blocks both activities. 

Isoniazid can cause convulsions and therefore should be prescribed with caution in patients with epilepsy. Isoniazid is an enzyme inhibitor and may increase carbamazepine levels. Rifampicin is an enzyme inducer and may decrease carbamazepine levels. 

An important family of inhibitors of procaryotic RNA synthesis are the antibiotics of the ansamycin series whose prototype is rifampicin. It inhibits bacterial RNA synthesis at the extremely low concentration of 0.01 Mg/ml (1.4 x 10-8 M) by binding to bacterial RNA polymerase35. ... 

Rifampicin was first shown by Hartmann et al. 54 to have a specific inhibitory effect on RNA polymerase from E. coli. Later, other active ansamycins were found and RNA polymerases from a large variety of bacteria other than E. coli proved to be sensitive to the drug. More recently, an RNA polymerase from E. coli containing only one subunit and probably involved in the initiation of DNA replication (dna G gene product) has been shown to be resistant to rifampicin5 s This holds true also for the various mammalian RNA polymerases. In contrast to non-specific inhibitors of transcription such as actinomycin and mitomycin, rifampicin interacts specifically with the bacterial enzyme itself. With the aid of 14C-labelled rifampicin it could be shown that the drug forms a very stable complex with the enzyme in a molar ratio of 1 1S6> 57 The dissociation constant of this complex is 10-9 M at 37 °C and... 

Itraconazole, an inhibitor of CYP3A, and rifampicin, an inducer of CYP3A, altered the pharmacokinetics and pharmacodynamics of oral midazolam in nine healthy volunteers (54). The half-life was prolonged from 2.7 to 7.6 hours by itraconazole and reduced to 1.0 hour by rifampicin. These effects were still present, although less marked, at 4 days after withdrawal of itraconazole and rifampicin. Similarly, after acute administration, the period of drowsiness was increased from 76 to 201 minutes with itraconazole and fell to 35 minutes with rifampicin the effects were again less marked 4 days after withdrawal. 

ACE INHIBITORS RIFAMPICIN 1 plasma concentrations and efficacy of imidapril and enalapril Uncertain. 1 production of active metabolites noted despite rifampicin being an enzyme inducer Monitor BP at least weekly until stable... 

RIFAMPICIN PROTEASE INHIBITORS 1 levels of protease inhibitor. Risk of hepatotoxicity with saquinavir Induction of metabolism Avoid co-administration... 

Many antibiotics are highly specific inhibitors of biological processes. Rifampicin and actinomycin are two antibiotics that inhibit transcription, although in quite different ways. Rifampicin is a semisynthetic derivative of rifamycins, which are derived from a strain of Streptomyces. 

Interactions. Involvement of protease inhibitors with the cytochrome P450 system provides scope for interaction with numerous substances. Agents that induce P450 enzymes (e.g. rifampicin, St John s wort) accelerate their metabolism, and reduce plasma concentration enzyme inhibitors (e.g. ketoconazole, cimetidine) raise their plasma concentration competition with other drugs for the cytochrome enzymes can lead to variable results. Ritonavir is itself a powerful inhibitor of CYP 3A4 and CYP 2D6. This effect is utilised when ritonavir in small quantity is combined (in capsules) with lopinavir to inhibit its metabolism and increase its therapeutic efficacy. The present account should be sufficient to warn the physician, and thereby the patient, to take particular heed when seeking to co-administer any drug a with protease inhibitor. 

---