Rifamycin derivatives

Chemical Properties and Derivatives, There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader... 

Rifampicin, the only commercially available ansamacroHde, is manufactured by MerreU Dow under the tradename Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also suppHed in combination with isoniazid or pyrazinamide [98-96-4]. The rifampicin—isoniazid combination is known as Rifamate (MerreU Dow), Rifinah (MerreU Dow), and Rimactazid (CIBA) the rifampicin—pyrazinamide as Rifater (MerreU Dow). Several other rifamycin derivatives including rifabutin and rifapentine are undergoing clinical studies. 

In order to overcome the limitations of the above drugs, a series of rifamycin derivatives with improved pharmacokinetic (i.e. virtually absence of GI absorption) and pharmacodynamic (i.e. with broad spectrum of antibacterial activity) properties have been synthesized at Alfa Wassermann laboratories [33]. Amongst the different molecules, the compound marked L-105 and later... 

The first study was performed by Venturini [97, 98] in both rats and dogs by using a microbiological assay (i.e. agar diffusion test and S. aureus 209 P FDA as test organism). Conversely from rifampicin, whose serum levels were already detectable 30 min after the administration and still measurable after 48 h, only trace amounts (i.e. 0.2 pg/ml) of rifaximin were detected in serum of fed rats 4 h later (fig. 6). The amount of detectable antibiotic was reduced by 50% in fasted animals. Similar results have been obtained in dogs after oral administration of 25 mg/ kg of both rifamycin derivatives [97, 98], No detectable amount of rifaximin was found in serum at any time. 

The effect of rifaximin on cardiovascular (CY) and respiratory systems was investigated in anesthetized rats and guinea pigs, respectively [59]. Rifaximin was given intraduodenally at doses up to 100 mg/kg and carotid pressure and flow as well as heart rate were continuously measured in rats while respiration amplitude and frequency were monitored in guinea pigs. The rifamycin derivative did not affect any of the measured parameters at any time after its administration. 

Hoover WW, Gerlach EH, Hoban DJ, Eliopou-los GM, Pfaller MA, Jones RN Antimicrobial activity and spectrum of rifaximin, a new topical rifamycin derivative. Diagn Microbiol Infect Dis 1993 16 111-118. 

Berti T, Benoni G, Miglioli PA, Velo GP Intestinal antibacterial activity of a new rifamycin derivative Compound Ul05. Chemioterapia (Florence) 1982 l(suppl4) 106A. 

Pelosini I, Scarpignato C Rifaximin, a peculiar rifamycin derivative Established and potential clinical use outside the gastrointestinal tract. Chemotherapy 2005 51(suppl 1) 122— 130. 

Alvisi V, D Ambrosi A, Loponte A, Pazzi P, Greco A, Zangirolami A, Palazzini E Rifaximin, a rifamycin derivative for use in the treatment of intestinal bacterial infections in seriously disabled patients. J Int Med Res 1987 15 49-56. 

Rifaximin is a synthetic rifamycin derivative, which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis [48]. It is virtually unabsorbed after oral administration and is, therefore, used primarily to treat gastrointestinal infections. Rifaximin possesses a broad spectrum of antimicrobial activity, covering Gram-positive and Gram-negative bacteria, both arerobic and anaerobic [49], Several studies [44, 49-62] have shown that in patients with HE rifaximin displays an efficacy similar to that of lactulose and neomycin (table 1). A recently published study [62] compared the efficacy and safety of... 

An increasing number of both clinical and laboratory-derived observations support the importance of luminal components in driving the inflammatory response in ulcerative colitis and Crohn s disease. Although its role is unclear, antibiotic therapy is commonly used in clinical practice for the treatment of moderately to severely active ulcerative colitis. Metronidazole and/or ciprofloxacin are currently employed in active Crohn s disease, particularly in patients with colonic involvement and with perianal disease. Rifaximin, a rifamycin-derived antibiotic, is characterized by a wide range of antibacterial activity and a very low systemic absorption. Some preliminary data show its efficacy in severe active ulcerative colitis, pouchitis and prevention of postoperative recurrence in Crohn s disease. 

Rifaximin, a Peculiar Rifamycin Derivative Established and Potential Clinical Use Outside the Gastrointestinal Tract... 

Rifaximin, a virtually nonabsorbed antibiotic, is a semisynthetic rifamycin derivative, with a broad antimicrobial spectrum that includes most Gram-positive and Gram-negative bacteria, both aerobes and anaerobes [1, 2], Unlike systemically available antibiotics, this antimicrobial allows localized targeting (e.g. enteric or cutaneous) of pathogens and is associated with a minimal risk of systemic toxicity or side effects [3, 4], Provided that nonabsorbed antibiotics are as effective as systemically absorbed drugs for the target illness, their safety and toler-... 

Lounis N, Roscigno G. (2004) In vitro and in vivo activities of rifamycin derivatives against mycobacterial infections. Curr Pharm Des 10 3229-3238. 

Pharmacology Rifapentine is a rifamycin-derivative antibiotic and has a similar profile of microbiological activity to rifampin. 

Among the antimycobacterials often a differentiation is made between first-choice and second-choice agents. The first-choice agents include iso-niazid, rifampicin, ethambutol, pyrazinamide and streptomycin or as alternatives the other aminoglycosides amikacine or kanamycine. The second-choice agents include the quinolones ciprofloxacin and ofloxacin and also the rifamycin derivative rifabutin. 

Chemical Properties and Derivatives. There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader-spectrum antibiotic having good oral absorption. Rifamycins B, O, and S have served as starting materials tor the preparation of numerous classes of derivatives. Several of the semisyntheUc derivatives are more active, have a broader spectrum of biological activity, and are therapeutically more effective than the parent antibiotics. 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

Meilhac, M., Typser, Z Chambon, P. Animal DNA-dependent RNA polymerases. 4. Studies on inhibition by rifamycin derivatives. Europ. J. Biochem. 28, 291 (1972)... 

Busiello, E., di Girolamo, A., di Girolamo, M., Fischer-Fantuzzi, L., Vesco, C. Multiple effects of rifamycin derivatives on animal-cell metabolism of macromolecules. J. Europ. Biochem. 35, 251 (1973)... 

Kobayashi, G.S., Cheung, S.C., Schlessinger, D., Medoff, G. Effect of rifamycin derivatives, alone and in combination with amphotericin B, against Histoplasma capsulation. Antimicrob. Ag. Chemother. 1974, 16... 

Szabo, C., Bissell, M.J., Calvin, M. Inhibition of infectious rous sarcoma virus production by a rifamycin derivative. J. Virol. 18, 445 (1976)... 

Pennington, T.H., Follett, E.A.C. Inhibition of pox virus maturation by rifamycin derivatives and related compounds. J. ViroL 7, 821 (1971)... 

Grimley, P.M., Moss, B. Similar effect of rifampin and other rifamycin derivatives on vaccinia virus morphogenesis. J. Virol. 8, 225 (1971)... 

Since none of the compounds at the concentrations used showed a complete supression of splenomegaly, one would expect a residual viral activity in spleen extracts of mice, which received FLV suspensions preincubated with these compounds. Studies are now in progress to evaluate the leukemogenic activity of cell-free spleen extracts, prepared from mice inoculated with pretreated suspensions. Wu etal.63 have carried out such studies with RLV and rifamycin derivatives. They reported that the inoculation of mice with inocula from mice infected with RLV pretreated with AF-ABDP and AF/DNF1 did not cause splenomegaly. 

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