In treatment of hepatitis

Disis ML, Feld JJ Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005 436 967. 

L. Clinical effects of a sorbent suspension dialysis system in treatment of hepatic coma (the Biologic-DT). Intern. J. Artif. Org. 1992 15 151-161... 

Clinical use and toxicity Ribavirin is used in aerosol form for respiratory syncytial virus infections. Early intravenous administration decreases mortality in Lassa fever and other viral hemorrhagic fevers. Ribavirin has recently been shown to have efficacy in treatment of hepatitis C viral infections. Aerosol ribavirin may cause conjunctival or bronchial irritation. Systemic use results in dose-dependent myelosuppression. Ribavirin is a known human teratogen. absolutely contraindicated in pregnancy. 

After the initial experience in treatment of hepatic tumours, RF ablation (RFA) was approved as a tissue-sparing, minimally invasive tool for successful tumour eradication resulting in satisfactory survival times in tumours of the kidneys and adrenals, of the lungs, bones, and soft tissue - comparable to surgery even considering the different selection criteria. 

Ash SR. Powdered sorbent hver dialysis and pheresis in treatment of hepatic failure. Ther Apher 2001 5 404-16. 

Cytokines and biological response modifiers represent a broad class of therapeutic agents that modify the hosts response to cancer or cancer therapies. The enormous body information about their clinical uses and their side effects is beyond the scope of this essay that can only give illustrative examples. For an up-to-date information the reader can resort to reference [5]. As many as 33 different interleukins are known and the list continues to grow IL-2 used in the treatment of kidney cancer is one example. Interferon alpha is used for chronic myelogenous leukeia, hairy cell leukaemia and Kaposi s sarcoma. Interferons are also used in the treatment of chronic infections such as viral hepatitis. Tumor necrosis factor (alpha), G/GM/M-CSF, and several other cellular factors are used in treatment of various cancers. Many of these cytokines produce serious side effects that limit their use. 

Niro GA, Rosina F, Rizzetto M (2005b) Treatment of hepatitis D. J Viral Hepat 12 2-9 Niro GA, Ciancio A, Gaeta GB, SmedUe A, Marrone A, OUvero A, Stanzione M, David E, Bran-caccio G, Fontana R, Perri F, AndriuUi A, Rizzetto M (2006) Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 44 713-720... 

The best example of using this knowledge in drug discovery is the identification of Prostratin. While working in Samoa to identify plants with potential chemotherapeutic properties, Dr. Paul Cox documented the use of Homalanthus nutans for the treatment of hepatitis [16]. Surprisingly, when extracts of this plant were incidentally examined for anti-HIV properties, the extract appeared effective for treatment of HIV [17]. Eventually, this compound was shown to be effective at activating the latently infected T-cell pool [18]. Importantly, this population of cells is a principal reason for HIV persistence [19]. 

Colchicine (a drug used in treatment of gout) and vinblastine (a cancer chemotherapy agent) may decrease liver uptake of americium. In rats that received an intraperitoneal injection of either colchicine and vinblastine prior to an intravenous or intramuscular injection of americium citrate, liver uptake of americium was lower, relative to controls, and kidney and skeletal americium uptake were higher (Seidel 1984, 1985). The effect is thought to involve disruption of hepatic microtubule formation, which is critical to the formation and intracellular processing of lysosomes, the initial site of accumulation of americium in the liver. 

Interferon-a is currently the only agent of proven clinical efficacy in the treatment of hepatitis C however, only 10 to 51% of patients enrolled in clinical trials showed a sustained improvement (Davis et al., 1989 Di Bisceglie et al, 1989). Current interferon-a therapy is, typically, 3 million units, thrice weekly, given subcutaneously for 12 months. Both HCV genotype and pretreatment viral load have been shown to influence the response to interferon (Lau et al., 1993 Yoshioka et al., 1992). 

Nevertheless, a rapid disappearance of resistant bacteria was observed after stopping the antibiotic treatment (fig. 5). Different kinetics of disappearance were, however, observed. The aerobic species showed a more rapid return to the baseline sensitive status whereas the anaerobic bacteria, especially the Gram-negative rods, regained sensitivity to rifaximin more slowly. In any case, 3 months after the end of treatment resistant strains were no longer detectable in the feces [82], These results support the cyclic use of rifaximin that has been adopted by the investigators in the treatment of hepatic encephalopathy [77] and colonic diverticular disease [79]. 

Williams R, James OF, Warnes TW, Morgan MY Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy A double-blind, randomized, dosefinding multi-centre study. Eur J Gastroenterol Hepatol 2000 12 203-208. 

As outlined in the excellent review by Gilles and Brogden [9], the current indications for rifaximin include surgical prophylaxis and the treatment of hepatic encephalopathy, infectious diarrhea and intestinal bacterial overgrowth syndromes. As such, rifaximin is aimed only at enteric flora. Owing to its lack of absorption, rifaximin will likely not be used for other conditions or indications. Such limited indications should help preserve the activity of the agent, since overuse for common conditions like urinary or respiratory tract infections will naturally not occur. Limited use should help retard the development of resistance among enteric flora. 

FeraG, AgostinacchioF,NigroM, SchiraldiO, Ferrieri A Rifaximin in the treatment of hepatic encephalopathy. Eur J Clin Res 1993 4 57-66. 

Infergen (interferon alfacon-1 or consensus interferon) is an engineered interferon recently approved for the treatment of hepatitis C (Table 8.8). The development of infergen entailed initial sequence comparisons between a range of IFN-as. The product s amino acid sequence reflects the most frequently occurring amino acid residue in each corresponding position of these native interferons. A DNA sequence coding for the product was synthesized and inserted into E. coli. The recombinant product accumulates intracellularly as inclusion bodies. 

IFN-a2b is now approved in the USA for the treatment of hepatitis B and C. Clinical studies undertaken with additional IFN-a preparations indicate their effectiveness in managing such conditions, and several such products are also likely to gain regulatory approval. 

Because of its antiviral and anticancer effects, IFN-a is used in the treatment of hepatitis and various forms of cancer, such as Kaposi s sarcoma, non-Hodgkin s lymphoma, and hairy cell leukemia. Exhibit 4.8 describes the treatment of hepatitis C with IFN- . IFN-jS is used for treating multiple sclerosis, a chronic disease of the nervous system. The medical application of IFN-y is for cancer, AIDS, and leprosy. 

PEG-Intron PEG-Intron is used for the treatment of hepatitis C. The product consists of a covalent conjugate of the recombinant interferon- -2b with monomethoxy polyethylene glycol (PEG) supplied in vials with 74/rg, 118.4/rg, 177.6/rg, or 222/rg of the active ingredient and 1.11 mg sodium phosphate (dibasic,anhydrous),l.ll mg sodium phosphate (monobasic, dihydrate), 59.2 mg sucrose, and 0.074mg polysorbate 80. The powder is reconstituted with sterile water-for-injection. 

Organ transplants The safety and efficacy of peginterferon alfa-2b alone or in combination with ribavirin capsules for the treatment of hepatitis C in patients who have received liver or other organ transplants have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection also has been reported, but a causal... 

Osmotic laxatives (e.g., lactulose, sorbitol) are poorly absorbed or nonabsorbable compounds that draw additional fluid into the GI tract. Lumen osmolality increases, and fluid movement occurs secondary to osmotic pressure. Lactulose is a synthetic disaccharide that is poorly absorbed from the GI tract, since no mammalian enzyme is capable of hydrolyzing it to its monosaccharide components. It therefore reaches the colon unchanged and is metabolized by colonic bacteria to lactic acid and to small quantities of formic and acetic acids. Since lactulose does contain galactose, it is contraindicated in patients who require a galactose-free diet. Metabolism of lactulose by intestinal bacteria may result in increased formation of intraluminal gas and abdominal distention. Lactulose is also used in the treatment of hepatic encephalopathy. 

Emtricitabine is a nucleoside reverse transcriptase inhibitor, launched for the treatment of HIV infection. It is also currently in phase III for the treatment of hepatitis B virus (HBV) infection (Fig. 35) [98]. 

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