Anti-hepatitis activity

Coelmont L, Paeshuyse J, Windisch MP, De Clercq E, Bartenschlager R, Neyts J (2006) Ribavirin antagonizes the in vitro anti-hepatitis C virus activity of 2 -C-methylcytidine, the active component of valopicitabine. Antimicrob Agents Chemother 50 3444-3446 D Abramo CM, Cellai L, GOtte M (2004) Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J Mol Biol 337 1-14... 

Wyles DL, Schooley RT, Kaihara KA, Beadle JR, Hostetler KY (2008) Anti-hepatitis C virus repli-con activity of alkoxyalkyl esters of (S)-HPMPA and other acyclic nucleoside phosphonates. In Abstracts of the 21st international conference on antiviral research, Montreal, QC, Canada, 13-17 April 2008. Antiviral Res 78 A21, no 15... 

Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, Dornsife RE, Wurster JA, Wilson LJ, Fyfe JA, Tuttle JV, Miller WH, Condreay L, Averett DR, Schinazi RF, Painter GR. The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and ( + ) enantiomers of cis-5-fluoro-l-[2-(hydroxymethyl)-l,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992 36 2686-2692. 

Schwendener RA, et al. S5 nthesis, in vitro anti-HIV and anti-hepatitis B activities and pharmacokinetic properties of amphiphilic heterodinucleoside phosphates containing ddC and AZT. Nucleosides Nucleotides 1999 18 949. 

Anti-hepatitis B virus activity in vitro and in vivo was also found in wogonin and baicalein (Fig. 4), the major active constituents of the traditional Chinese medicine Scutellaria radix.More recently, Blach-Olszewska et al investigated the effect of baicalein and wogonin on two important mechanisms of innate immunity The secretion of cytokines, and the natural resistance of human leukocytes to viral infection. The results obtained indicate that these fiavonoids modulate cytokine production, that is they inhibit interferons-a and -y, and stimulate tumor necrosis factor-a and interleukin production. They also augment the resistance of peripheral blood leukocytes to the vesicular stomatitis virus. 

PHARMACOLOGICAL ACTIVITIES AND CLINICAL TRIALS Alkaline phosphatase stimulation. Extract of the leaf, administered orally to adults, was active. Patients with subacute hepatic necrosis had negative workup, except for consumption of 15 tablets of the herbal extract per day for 4 months L Anthelmintic activity. Water and petroleum ether extracts of the dried oleoresin were active on Eimeria tenella in chicken - . Anti-amoebic activity. The resin of Larrea produced inhibitory activity at a concentration of 1 ppm on Entamoeba invadens PZ axenic cultures. The nordihydroguaiaretic acid activity was observed at 10" to 10" concentrations - . 

Antitoxic effect. Sesame oil, adiministered to male Wistar rats, ameliorated hepatic and renal damage in a dose-dependent manner and increased survival in lipopolysaccha-ride-treated rats. It decreased lipid peroxide concentration in serum but not in liver and kidney. Serum nitrite production was unaffected by sesame oil ingestion, and the activity of xanthine oxidase was reduced in the lipopolysaccharide-challenged rats k Anti-tumor activity. Water extract of the dried seed, administered intragastrically to mice at a dose of 50 mg/animal daily for 5 days, was active on CA-Ehrlich-ascites, 18% increase in life-span. Intraperitoneal administration was active on Dalton s lyphoma and CA-Ehrlich-ascites, 19 and 39% increase in life-span, respectively ". Seed oil, administered to rats intraperito-neally with 1,2,5,6-dibenzanthracene or re-tene, was active on sarcoma ". 

Anti-amoebic activity. Ethanol (80%) extract of the dried rhizome was inactive on Entamoeba histolytica, minimum inhibitory concentration (MIC) greater than 1 mg/ mL The extract, administered intragas-trically to male hamsters at a dose of 800 mg/kg, was active vs experimentally induced hepatic amebiasis . A dose of 250 mg/kg, administered intragastrically to rats on days 1-5, produced weak activity and a dose of 500 mg/kg was active " ". Anti-atherosclerotic activity. Ethanol (50%) extract of the dried rhizome, administered intragastrically to male rabbits at a dose of 500 mg/kg, reduced atherogenic index from 4.7 to 1.2 on the aorta . Antibacterial activity. Decoction of the dried entire plant, on agar plate, was inactive on Proteus vulgaris, Staphylococcus aureus, and Staphylococcus epidermidis MIC 125 mg/mL. Bacillus subtilis, Bordetella... 

Several anti-HBV agents have anti-HIV activity as well, including lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treatment. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents. 

Prochlorperazine is widely used for its anti-emetic activity and its effectiveness in suppressing dizziness due to labrintine disorder. Oral bioavailability is very low, due to extensive intestinal and hepatic frrstpass metabolism. Furthermore, the oral route is impractical in patients with nausea and vestibular disturbance, who have been demonstrated to have impaired gastric emptying. 

Induction of mRNAs for several other specific rat hepatic proteins by GH has also been demonstrated [81-83]. The effect could be demonstrated in vivo and in vitro and involved a relatively rapid induction with a 5-fold increase in mRNA levels within 4 h of the administration of GH, although synergism with cortisol (possibly and/or thyroxine) was necessary for a maximal response [83]. cDNAs corresponding to two of the induced proteins have been cloned [82,83] and found to have sequences homologous to those of a known family of serine protease inhibitors. One of these proteins was shown to be secreted as a heavily glycosylated serum protein, and to have potent anti-trypsin activity [83]. Regulation of the production of this protein by GH was shown to occur mainly at the transcriptional level [83]. 

Isradipine (Fig. 7.5) is a further nifedipine analogue, which has been used in the treatment of hypertension either alone or in combination with diuretics. Isradipine possesses high calcium antagonist activity, which results in a peripheral vasodilatation without any detrimental effect on cardiac conduction. Its oral bioavailability is 90-95% of the administered dose, but the hepatic first-pass effect reduces this to 15-24%. Isradipine was shown to possess anti-atherosclerotic activity in a number of experimental models, but clinical studies (MIDAS) failed to confirm these findings in patients. 

Examples of seven-membered heterocycles with significant antiviral activity include imidazo[4,5-e][l,3]diazepine-4,8-diones with anti-hepatitis C virus (HCV) activity <07BMCL2225> <07BMC4933> and benzo(indolo)fused 1,4-oxazepine derivatives as HCV RNA polymerase inhibitors that show excellent replicon potency <07BMCL3181>. Novel 2-chloro-8-[(arylthio)methyl]dipyridodiazepinone derivatives show activity against HIV-1... 

Adefovir is an acyclic analogue of adenosine monophosphate. When phosphorylated by host enzymes, it is a potent inhibitor of hepatitis B Virus (HBV) DNA polymerase, including reverse transcriptase. Adefovir was initially studied in the management of HIV infection. Large doses that were required to achieve anti-HIV activity were associated with dose-hmiting nephrotoxicity. Adefovir is currently only FDA approved in lower dosages for the management of HBV infection as at a dose of 10 mg/ day adefovir has not been found to be nephrotoxic in randomized controlled trials. 

While all NSAIDs have the potential for inducing renal failure, there has been speculation of quantitative differences among the individual NSAIDs. Sulindac was thought to be renal sparing, possibly because of its unusual metabolic pathway [29, 77-79]. The parent compound, sulindac sulphoxide, is an inactive prodrug, which undergoes hepatic metabolism to sulindac sulphide, the metabolite responsible for its anti-inflammatory activity. Sulindac sulphoxide is also metabolized to a much lesser extent to an inactive metabolite, sulindac sulphone. It was hypothesized that, within the human kidney, sulindac sulphide was reversibly oxidized to the inactive parent compound, sulindac sulphoxide, with the result that renal prostaglandin production was not perturbed [29, 78]. 

Some 3 -5 e-substituted dideoxynucleosides in racemic forms, as well as the a- and p-anomers of oxaselenolane nucleosides have been synthesized and exhibited potent anti-HIV and anti-HBV activities. The synthesized racemic nucleosides (125, 126) were evaluated for antiviral activity against HIV virus type-1 and hepatitis B virus in peripheral blood... 

Jacquard, A.-C., Brunelle, M.-N., Pichoud, C., et al. (2006) In vitro characterization of the anti-hepatitis B vims activity and cross-resistance profile of 2, 3 -didcoxy-3 -fluoroguanosine. Antimicrob. Agents Chemother., 50, 955-961. 

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