Hcv Ebook

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

Alternative Hepatitis C Treatments Summary


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Case 2 HCV Inhibitors

(A) Beaulieu et al.38,39 at Boehringer Ingelheim reported in two consecutive articles how parallel solid-phase synthesis was used for the discovery and optimization of benzimidazole 5-carboxamide analogs as inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). This work began with two hits found in a high-throughput screening exercise against HCV polymerase. The two active compounds shared a benzimidazole core with identical 5-carboxamide

Treatment of Hepatitis CAssociated Glomerular Disease

Summary Hepatitis C virus (HCV) infection can lead to chronic active hepatitis, cirrhosis (liver scarring), and liver failure however, it is also associated with a wide range of extrahepatic features. This article reviews the treatment of glomerular disease (kidney disease) associated with HCV infection. Renal manifestations include cryoglobulinemic membranoproliferative glomerulonephritis and membranous nephropathy. The authors caution that treatment of HCV with alpha interferon is only moderately effective and suffers from a high relapse rate. More recently, combination therapy with ribavirin has led to improved suppression of HCV RNA levels. Rapidly progressive renal disease or severe cryoglobulinemic vasculitis may respond to immunosuppression with steroid, cyclophosphamide, and plasmapheresis in the acute phase. After 2 to 4 months of immunosuppression, antiviral therapy (with alpha interferon and ribavirin) should be tried. Promising new therapies on the horizon include agents...

Hepatitis C Virus Infection

In Japan and other Asian countries, hepatitis C virus (HCV) infection is a serious problem, leading to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In HCV infection, iron deposition in the liver induces oxidative stress and in some cases serum ferritin levels and serum TRX levels are elevated. Interestingly, cases with elevated serum ferritin and TRX levels are resistant to interferon therapy to reduce viral loads 57-59 . Therefore, serum TRX levels may reflect the redox status in the liver and be a good indicator for interferon therapy.

Interferons In Viral Hepatitis

Greenberg in 1976 6 was the first to report that interferon has activity against a hepatitis virus. Four patients with chronic hepatitis B received short courses of low-dose interferon (6 x 103 to 17 x 104 units per kilogram per day). Three of the four patients demonstrated a reduction in viral replication, and two appeared to have permanently lost hepatitis B e antigen (HBeAg). Unfortunately, the limited production and purity of the Cantell interferon did not allow for continuation of these experiments. Based on current treatment recommendations, the entire production of Cantell interferon in 1980 would have allowed treatment of only about 200 to 250 patients with hepatitis B or C. Genentech employed mRNA isolated from Cantell interferon-producing buffy-coat lymphocytes and cell lines to develop clones that were used for large-scale production of a-interferon by recombinant technology 5 .The recombinant interferons that were subsequently approved for use in viral hepatitis were...

Interferon Treatment of Chronic Hepatitis C

Hepatitis C virus (HCV) is an RNA virus that is a common cause of parenterally acquired viral hepatitis chronic infection follows acute infection in 80 to 85 of cases. Although liver disease resulting from chronic HCV infection is only slowly progressive, HCV is the most common cause of chronic liver disease in the United States, the most common etiology for hepa-tocellular carcinoma, and the leading indication for liver transplantation 34-36 . Because of the risk of progressive liver disease, efforts toward controlling HCV infection have been vigorous and were underway even before the virus was iden tified in 1989 37 . Indeed, the beneficial effects of interferon in HCV infection were shown in the very first study of recombinant a-interferon for chronic non-A, non-B hepatitis (subsequently renamed chronic hepatitis C after the discovery of the virus). That study showed improvement with normalization of serum ALT levels in 8 of 10 interferon-treated subjects as well as histo-logical...

Interferon Treatment of Chronic Hepatitis B

Hepatitis B virus (HBV) is a DNA virus that causes one of the most common infec tious diseases in the world, affecting about two billion people at some time during their lives 13 .About 15 of infected individuals develop chronic infection, characterized by persistence of hepatitis B surface antigen (HBsAg) in serum and some degree of HBV replication. Infected patients with active liver disease usually have detectable hepatitis B e antigen (HBeAg) and high levels of serum HBV DNA, while those without active liver disease typically lack HBeAg but have antibody to HBeAg (anti-HBe), low alanine aminotransferase (ALT) levels, and undetectable or low-titer HBV DNA replication 14 . The US Food and Drug Administration (FDA) approved recombinant ainterferons for the treatment of chronic hepatitis B in 1992. These agents are currently recommended for patients with compensated chronic hepatitis B and detectable HBsAg, HBeAg, and HBV DNA in serum. Other subsets of patients with chronic hepatitis...

Use of Cannabinoids as a NoveL Therapeutic Modality Against Autoimmune Hepatitis

Cannabinoid Endocannabinoid System in Hepatitis 494 A. Controversies on the beneficial and deleterious roles of Autoimmune hepatitis is a severe immune mediated chronic liver disease with a prevalence range between 50 and 200 cases per million in Western Europe and North America and mortality rates of up to 80 in untreated patients. The induction of CB1 and CB2 cannabinoid receptors during liver injury and the potential involvement of endocannabinoids in the regulation of this process have sparked significant interest in further evaluating the role of cannabinoid systems during hepatic disease. Cannabinoids have been shown to possess significant immunosuppressive and anti-inflammatory properties. Cannabinoid abuse has been shown to exacerbate liver fibrogenesis in patients with chronic hepatitis C infection involving CB1 receptor. Nonetheless, CB2 receptor activation may play a protective role during chronic liver diseases. Thus, differential targeting...

Hepatitis C

Wright and co-workers documented cytokine profiles of patients grouped based on their viral titers before and after standard therapy 14 . They found that they were able to demonstrate the prognostic power of serum cytokine profiling in chronic hepatitis C virus (HCV) infection. The study demonstrated that overall serum cytokine levels were significantly higher in patients than in controls and that the levels dropped significantly after therapy in concert with their viral titer. Distinct cohort subgroups based on changes in viral titers correlated to specific sets of cytokines that decreased in each group. This could allow for new efforts to stratify patients and increase efforts to find improved therapies.

Definitions And Applications

Markers that reflect a response to therapy or drug treatment are called drug activity markers. They are used to demonstrate proof of concept, to establish dose regimens, and for optimizing combination therapies. They are used to measure the pharmacodynamic response, where the magnitude of the change defines the potency of the candidate drug. Examples include biochemical markers for bone resorption and deposition in studies on osteoporosis, such as osteocalcin, bone-specific alkaline phosphatase, and type I collagen propeptides and telopeptides 4 and viral load (hepatitis or human immunodeficiency virus) for measuring response to antiviral therapy 3 .

Interferons and interleukins

Hepatitis C Hepatitis B Hepatitis C Chronic hepatitis C Chronic hepatitis Hepatitis, chronic Hepatitis C, paediatric hepatitis B Recombinant hepatitis B surface antigen (rHBsAg) was the first (and, thus far, only) subunit vaccine to gain regulatory approval. Merck's Recombivax HB was approved by the FDA in 1986. Since then, a number of additional recombinant HbsAg based products have gained approval. Some are combination vaccines, also containing non-recombinant constituents. Examples include SmithKline Beecham's Infanrix HepB, Twmrix paediatric and Tritanrix. Additional subunit vaccines remain in clinical trials.

Nanobiotechnology and artificial cells

Waiting for typing and crossmatching in the hospital. They are also free from infective agents such as HIV, hepatitis C, bacteria, parasites and so on. Furthermore, whereas donor blood has to be stored at 4 C and is only good for 42 days, PolyHb can be stored at room temperature for more than a year. Thus, PolyHb can have important uses in a number of clinical conditions notably for surgery.

Hemoglobin as Oxygen Carrier

As shown in Fig. 1.1, red blood cell membranes contain blood group antigens, and typing and matching are needed before red blood cells can be transfused into patients. This results in delays in emergency situations. With the standard method, red blood cells can be stored for only about 42 days. Red blood cells cannot be sterilized to remove infective agents like hepatitis viruses, HIVand other potential emerging infective agents. Thus, red blood cell substitutes are being developed (Fig. 1.1). Red blood cell (rbc) contains Hb, antioxidant enzymes and a multienzyme system to preventthe conversion of Hb to nonfunctioning metHb. As such, preparing a clinically useful complete artificial red blood cell has been a very complicated process and will be discussed in the next two chapters. In the meantime, nanobiotechnology has allowed the development of simpler oxygen carriers containing only Hb. Although the simpler oxygen carriers are not as complete as the artificial red blood cell, some...

Clinical studies in the elderly multivitamins

Associated deaths reported in 1991 in the USA, more than 90 were in persons aged 65 and older. For bacterial pneumonia, there is a vaccine, which, however, is only 56 effective in preventing pneumococcal pneumonia, the most common cause of bacterial pneumonia. Currently, only 28 of the elderly receive pneumococcal vaccination 52 receive influenza vaccination. Thus, it is especially important to improve immune responses in this at-risk population because another major consequence of reduced immune responses in the elderly is decreased effectiveness of vaccination (which can be predicted by reduced antibody titre following inoculation). Poor immune responses to vaccines, such as the pneumococcal, hepatitis and flu vaccines, can increase the risk of morbidity and mortality, especially in the frail elderly.

Vitamin E studies in the elderly

Meydani et al. (1997) extended their earlier findings and examined the effects of 6 months of supplementation with 60, 200, or 800 IU day-1 of vitamin E in a placebo-controlled, double-blind study in healthy, free-living elderly subjects. In addition to DTH responses, they determined in vitro proliferation and ex vivo antibody titres to clinically relevant vaccines. DTH responses were significantly increased above placebo levels in all three supplemented groups the greatest responses were seen in the 200 IU group. In vitro proliferative responses were highest in the 800 IU group. Antibody titres to tetanus were unaffected by vitamin E supplementation, but titres to hepatitis B vaccine were highest in the 200 IU group.

Cytokines And Mood Disturbances

Since immunotherapy has been used in several diseases, e.g. the treatment of hepatitis or morbus behcet with interferons or the treatment of certain neoplastic diseases with interleukins, neuropsychiatrie symptoms as side effects of those therapies have become evident (Meyers and Valentine, 1995). Neurostimulatory effects due to cytokines, which can be observed under experimental or therapeutic conditions, demonstrate that peripheral administration of those soluble proteins affect the CNS (Bartfai and Schultzberg, 1993 Denicoff, Rubinow, & Papa, 1987 Fabry et al., 1994 McDonald, Mann, & Thomas, 1987). The cytokine IL-1 is able to induce depressive-like symptoms such as psychomotor and appetite disturbances, alterations of sleep, lethargy, and weakness (Cunningham and DeSouza, 1993 Hopkins and Rothwell, 1995). IL-1 and IL-6 activate the hypothalamic-pituitary axis (HPA) with subsequent release of CRH and ACTH (Bartfai and Schultzberg, 1993 Hopkins and Rothwell, 1995). Alterations of...

Prospective Assessment Of The Cns Effects Of Ifna

We have also assessed several patients with hepatitis before and during lower dose IFN-a treatment. At this time we have only 6 patients with pre-treatment and follow-up assessment. The dose for all of these individuals was 3 million units (MIU) three times per week and the follow-up interval was 4.2 months (range 3-5 months). The demographic characteristics of this sample is very similar to the CML patients (mean age 42.8 years, mean education 13.7 years). Although this data is very preliminary, we have found that these patients tended to perform better on the cognitive tests at follow-up, the expected pattern due to practice effects. Only one of the 6 patients experienced increased depression (as assessed by the Beck Depression Inventory). Table 3 summarizes the preliminary results of these prospective studies.

Herbal Remedies And Abnormal Liver Function Tests

Case in which severe hepatitis was associated with kava use. A 50-year-old man took three or four kava capsules daily for 2 months and liver function tests showed 60-70-fold increases in AST and ALT. Serology was negative for hepatitis A, B and C, CMV and HIV. The patient eventually received a liver transplant.49 Humberston et al. also reported a case of acute hepatitis induced by kava-kava.50 Other cases of hepatotoxicity due to the use of kava have been documented.51 In January 2003, kava extracts were banned in the entire European Union and Canada. The FDA strongly cautioned against using kava. Eleven cases of serious hepatic failure and four deaths have been reported in association with kava use. There are also 23 reports indirectly linking kava-kava with hepatotoxicity.52 Chaparral can be found in health food stores as capsules and tablets and is used as an antioxidant and anti-cancer herbal product. Leaves, stems and bark in bulk are also available for brewing tea. However, this...

Interferon alfa2a and its Limitations as a Therapeutic Agent

A cornerstone of the treatment regimen for chronic hepatitis C infection is an alpha interferon (IFN). IFNs are endogenous glycoproteins produced by a variety of cells, usually in response to a viral infection. The mechanism by which IFN acts against the hepatitis C virus is not completely understood. Possible actions include a direct antiviral effect and to a lesser extent, immune system modulation6'7. Immune system modulation by IFN may be important in that decreases in liver inflammation and fibrosis are considered to be long-term goals in the disease's management. Clearly, an immediate goal in the treatment of chronic hepatitis C infection is the eradication of the virus from the serum. A sustained virological response is defined as the inability to detect hepatitis C virus in the serum 6 months after treatment has been completed. The antiviral effect of IFN in patients with chronic hepatitis C infection is well established8. The standard therapeutic schedule of IFN consists of 3...

Liver Cirrhosis Causes and Therapy

Cirrhosis is among the top 10 causes of death in the Western World. This is largely the result of alcohol abuse, viral hepatitis and biliary diseases 75 . The causes for cirrhosis can be roughly divided into six categories 2. Viral hepatitis resulting from infection with the hepatitis B, C or D viruses, 4. Autoimmune diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholan-gitis (PSC) and autoimmune hepatitis, Obviously the best treatment for cirrhosis is removal of the injurious event. In the case of viral hepatitis, viral load can at least be temporarily reduced with anti-viral agents such as lamivudine, ribavirin and or IFNa 76 . Unfortunately, complete removal of the injurious event is frequently not possible. Moreover, by the time cirrhosis is diagnosed the fibrotic process has usually progressed beyond 'the point of no return' and removal of the injurious event will have little effect. Successful pharmacological treatment to reverse the fibrotic Several types...

History of Pegylating Interferon alfa2a

The aim of pegylating IFN has been to optimize the pharmacological activity of the protein such that efficacy is enhanced, adverse effects minimized, and patient compliance and quality of life are improved. In the early 1990's, Hoffmann-La Roche attempted to benefit from the advantages that pegylation could afford by developing a linear 5 kDa pegylated form of IFN alfa-2a. In 1994, the clinical development of this linear 5 kDa pegylated IFN alfa-2a was discontinued because with once weekly dosing, the efficacy of this linear 5 kDa pegylated IFN alfa-2a was not equivalent to IFNalfa-2a given three times a week in a comparative Phase II clinical trial in patients with chronic hepatitis C infection. Roche scientists with collaboration from Shearwater Corporation (Huntsville, Alabama) went back to the drawing board to develop an optimized pegylated alpha interferon.

Optimizing the Pegylation of Interferon alfa2a

An optimal pegylated IFN for use in the treatment of hepatitis C infection would be absorbed in a sustained fashion, would be distributed predominantly to the liver and remain in the circulation and interstitial fluids, and would have a reduced clearance from the body compared to IFN. The pegylation of IFN would result in a less active molecule in vitro than that of the native endogenous protein, IFN, however the in vivo pharmacological activity related to efficacy would be better than that of IFN because sustained therapeutic concentrations would be maintained throughout a one week dosing interval (Figure 2). Conceptually then, the size, branching and pegylation process needs to be optimized for each protein such that therapeutically active concentrations are maintained for the appropriate period of time.

Peginterferon Alfa2a 40kd In Clinical Trials

Sustained virological responses and were often seen among patients who did not achieve a sustained virological response. The efficacy and an acceptable safety profile were also seen in the difficult-to-treat patient with hepatitis C (patients with cirrhosis and hepatitis C genotype 1 virus)25, 26. Phase III efficacy and safety results confirmed that the optimization of pegylation of IFN and the optimization of the pharmacokinetics and pharmacodynamics of a pegylated interferon led to superior efficacy and a better benefit risk ratio than that seen with IFN. Newer therapeutic regimens will include a pegylated interferon in combination with ribavirin or another antiviral agent so that greater than 50 of patients achieve a sustained virological response. Much progress in the treatment of hepatitis C has been made in the last 5 years and pegylated interferons play a significant role in this progress.

Steric Block Biological Activities of PeptidePNA Conjugates

Encapsidation signal duck hepatitis virus duck primary hepatocytes Robaczewska et al.,96 have shown that an unconjugated 15-mer PNA directed to the viral encapsidation signal of duck hepatitis B virus was able to decrease the viral genomic DNA by 30 in infected duck primary hepatocytes, compared to mismatch controls. Upon conjugation to an oligoarginine (R7) peptide the construct was able to decrease the viral DNA genome by 65 under the same experimental conditions. However, an NLS-PNA conjugate did not improve antiviral activity compared to PNA alone.

Selective Drug Delivery for the Treatment of Other Hepatic Disorders

Drug targeting preparations based on lactosylated HSA have been used for the treatment of chronic viral hepatitis, because these viruses reside in hepatocytes. Fiume et al. coupled several anti-viral nucleoside analogues to this carrier for the treatment of hepatitis 194,195 . The conjugate of adenine arabinoside monophosphate and lactosylated HSA (araAMP-lacHSA) has been studied in animals as well as in humans 1,196 . From the clinical trials it was concluded that use of this conjugate allowed more prolonged treatment of chronic hepatitis B than free araAMP, because of the lack of side-effects after chronic application of the conjugate, which enhanced its chemotherapeutical index. To date, however, no follow-up has been published.

RNA Editing of HTR2C in Mental Disorders Cellular and Animal Studies

RNA editing status of HTR2C could be changed in response to stress and drugs in cellular and animal models (Iwamoto et al. 2009). The adverse effects of interferons, which are clinically used for treatment of hepatitis, cirrhosis, and cancer, include depression (Schaefer et al. 2002). Among the three ADARs, expression of ADAR1 is induced by interferon. This resulted in the generation of the ADAR1 protein with higher molecular weight (150 kDa) than that produced from a constitutive promoter (110 kDa) (Fig. 8.1) (Patterson and Samuel 1995). Using glioblastoma cell lines, Yang et al. reported that interferon induced expression of 150 kDa ADAR1 and resulted in increased RNA editing at sites A, B, and C and decrease at site D (Yang et al. 2004). They suggested the involvement of RNA editing in the pathophysiology of depression caused by interferon treatment.

Interferon betalb the first longterm effective treatment of relapsingremitting and secondary progressive multiple

Abstract Beta-interferons like other type I interferons are produced in response to viral infections by various mammalian cells. These include macrophages, dendritic cells and fibroblasts. Type I interferons have non-specific antiviral and anti-proliferative effects, as well as a broad spectrum of immunomodulatory activities. On this basis, type I interferons are used successfully in the treatment of viral infections such as hepatitis C, papilloma and HIV-1 virus. They are also used (mostly in combination with other drugs) to treat some forms of cancer, including leukemia. Whilst these effects could be anticipated from the biological function of type I interferons, it came as a surprise to most when a group of neurologists presented convincing clinical and laboratory evidence of a relevant and important effect of interferon beta-lb in multiple sclerosis (MS). These effects were first noted with regard to its earlier relapsing-remitting form, which is marked by reversible exacerbation,...

Laboratory studies in PACNS

CNS vasculitides, diagnosed as PACNS, are reported to occur in patients with viral and to a lesser extent with bacterial and other infections, both in immunocompromised and immunocompetent patients. The most commonly encountered infections associated with CNS vasculitis are varicela-zoster virus (VZV), HIV, cytomegalovirus (CMV) and, rarely, Mycobacterium tuberculosis, Borrelia burgdorferi and Treponema pallidum. Several fungal and rickettsial infections have also been reported in association with vasculitis of the nervous system.6,7 Hence, serological studies should be carried out to exclude these infections as well as hepatitis B and hepatitis C virus infections, which are known to be associated with systemic vasculitic syndromes.20

MicroRNAs in Human Disease

The expanding inventory of human miRNAs along with their highly diverse expression patterns and high number of potential target mRNAs suggest that miRNAs are involved in a wide variety of human diseases. One is spinal muscular atrophy (SMA), a paediatric neurodegenerative disease caused by reduced protein levels or loss-of-function mutations of the survival of motor neurons (SMN) gene.116 A mutation in the target site of miR-189 in the human SLITRK1 gene was recently shown to be associated with Tourette's syn-drome,117 while another recent study reported that the hepatitis C virus (HCV) RNA genome interacts with a host-cell miRNA, the liver-specific miR-122a, to facilitate its replication in the host.118 Other diseases in which miRNAs or their processing machinery have been implicated include fragile X mental retardation (FXMR) caused by absence of the fragile X mental retardation protein (FMRP),119,120 DiGeorge syndrome,121 human immunodeficiency virus (HIV) replication and coronary...

Animal Models of Wilsons Disease and ICC

There are two proven rodent models of WD, the Long-Evans Cinnamon (LEC) rat and the toxic milk (tx) mouse. The LEC rat accumulates high levels of hepatic copper in the first few months after birth (78) and this excess copper is the likely the cause of early-onset hepatitis. A deletion of the 3' portion of ATP7B has been reported thus demonstrating the LEC rat is a true model of WD (79). Recent experiments have used this rat model to study the possibility of gene correction in WD (80).

Nervous system vasculitis secondary to drugs and substance abuse

Recreational drug abusers are known to have higher incidences of coexisting infections, such as hepatitis B, HIV, and syphilis, all independently associated with nervous system vasculitides. However, CNS vasculitis secondary to drug and substance abuse has been histologically verified in users of cocaine, amphetamines and related drugs such as phenylpropanolamine, metamphetamine, and methylphenidate, as well as in abusers of multiple drugs unrelated to such infections.22,41,59 Phenyl-propanolamine, which was present in appetite suppressants and in some over-the-counter cough and cold remedies, was recently reported to be an independent risk factor for haemorrhagic stroke in women in a case-control study.60 Subsequently, the FDA issued a public health advisory concern on this risk, and many products containing phenyl-propanolamine were withdrawn from the market. However, the relationship between this vasoconstrictor drug and cerebrovascular events, including

Short Abstracts Session IV

A link between inflammation and cancer has been suspected for over two millennia, but its molecular nature remained ill defined. It has also been observed that certain bacterial (for instance Helicobacter pylori) and viral (for instance HBV and HCV) pathogens are major risk factors for certain types of cancer, most notably gastric and liver cancers. In trying to understand molecular mechanisms that link chronic infections and inflammation to cancer, we have postulated that transcription factor NF-kB may be at the center of this nexus, as NF-kB is activated in response to infection and inflammation and in turn upregulates expression of antiapoptotic and growth promoting genes. As there are several NF-kB transcription factors, we decided to inactivate the critical catalytic subunit of the IkB kinase (IKK) complex, IKKp, as a way to inhibit activation of most NF-kB forms. We used conditional gene targeting to inactivate IKKp in either cells that give rise to the malignant component of...

Repression of the 5 PolyA Site

Inhibition of 5' polyadenylation requires the rapid folding of the polyA hairpin structure on the nascent viral transcript in order to occlude the AAUAAA signal and thereby delay binding of polyadenylation factors that are part of the elongating RNA polymerase II complex (Fig. 5). In fact, this enzyme complex should have advanced up to position 120 on the HIV-1 template before the nucleotides that form the base-paired stem of the polyA hairpin are extruded from the elongating enzyme, which encompasses approximately 16 nucleotides of the nascent transcript (Komissarova and Kashlev, 1998). Rapid folding seems possible because the approximate time scale for the formation of such secondary structure is in the 10 4- to 10 5-s range (Sclavi et al., 1998 Batey and Doudna, 1998). Nevertheless, the hairpin structure will be in equilibrium with the open form (''breathing''), and the AAUAAA signal will eventually be exposed. It is likely that the delayed interaction with polyadenylation factors...

Lossoffunction Models

Examples of mutant monomeres acting as dominant negative mutants were described by Lavigueur et al. (1989). A mutant p53 tumour suppressor gene was expressed in transgenic mice. Such mice reproducibly succumb to a variety of tumours. Dycaico et al. (1988) succeeded in reproducing in transgenic mice a neonatal hepatitis by expressing the human allele of al-antitrypsin carrying the dominant mutation responsible for the disease in humans.

External quality assessment

Validation of nucleic acid amplification techniques (NAT) for the detection of hepatitis C virus (HCV) RNA in plasma pools guidelines The majority of nucleic acid amplification analytical procedures are qualitative (quantal) tests for the presence of nucleic acid with some quantitative tests (either in-house or commercial) being available. For the detection of HCV RNA contamination of plasma pools, qualitative tests are adequate and may be considered to be a limit test for the control of impurities as described in the Pharmeuropa Technical Guide for the elaboration of monographs, December 1999, Chapter III Validation of analytical procedures . These guidelines describe methods to validate only qualitative nucleic acid amplification analytical procedures for assessing HCV RNA contamination of plasma pools. Therefore, the two characteristics regarded as the most important for validation of the analytical procedure are the specificity and the detection limit. In addition, the robustness...

Artificial cells and regenerative medicine

Liver failure severe enough to be not compatible with life. This can be caused by acute hepatitis, massive traumatic injury or extensive cancer resection. Liver has the ability to regenerate itself to its original size if the patients can survive for a sufficient length of time under suitable conditions. Lower. We studied the use artificial cells with 3 different contents for liver regeneration. (1) hepatocytes (2) hepatocytes plus bone marrow stem cells or (3) bone marrow stem cells alone. Fig. 9.1. Upper. Liver failure severe enough to be not compatible with life. This can be caused by acute hepatitis, massive traumatic injury or extensive cancer resection. Liver has the ability to regenerate itself to its original size if the patients can survive for a sufficient length of time under suitable conditions. Lower. We studied the use artificial cells with 3 different contents for liver regeneration. (1) hepatocytes (2) hepatocytes plus bone marrow stem cells or (3)...

Examples of Applications

In cases where the activation of one specific signaling cascade is under investigation, a synthetic promoter containing the respective response element may be the best approach. Multiple copies of the response element are usually coupled to enhance the regulatory effect. A whole variety of promoter elements that are responsive to the activation of different second messenger pathways are available. One such response element is TRE (tissue plasminogen activator (TPA) responsive element), which is activated by the signal transduction pathways mediated by PKC.45 GPCRs coupling to Gai and GaS can be investigated by CREs (using cAMP responsive elements),46,47 which bind CRE-binding (CREB) protein phosphorylated by PKA.35 Those coupling to Gaq signal through calcium, which activates the NFAT response element.48 Genetic engineering of a luciferase reporter cell line under the control of multiple copies of the hypoxia-responsive element (HRE) allow one to investigate the totally different...

Immune Mechanisms Involved in RHD

Early studies on degeneracy of T cell response was done by Fujinami and Oldstone 48 , showing that injection of hepatitis B antigens cross-reactive or similar to MPB could induce encephalomyelitis in rabbits by molecular mimicry. This and another study 49 demonstrated that similarity over a few amino acid residues could be sufficient to trigger a T cell immune response. The high levels of cross-reactivity observed in animal models, showed that a single T cell must react to over 104 different nonamer peptides, by sequences or conformational homologies. These data suggest that the cross-reactivity is necessary to maintain the immune response to foreign peptides, meaning that cross-reactivity could be physiological and or pathological. T cell flexibility of antigen recognition was evaluated by Mason that using a mathematical approach and experimental models estimated that T cells can react with a very large number of peptides by cross-reactivity

Antibacterialactivity And Bacterial Resistance

Untoward effects Rifabutin generally is well tolerated in persons with HIV infection primary reasons for discontinuation of therapy include rash (4 ), GI intolerance (3 ), and neutropenia (2 ). Overall, neutropenia occurred in 25 of patients with severe HIV infection who received rifabutin. Uveitis and arthralgias have occurred in patients receiving rifabutin doses 450 mg daily in combination with clarithromycin or fluconazole. Patients should be cautioned to discontinue the drug if visual symptoms occur. Like rifampin, the drug causes an orange-tan discoloration. Rarely, thrombocytopenia, a flu-like syndrome, hemolysis, myositis, chest pain, and hepatitis have occurred.

Analytical procedures

Cholinesterase activity pose a serious problem. For example, plasma cholinesterase activity may be depressed by cirrhosis, chronic hepatitis or other liver diseases and also by drug use and abuse.34 There are no differences in cholinesterase activity associated with race in general, but plasma cholinesterase activity in North American black races has been reported to be lower than in caucasians of the same sex.24 Any results obtained using enzyme inhibition monitoring should therefore preferably be compared with values for the innate cholinesterase activity of each subject, if possible the median of three samples obtained in a pre-exposure period.35

Copper Accumulating in the Body and Its Toxicity

Monovalent Cu is a potent reducing agent and catalyzes one electron reduction of reactive oxygen species (i.e., reduces hydrogen peroxides to hydroxyl radicals by the Fenton reaction Fig. 2 ) (2325). The supply of monovalent Cu produces the reactive oxygen species in the medium, which is assumed to cause acute hepatitis in LEC rats, the animal model of Wilson's disease. The sequestration of radicals reactive oxygen species is one of the well-known biological roles of MT together with the protection of the body from the harmful effect of heavy metals. However, the production of reactive oxygen species under the present condition suggests that MT becomes a pro-oxidant when Cu accumulates more than the capacity to synthesize Cu-MT (Fig. 1).

Recommended dosage and monitoring requirements The recommended dose of

Infergen for treatment of chronic HCV infection is 9 mg three times weekly, administered subcutaneously for 24 weeks. At least 48 hours should elapse between doses of Infergen. Patients who tolerated previous interferon therapy and did not respond or relapsed following its discontinuation may be subsequently treated with 15 mg of Infergen thrice weekly for 6 months. If home use is determined to be desirable by the physician, instruction on appropriate use should be given by a health care professional. There are significant differences in specific activities among interferons. Health care providers should be aware that changes in interferon brand may require adjustments of dosage and or change in route of administration. Patients should be warned not to change brands of interferon without medical consultation.

Pharmacology and pharmaceutics

Least five times higher specific activity in vitro than interferon alfa-2a (Roferon) and interferon alfa-2b (Intron), both of which are used in the treatment of HCV infection. Pharmacokinetics The pharmacoki-netic properties of Infergen have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after subcutaneous injection of interferon alfacon-1 at doses up to 9 mg. Plasma levels of interferon alfacon-1 at any dose were too low to be detected. However, analysis of Infergen-induced cellular products induction of 2'5' oligoadenylate synthetase and (beta)-2 microglobulin after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC). E. Therapeutic response Efficacy of Infergen therapy was determined by measurement of serum alanine amino-transferase (ALT) concentrations at the end of therapy (24 weeks) and following 24 weeks of observation...

Gene therapy the real diseases

Viral infections offer similar opportunities for specific genetic interventions. Indeed, in cancers with a known viral aetiology, the presence of viral genes upon which the evolution of the malignant phenotype depends offers more cause for optimism than in the treatment of non-viral cancers because of the presence of specific targets that are separate from cellular genes. Thus, gene therapy designed to abrogate the expression of papilloma transforming proteins E6 and E7 might be effective in the treatment of cervical cancer similarly, hepatitis B (hepatocellular carcinoma), human T-cell lymphotropic virus types 1 and 2 (adult T-cell lymphoma leukaemia) and Epstein-Barr virus (nasopharyngeal carcinoma and Burkitt's lymphoma) all offer virus-specific targets for gene therapy intervention in the infected target cells.

Necrotizing Arteritis And Nonconnective Tissue Disorder

NA occurs in retroviral infection, in patients with chronic hepatitis and in association with hepatitis B infection. Infection with hepatitis B virus was found in 19 of our patients, including two with chronic hepatitis. These figures confirm that infection with the hepatitis B virus is more common in patients with NA than in controls and that it may play a role in the onset of NA.42-45 Hepatitis C virus infection, associated or not with chronic hepatitis, is also occasionally associated with vasculitic neuropathy, and at times with cryoglobulinemia.

Summary of Common Building Principles for Oligonucleotide Carriers

Extensive PEGylation shields the cationic surface charge almost completely and prohibits electrostatic binding to the endothelia, but it also interferes with the cellular uptake process.58,66 This 'PEGylation dilemma' has been addressed in two different ways (1) by using weakly bound, diffusible PEG-lipids for transient protection of the carrier or (2) by insertion of ligands that provide homing and internalization in specific cell types. Schiffelers and co-workers clearly re-established the activity of otherwise inactive PEGylated poly-ethylenimine formulations after decoration with RGD peptides at the tip of the PEG chain.66 Likewise, PEGylated cyclodextrin-based polymer formulations gain activity when a small percentage of transferrin-modified PEG molecules are blended into the surface modification mix.64 Transient PEGylation is achieved when a PEG molecule is grafted onto a lipid with a short membrane anchor, e.g. a C14 chain. Cationic liposome formulations that contain these...

Recombinant Human InterferonaA

In another study, the same authors (20) studied the effect of IFN-aA (single intramuscular dose) on theophylline clearance in five patients with stable chronic active hepatitis B and four healthy subjects. Like antipyrine, theophyl-line clearance was reduced and varied from 31 to 81 in eight of nine patients. In one patient, no change in theophylline clearance was observed.

Effect of IFNaRibavirin Biotherapy on Cyrochrome P450

Becquemont et al. (21) studied the effect of IFN-a and ribavirin combination therapy on the activities of CYP1A2, CYP2D6, CYP3A4, and N-acetyltransferase-2 (NAT2) after one month of treatment. There were 14 patients with chronic hepatitis C in the study. The patients received three MU of IFN-a three times a week and 600 mg ribavirin twice a day in five patients and 500 mg ribavirin twice a day in nine patients (who were less than 75 kg of body weight). Before the initiation of the therapy, the patients also received 80 mg dextromethorphan and 140 mg caffeine. The results of this study are summarized below Overall, the study indicates that IFN-a and ribavirin combination therapy can decrease or increase the activities of CYP3A4 and CYP2D6 in patients with chronic hepatitis C. Therefore, individual therapeutic drug monitoring may become necessary in this patient population if they are taking any drug that is a substrate for either CYP3A4 or CYP2D6.

Cytochromes p450 in the metabolism of xenobiotics

Such as DNA, RNA, and proteins, to provoke various types of toxicity thus, in this case, metabolism confers on the chemical adverse biological activity (Figure 19.2). The generated reactive intermediates may interact with DNA to form adducts that, if they escape the repair mechanisms of the cell, may be fixed and passed to the progeny, thus giving rise to a mutation. Reactive intermediates of chemicals may also induce DNA damage through an alternative mechanism that involves interaction with molecular oxygen to generate reactive oxygen species that can cause cellular damage similar to that resulting from the covalent interaction of the reactive species of chemicals with cellular components they oxidize (1) DNA to induce mutations, (2) lipids to form lipid peroxides, which appear to play an important role in the promotion and progression stages of chemical carcinogenesis, and also (3) proteins.13 The reactive intermediates of chemicals may also interact covalently with proteins,...

Clinical pharmacology The interferons

Motherapy had a significantly longer progression-free survival than patients who received chemotherapy alone. Intron A treatment of condylomata was significantly more effective than placebo, as measured by disappearance of lesions, decreases in lesion size, and by an overall change in disease status. Studies in patients with chronic hepatitis C demonstrated that Intron A therapy can produce meaningful effects on this disease, manifested by normalization of serum alanine aminotrans-ferase and reduction in liver necrosis and degeneration. F. Role in therapy According to Micromedex, Intron A is the agent of choice for the treatment of malignant melanoma (surgical adjuvant) and chronic hepatitis B. It is also the drug of choice for chronic hepatitis C in combination with ribavirin. The combination is available under the name Rebetron. Intron A is an alternative (unresponsive intolerant patients) to pentostatin in hairy-cell leukemia, topical podophyllin regimens in condyloma acuminata,...

Studies of Cancer in Humans

Beginning in the 1960s and throughout the 1980s, a large number of ecological correlation studies were carried out to look for a possible correlation between dietary intake of aflatoxins and risk of primary liver cancer (IARC, 1993). Most of these studies were carried out in developing countries of sub-Saharan Africa or Asia, where liver cancer is common. With some notable exceptions, and despite the methodological limitations of these studies, they tended to show that areas with the highest presumed aflatoxin intake also had the highest liver cancer rates. However, the limitations of these studies, including questionable diagnosis and registration of liver cancer in the areas studied, questionable assessment of aflatoxin intake at the individual level, non-existent or questionable control for the effect of hepatitis virus and the usual problem of making inferences for individuals from observations on units at the ecological level, led to increasing recognition of the need for studies...

Pegylated Interferona2b and Methadone

To determine the effect of peg-IFN-a2b on opiate withdrawal symptoms, Berk et al. (25) evaluated their patients with HIV and chronic Hepatitis C virus infection using subjective opiate withdrawal scale (SOWS) and objective opiate withdrawal scale (OOWS) assessment methods at baseline and 7, 14, and 21 days after the administration of the first dose. Weekly clinical evaluation for signs and symptoms of methadone withdrawal of peg-IFN-a2b was conducted. The results of this study indicated that SOWS and OOWS scores of methadone were not statistically different with and without peg-IFN-a2b. Therefore, the authors recommended that methadone dosage adjustment, when given with peg-IFN-a2b, is not necessary in patients with HIV and chronic Hepatitis C virus infection.

Buprenorphine Therapy

In France since February 1996, general practitioners have also been allowed to prescribe buprenorphine in high dosage for maintenance treatment of major opioid drug addiction. A prospective cohort study (Duburcq et al. 2000) of 919 major opioid addicts was performed to assess patient outcomes with a follow-up of up to 2 years. High dosage of buprenorphine was prescribed by general practitioners for 3 months to opioid addicts who had a long serious history of drug addiction, parallel consumption of cocaine, and other illicit drugs. In 2 years, about two-thirds of the patients remained in follow-up by two general practitioners there was a reduction in drug-related harm such as seroconversions for hepatitis B, hepatitis C, and HIV substitution treatment rate was 84 duration of prescription and dispensing increased heroin intake fell by 25 and declaration of drug intake fell by about 30 (Duburcq et al. 2000).

Hepatic Stellate Cells

Hepatic stellate cell activation is also associated with the induction of other liver diseases. In livers of patients with chronic hepatitis, an increased number of activated HSC were detected 87 . Recently, an interaction of hepatitis C virus (HCV) with HSC was reported 88 . Furthermore, HSC activation is associated with the development of liver tumors, for instance, hepatocellular carcinomas (HCC). Mediators like TGF-a and TGF-P derived from dysplastic hepatocytes

Limitations of recent studies

Many recent studies have used HBsAg as the marker of exposure to HBV. However, among liver cancer cases that are negative for HBsAg, HBV DNA can be detected in 33 (serum) and 47 (liver) of the cases, notably those from areas of high viral prevalence. Similarly, HCV RNA can be found in 7 (serum) and 26 (liver) of anti-HCV-negative liver cancer cases (Brechot et al., 1998). Thus studies relying on HBsAg or anti-HCV measurements may underestimate viral exposure and this may affect an evaluation of interaction between hepatitis viruses and aflatoxin (Paterlini et al., 1994 Kew et al., 1997 Kazemi-Shirazi et al., 2000).

Chronic Liver Diseases Of Interest For Drug Targeting

As mentioned before, drug targeting to the liver may be a promising therapeutic approach for hepatic diseases with a chronic character. Examples of such diseases are liver cirrhosis, viral hepatitis and other infectious liver diseases, liver carcinomas or metastases of tumors, and hepatic autoimmune diseases (hemochromatosis, Wilson's disease, and a antitrypsine deficiency). The problem with the available pharmacotherapy in these diseases is that most drugs are not liver-specific and often exhibit undesirable toxicity. In the next paragraphs, we describe the pathosis of chronic liver diseases that are the subject of experimental therapies based on the application of drug delivery systems. This knowledge is important for the development of specific carriers and for the identification of molecular regulatory pathways that may serve as targets for therapeutical interventions.

Molecular Targets of NOASA in Cancer

M-NO-ASA inhibits cytokine production from endotoxin-stimulated human monocytes and macrophages (Fiorucci, Santucci, Cirino, et al., 2000) and when administered to mice, decreased IL-1p, IL-8, IL-12, IL-18, TNF-a, and INF-g production and protected against concanavalin A-induced acute hepatitis (Fiorucci, Santucci, Antonelli, et al., 2000). The effect exerted by NO-ASA on cytokine production was COX-independent

Cancer Prevention And Diet

In most human cancers, carcinogens are not so clearly defined that they can be eliminated or avoided. Even the carcinogens discussed in the previous section are not the only causes of the respective cancers. Thus, more careful exposure to sunlight will prevent many, but not all skin cancers. Vaccination against HBV (and eventually HCV) is expected to prevent liver cancers resulting from chronic viral

Administration with known carcinogens and other modifying factors

Transgenic mouse Hepatitis B virus-positive (HBV+) C57BL 6 mice were bred with TP53-null mice (TP53-) to produce TP53+, HBV+ mice. These mice and control litter mates (TP53+ +, HBV+ and TP53+-, HBV-) were randomly divided into groups of 16-24 animals. Approximately half of the animals in each group were females. The experimental group received a single intraperitoneal injection of 10 mg kg bw aflatoxin B1 in tricaprylin, while the controls received tricaprylin alone at the age of one week. Surviving animals were sacrificed at 13 months and assessed for HBV positivity by HBsAg expression. The incidence of hepatocellular tumours of Beckers classification grade 2 or higher adenomas and carcinomas was 100 in males that were heterozygous for the TP53 allele and that carried HBV and received aflatoxin B1 and was 62.5 in males that were homozygous for the wild-type TP53 allele and had both risk factors (HBV and aflatoxin B1). The presence of HBV without aflatoxin in heterozygous animals was...

Prevention Of Cancers In Groups At High Risk

Recommending dietary changes such as 'Take 5 ' ( 20.3) is a cancer prevention strategy that addresses the overall population. This strategy is unproblematic. No adverse effects are to be feared and the same changes in diet supposed to decrease the risk of major cancers very likely diminish the risk of cardiovascular disease and diabetes, to a perhaps even greater extent. It is similarly unproblematic to pursue cancer prevention by vaccinating an entire population against HBV or HCV, which likewise has the additional benefit of preventing acute and chronic liver disease. There are risks involved in vaccination, since a few individual show adverse reactions, but they are much lower than the risks associated with actual infections. Moreover, as HBV does not seem to possess an animal reservoir, there is hope that this virus may not only be contained, but eventually be exterminated by vaccination. No foreseeable downside would be associated with its demise.

HSV1 Based Vectors Applications

Moreover, amplicons could also allow antigens to be presented by both MHC pathways during the same immunization protocol. This could be achieved (i) by introducing the transgene both in the amplicon genome and in the helper genome or, (ii) by inducing the in vivo production of empty virus-like capsids of selected viruses (e.g., HIV-l,HCV,or HPV-16). Concerning this last property, it has been shown that HSV-1 amplicons encoding Moloney murine leukemia virus gag, pol and env genes can induce the synthesis of retrovirus-like particles in cultured cells. Amplicons have been used to efficiently transduce the full set of proteins of MoMLV retrovirus vectors, thus rescuing integrated retrovirus vectors,100101 as well as the nonstructural102 or structural103 proteins of HCV.104 An interesting remark is that amplicon expressing cytokine genes have been found to be a promising strategy for the development of tumor vaccines.105,106

Mechanism Of Action

Moving from intestine to liver and concentrating in liver cells. Protein synthesis is induced in the liver by silybin, whose steroid structure stimulates both DNA and RNA synthesis. Through these activities, the regenerative capacity of the liver is activated. Silymarin is reported to alter the outer cell membrane structure of liver cells, blocking entrance of toxic substances into the cell. This blockage is so pronounced that it can reduce the death rate from Amanita phal-loides poisoning. Silymarin's effect can be explained by its antioxidant properties it scavenges free radicals. By this effect, the level of intracellular glutathione rises, becoming available for other detoxification reactions. Silybin inhibits enzymes such as lipoxygenase,66 blocking peroxidation of fatty acids and membrane lipid damage. Studies also show that silymarin protects the liver from amitriptyline, nor-triptyline, carbon tetrachloride, and cisplatin. When treated, patients with alcoholic cirrhosis showed...

Human carcinogenicity data

Studies evaluated in Volume 56 of the IARC Monographs led to the classification of naturally occurring aflatoxins as carcinogenic to humans (Group 1). Recent studies have incorporated improvements in study design, study size and accuracy of measurement of markers of exposure to aflatoxin and hepatitis viruses. In a large cohort study in Shanghai, China, risk for hepatocellular carcinoma was elevated among people with aflatoxin metabolites in urine, after adjustment for cigarette smoking and hepatitis B surface antigen positivity. No association was observed between dietary aflatoxin levels, as ascertained by a diet frequency questionnaire, and risk for hepatocellular carcinoma. There were four reports from cohort studies in Taiwan, China, although three of them partly overlapped. Selected subjects in the three overlapping studies were enrolled, were interviewed, had biological specimens taken, and were followed up intensively for liver cancer. In nested case-control studies, including...

Animal carcinogenicity data

A study in transgenic mice overexpressing transforming growth factor P showed no increased susceptibility to induction of hepatocellular adenomas and carcinomas after intraperitoneal administration of aflatoxin B1. In another study, induction of hepato-cellular tumours by aflatoxin B1 was significantly enhanced in transgenic mice heterozygous for the TP53 gene and expressing hepatitis B surface antigen. The tumour response for aflatoxin B1 was reduced in the absence of either one of these risk factors. The presence of the TP53 246ser mutant not only enhanced the synergistic effect of hepatitis B virus and aflatoxin B1 but also increased tumorigenesis due to aflatoxin B1 in the absence of hepatitis B virus. In tree shrews, the incidence of hepatocellular carcinomas was significantly increased and the time of occurrence was shortened in animals treated with aflatoxin B1 and infected with (human) hepatitis B virus compared with aflatoxin B1-treated animals. Woodchucks infected with...

RNAi Approaches to Inhibit HIV Replication

HIV was the first infectious agent targeted by RNAi, perhaps because the life cycle and pattern of gene expression of HIV is well understood. Synthetic siRNAs and expressed shRNAs have been used to target virtually all of the HIV-encoded RNAs in cell lines, including tat, rev, gag, pol, nef, vif, env, vpr and the LTR.33 37 Subsequent work showed a host of other viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), poliovirus, respiratory syn-cytial virus (RSV) and others were targetable by RNAi (recently reviewed in Leonard and Schaffer38). A variety of approaches are being explored to express multiple siRNAs.69 The target sequence of a typical siRNA is 21 nucleotides. Long hairpin RNAs (lhRNAs) greater than 50 base pairs in length can be expressed in cells and create multiple siRNAs via Dicer-mediated processing.70 73 Expressed lhRNAs have been shown to be effective in cell culture against targets for HCV and HIV and in vivo for targets against HBV.71,73 76 However,...

Other relevant data

Current knowledge of the molecular mechanisms contributes to the understanding of the nature of the interaction between hepatitis B virus and aflatoxins in determining risk for hepatocellular carcinoma. Infection with hepatitis B virus may increase aflatoxin metabolism in hepatitis B virus-transgenic mice, liver injury is associated with increased expression of cytochrome P450 (CYP) enzymes. Glutathione -transferase activity is also reduced in human liver in the presence of hepatitis B virus infection. Other molecular mechanisms are, however, also likely to be relevant to aflatoxin-induced carcinogenesis.

Side Effects Of Hexaethyltetraphosphate

Metabolism of, 78-79 Hammett's constant, 20 HAV. See Hepatitis A vaccines HBV. See Hepatitis B vaccines HC-3. See Hemicholinium hCG. See Human chorionic gonadotropin HCV. See Hepatitis C vaccines Heart disease HRT and, 847 ischemic, 617-618, 618 Helicobacter pylori, 760, 764 Helixate. See Antihemophilic factor, recombinant Helminthic infections, 224-225 Hemabate. See Carboprost tromethamine Hemagluttin, 336 Hemophil M. See Antihemophilic factor Henderson-Hasselbalch equation, 12 Heparin, 655, 657-658 Hepatitis A vaccines (HAV), 170 Hepatitis B vaccines (HBV), 171 Hepatitis C vaccines (HCV), 171 Hepatitis E vaccines (HEV), 171 Hepatitis vaccines, 170-171 Hepatobiliary aminodiacetic acids, 424 Hepatobiliary iminodiacetic acids (HIDA), 425 Hepatolite. See Technetium (99mTc) disofenin Hepatotoxicity, of acetaminophen and phenacetin, 805-806, 806 Heptane antihistamines, 740t Herbal medicines, as anti-infective agent, 179 Herbs. See Medicinal herbs Herceptin. See Trastuzumab Heroin, 783 ,...

Nervous system vasculitis secondary to infections and related conditions

Hepatitis C virus hepatitis B virus hepatitis A virus Bacteria The pattern of neuropathy in vasculitic peripheral neuropathy associated with HIV infection varies and can be seen as a distal symmetrical sensory neuropathy, as a symmetrical or asymmetrical sensorimotor polyneuropathy or as mononeuritis multiplex.45,47 Most occur early, are not associated with multisystem involvement, can be painful and have a monophasic course.45,47 Cryoglobulinaemia, which may be associated with vasculitis, has also been described in patients with HIV infection and mononeuritis multiplex, in the absence of co-infection with hepatitis B or C viruses.45 Secondary infections and lymphoproliferative diseases also need to be considered in the differential diagnosis of PNS vasculitis in HIV infection, as their treatment protocols are different. Hepatitis viruses Neurological complications resulting from infection with the hepatitis viruses are relatively uncommon, and when they occur they are either directly...

O Factors Affecting Drug Metabolism

Factors Affecting Drug Metabolism

The effect of old age on drug metabolism has not been as well studied. There is some evidence in animals and humans that drug metabolism diminishes with old age.491,492 Much of the evidence, however, is based on prolonged plasma half-lives of drugs that are metabolized totally or mainly by hepatic microsomal enzymes (e.g., antipyrine, phenobarbital, acetaminophen). In evaluating the effect of age on drug metabolism, one must differentiate between normal loss of enzymatic activity with aging and the effect of a diseased liver from hepatitis, cirrhosis, etc., plus decreased renal function, because much of the water-soluble conjugation products are excreted in the liver.

Amine Group In Erythromycin

Base Hydrolysis Sulfate Half Ester

The toxicity of erythromycin is comparatively low. Primary adverse reactions to the antibiotic are related to its actions on the GI tract and the liver. Erythromycin may stimulate GI motility following either oral or parenteral ad-ministration.211 This dose-related, prokinetic effect can cause abdominal cramps, epigastric distress, and diarrhea, especially in children and young adults. Cholestatic hepatitis occurs occasionally with erythromycin, usually in adults and more frequently with the estolate. Erythromycin estolate, erythromycin propionate lauryl sulfate (Ilosone), is the lauryl sulfate salt of the 2'-propionate ester of erythromycin. Erythromycin estolate is acid stable and absorbed as the propionate ester. The ester undergoes slow hydrolysis in vivo. Only the free base binds to bacterial ribosomes. Some evidence, however, suggests that the ester is taken up by bacterial cells more rapidly than the free base and undergoes hydrolysis by bacterial esterases within the cells....

Effects of Upstream and Downstream Processes

The suppressors of SOCS system, which modulates certain cell surface receptors by inhibiting downstream signal transduction pathways and targeting receptors for degradation through the proteosome, may have effects upstream or downstream of the therapeutic target (see sect. Target-Mediated Elimination Pathways ). Specific SOCS family proteins have been shown to regulate signaling by IFN-a, insulin, leptin, G-CSF, and somatotropin (31,32,39-41). Several Pgx studies have found significant associations between SOCS1 and SOCS3 genotypes or pretreatment mRNA levels and response to IFN-a treatment in chronic hepatitis C patients (35-38).

Rdnaderived Miscellaneous Products

Antihemophilic factor (factor VIII) (Humate-P, Hemophil M, Koate HP, Monoclate-P) is a glycoprotein found in human plasma and a necessary cofactor in the blood-clotting mechanism. This high-molecular-weight glycoprotein has a complex structure with several components (subcofactors).95 The commercially available concentrates derived from blood collected from volunteer donors by the American Red Cross Blood Services are used primarily for the treatment of patients with hemophilia A. Because the commercially available products are purified concentrates derived from blood pooled from millions of donors, the major precautions in using the products relate to transmission of viruses, such as hepatitis virus, herpesvirus, and HIV. This major problem has been alleviated, mostly because of the development and marketing of rDNA-derived antihemophilic factors.

LCM and Two Dimensional Gel Electrophoresis

The relative low number of microdissected cells emphasizes the importance of loading equivalent amounts of protein on the gels. Thus, Shekouh and coworkers (18) followed a strategy to increase the accuracy of 2D PAGE from LCM samples. The samples were first separated by one-dimensional sodium dodecyl sulphate (SDS)-PAGE, stained with silver and subsequently subjected to densitometry. Evaluation of the staining intensity was used to normalize the samples. The 2D PAGE silver stained images from 50,000 microdissected adenocarcinoma cells were compared with the images from whole sections of pancreatic samples. Spots of their interest were subjected to MALDI-TOF TOF MS, resulting in the identification of S100A6 as an over-expressed protein in pancreatic cancer cells (18). The same methodology has been used to understand the mechanism of a specific molecule such as (HER-2 neu) in breast cancer (19). Breast cancer tissue was used to microdissect about 50,000-70,000 cells from three HER-2...

Historical Perspective Of Pharmaceutical Biotechnology

The biotechnology milestones are graphically presented in Figure 1.1. While each event listed in Figure 1.1 may not by itself have permitted the rapid application of biotechnology to drug development, in the aggregate they have led to the development of dozens of pharmaceutical products that could not have been realized without the availability of these technologies. The advances in technologies make the process possible or accelerate it, or just simply make the product cost-effective and much safer than the same material extracted from tissue sources. For example, the development of a yeast plasmid vector permitted mass production of hepatitis B surface antigen for vaccine development and the economical manufacture of recombinant human insulin.

Effects Of Antidepressants On Depression Induced By Immune Activation

Bendsen Signs

Antidepressants have been used successfully in treating depressive symptoms associated with various medical conditions (Katon & Sullivan, 1990). Both tricyclic antidepressants (TCAs) (Schiffer & Wineman, 1990) and selective serotonin reuptake inhibitors (SSRIs) (Scott, Nussbaum, McConnell, & Brill, 1995) have been used successfully in the treatment of depression associated with multiple sclerosis, stroke (Lauritzen, Bjerg Bendsen, Vilmar, Bjerg Bendsen, Lunde, & Bech, 1994), Alzheimer's disease (Gottfries, 1997 Tueth, 1995), HIV infection (Ayuso, 1994 Rabkin, Wagner, & Rabkin, 1994), and depression induced by IFN administration (e.g., in hepatitis C or multiple sclerosis patients) (Levenson & Fallon, 1993 Mohr, Goodkin, Likosky, Gatto, Baumann, & Rudick, 1997).

Effects of CPP Sequences on PPMO Efficacy

Murine hepatitis virus (MHV) cell culture and mouse models were used to compare the PMO delivery efficacy of R9F2C, (RXR)4XB and their derivatives. (RXR)4XB PPMO caused statistically significant reduction of MHV viral titer in the target organs of the MHV-infected mice, but R9F2C PPMO did not, although both PPMOs were equally effective in a cell-culture model. Shortening the (RXR)4XB CPP or modifying the CPP with mannose significantly reduced the activity of the resulting PPMOs.90

Consequences Of Antibodies To Therapeutic Proteins

The consequences of the specific interaction between protein drugs is dependent on the affinity of the antibody translating in binding and or neutralizing capacity. Binding antibodies may influence the pharmacokinetic behavior of the product, and both increases and reductions of half-life have been reported, resulting in enhancement or reduction in activity. Persisting levels of neutralizing antibodies in general result in a loss of activity of the protein drug. In some cases the loss of efficacy can easily be monitored by the increase of disease activity. For example, in interferon alpha treatment of hepatitis C, viral activity can be monitored by transaminase activity. Loss of efficacy is correlated directly by increased viral activity and increase in transaminase levels.

Effect of Interferona2b on Methadone Pharmacokinetics

Methadone, a racemic mixture, is primarily metabolized by CYP3A4, secondarily by CYP2D6, and to a lesser extent by CYP1A2 and CYP2B6 (18). Gupta et al. (24) evaluated the effects of multiple doses of peg-IFN-a2b (PEGASYS) on the steady-state pharmacokinetics of methadone in patients with hepatitis C. Twenty adults with hepatitis C virus infection received peg-IFN-a2b (1.5 mg kg wk) SC for four weeks and maintained their normal methadone regimen (approximately 40 mg day). There was approximately 15 increase in the exposure of individual isomers as well as total methadone after four weekly doses of peg-IFN-a2b, as compared with the exposure observed before peg-IFN-a2b administration. According to the authors, this increase in methadone exposure may not be of any clinical significance, although this study further supports the concept that peg-IFN-a2b can modulate metabolic enzyme functions associated with drug clearance. Berk et al. (25) studied the effect of peg-IFN-a2b (1.5 mg kg given...

Cytoprotective Effects of Thioredoxin

Thioredoxin has been shown to play crucial roles in cytoprotection against a variety of oxidative stress. Recombinant thioredoxin can protect cells from anti-Fas antibody-induced apoptosis and cytotoxicity induced by TNF-alpha, hydrogen peroxide and activated neutrophils.1516 Thioredoxin is also a potent costimulator of various cytokine expression.17,18 Recently, Nilsson et al. reported that thioredoxin induces the secretion of TNF-alpha and maintains the expression of Bcl-2, whereby prolongs survival of B-LCL.19 Overexpression of thioredoxin has been observed in a wide variety of oxidative conditions such as viral infection, diabetes, ischemic reperfusion and malignant tissues.20 22 During viral infection, considerable amount of ROS is generated, causing tissue damage and DNA breaks. As thioredoxin was first purified from HTLV-1 transformed cells,21 thioredoxin is induced and or secreted from transformed cells related to infection of viruses such as HTLV-1, EBV,23 hepatitis C virus...

Antiprotozoal Effects

Sulfonamides or sulfones usually account for most toxicity associated with coadministration of these antifolate drugs (see Chapter 43). The combination of pyrimethamine (25 mg) and sulfa-doxine (500 mg) (fansidar) causes severe and even fatal cutaneous reactions in up to 1 in 5000 people. This combination also has been associated with serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated in individuals with previous reactions to sulfonamides, lactating mothers, and infants

Opioid Dependence and Its Treatment

Opioid dependence is a medical condition characterized by an individual's preoccupation with and strong desire to take opioids coupled with persistent drug-seeking behavior. It involves a sense of compulsion to consume the psychoactive substance, an inability to stop using it or to control the mode of drug-taking behavior. Obtaining the drug takes on high priority and the condition is frequently accompanied by psychiatric comorbidity and multiple substance abuse, resulting in numerous social, psychological and biological problems. These include high risk behavior such as prostitution and drug-related crime, an increased risk of obtaining infectious diseases such as hepatitis and HIV through shared use of needles and sexual activity, leading to an increased mortality rate accidental deaths by fatal overdose and suicides also contribute to these. According to the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision) clinical guidelines, three of the...

Methods Of Vaccine Production

Preparing Vaccine

The surface antigen (i.e., what is recognized as foreign) is harvested from the pathogen, purified, and reconstituted into a vaccine preparation. These antigens can take several forms, including the carbohydrate capsule, as in Neisseria meningitidis pili, as in N. gonorrhoeae flagella from motile bacteria (the basis for an experimental cholera vaccine) or the viral protein coat, as in the vaccine for hepatitis B. Advantages of the method are that there is virtually no chance of disease, contamination, or reversion and there are no storage problems. This method is currently as close to a perfect approach as we have. A problem is that the pathogen must be grown under careful control or an unsure source must be relied on. For example, hepatitis B vaccine was originally prepared from the serum of a controlled population of human carriers. Imagine the impact if one of the carriers developed another blood-borne disease. Additionally, these are strain-specific antigens (e.g., N. gonorrhoeae...

Physiological Manipulations

Receiving interferon treatment for cancer or hepatitis C (Asnis and De La Garza 2006). These findings suggest that drugs that block proinflammatory mediators may be novel antidepressants. Recent support for this possibility comes from a guinea pig model of stress-induced sickness behavior (Hennessy et al. 2007).

Iterative library deconvolutions

Easter Connect The Dots Hard

Peptides binding to the extracellular portion of the dopamine D2 receptor were found within a library of pentapeptides using a magnetic bead affinity selection methodology with Kd's as low as 0.1 pM 43 . An endothelin receptor antagonist hexapeptide was developed from a small library via three rounds of deconvolution 44 . A library of phos-phinic peptides provided subnanomolar selective tetrapeptide inhibitors of zinc endopep-tidases 45 . A peptide mimic of the hepatitis A antigenic sequence was found from a hexapeptide library, and from this a series of effective antibodies was developed 46 . The use of mass spectrometry to deconvolute a peptide library was described by Youngquist et al. 47 and was the subject of an issued patent 48 . Novel calcium-independent antigens to a calcium-dependent monoclonal antibody with potencies greater than that of the original antigen were reported recently 49 .

Sources And Manufacture Of Biopharmaceutical Products

Recombinant proteins may be expressed in a number of other microbial systems which do contain the enzymatic activities to facilitate post-translational processing. Various proteins have been expressed, both in yeast (particularly Saccharomyces cerevisiae) and fungi (especially various Aspergilli) (9-11). While such microorganisms are capable of glycosylating recombinant therapeutic proteins, the pattern of glycosylation usually differs to that associated with such proteins when expressed naturally in the human body. Such microbial expression systems exhibit a number of characteristic advantages and disadvantages in terms of recombinant protein production. Thus far, however, few recombinant biopharmaceuticals developed are produced in either yeast or fungal systems. Two approved biopharmaceuticals are produced in Saccharomyces cerevisiae. Refludan (recombinant hirudin, an anticoagulant marketed by Behringwerke AG) and recombinant hepatitis B surface antigen, incorporated into various...

Liver Cirrhosis or Fibrosis

Manufacturing Process For Aleve

Liver cirrhosis is among the top 10 causes of death in the Western world. The disease occurs after chronic damage to hepatic cells, mainly hepatocytes, which can be caused by viral hepatitis, chronic alcohol abuse or toxic injury, biliary disease, and metabolic liver disorders 64 . Liver cirrhosis is characterized by an abnormal deposition of connective tissue in the liver, which hampers the normal functions of the liver. Other features of the disease are general tissue damage, chronic inflammation, and the conversion of normal liver architecture into structurally abnormal nodules. Secondary to these anatomical changes are disturbances in the liver function and in the hemodynamics leading to portal hypertension and intrahepatic shunting 39, 64, 103 .

Absorption distribution metabolism and excretion

Rodent studies (see below) have demonstrated that viral damage to the liver affects the metabolism of aflatoxin. Kirby et al. (1996a) examined the expression of CYP enzymes in sections of normal human liver and in livers with hepatitis and cirrhosis. By use of immunohistochemical techniques, it was shown that in sections infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the concentration of CYP2A6 was increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. In the same tissues, CYP3A4 and CYP2B1 were somewhat increased and CYP1A2 was unaffected compared with normal liver. In HCV-infected liver, CYP2A6, CYP3A4 and CYP2B1 were increased in hepatocytes that had accumulated haemosiderin pigment.

Selective Removal of Copper Bound to Metallothionein

Diagram Copper Transport Liver

The concentration of Cu accumulating in the form bound to MT can be decreased either by reducing the intake of Cu or by removing the Cu accumulating in the liver. The former approach is possible by feeding diets and water of low Cu content, by competing the uptake absorption of Cu with Zn (30,31), or by inhibiting the uptake absorption of Cu by complexing with chelating agents, trientine, and D-penicillamine (31-34). The chelating agents may remove Cu not bound to CP in the bloodstream as well. However, the affinity of Cu to MT is greater than those of these chelating agents, and the Cu bound to MT in the liver cannot be removed. The former approach with diets of low Cu content may be possible for experimental animals but not practical for humans. The use of chelating agents is effective in retarding the onset of hepatitis (35). However, chelating agents are not powerful enough to remove Cu accumulating in the form bound to MT in the liver (36).

Cytotoxic And Immunosuppressant Drugs

Potential risk for hepatic fibrosis, such as a history of alcohol abuse or infection with hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug. Pregnancy and lactation are absolute contraindications to methotrexate use. Mechlorethamine hydrochloride (mustargen) and carmustine (bischloronitrosourea, BCNU, bicnu) are used topically to treat cutaneous T-cell lymphoma. Both can be applied as a solution or in ointment form. It is important to monitor complete blood counts and liver function tests because systemic absorption can cause bone marrow suppression and hepatitis. other side effects include allergic contact dermatitis, irritant dermatitis, secondary cutaneous malignancies, and pigmentary changes. Carmustine also can cause erythema and posttreatment telangiectasias.

Antiviral Agents 6121 Viral Diseases

A number of diseases of man are of viral origin. These include poliomyelitis, common cold (rhinovirus), influenza, hepatitis A and B (liver disease), herpes simplex (cold sores), rubella and measles, papillomas (warts) and the human immunodeficiency virus (HIV-AIDS). A virus

First observation of recovery of consciousness in hepatic coma

A 50-year-old female was admitted with a history of alcohol abuse, onset of jaundice, fatigue, nausea, vomiting, and dark urine. There was no history of contact with hepatitis or of intravenous or intramuscular medication. On admission, she had spider nevi and ascites. The diagnosis was acute alcoholic hepatitis. Her condition deteriorated after admission and she became comatose and unresponsive. After remaining comatose for two days, her condition was considered as terminal and with the insistence of her relatives she was referred by her physician to me for possible hemoperfusion since nothing else could be done. One hour after hemoperfusion, she started to regain consciousness and began to recognize her relative and answer questions in sentences. Hemoperfusion was carried out for a total of 80 min. She remained conscious for about an hour after the end of the hemoperfusion, but lapsed into coma again. Three days later she was still comatose, and a second hemoperfusion was initiated....

Pharmacotherapy Of Alcoholism

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a slip occurs. It is not a cure for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy. It typically is administered after detoxification and given at a dose of 50 mg day for several months. Adherence to the regimen is important to ensure the therapeutic value of naltrexone and has proven to be a problem for some patients. The most common side effect of naltrexone is nausea, which is more common in women than in men and subsides if the patients abstain from alcohol. When given in excessive doses, naltrexone can cause liver damage. It is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease.


Diphtheria, tetanus and hepatitis B (rDNA) vaccine (adsorbed) (2062) Avian infectious bronchitis vaccine (live) (0442) Avian infectious bursal disease vaccine (live) (0587) Avian infectious encephalomyelitis vaccine (live) (0588) Avian infectious laryngotracheitis vaccine (live) (1068) Canine leptospirosis vaccine (inactivated) (0447) Duck viral hepatitis type I vaccine (live) (1315) Fowl-pox vaccine (live) (0649) Marek's disease vaccine (live) (0589) Newcastle disease vaccine (live) (0450)


Recombivax and Engerix-B are interchangeable for immunization against hepatitis B virus (HBV, serum hepatitis). Both contain a 226-amino acid polypeptide composing 22-nm diameter particles that possess the antigenic epi-topes of the HBV surface coat (S) protein. The products from two manufacturers are expressed from recombinant S. cerevisiae. It is recommended that patients receive 3 doses, with the second dose 1 month after the first and the third dose 6 months after the first. The route and site of injection are IM in deltoid muscle or, for infants and young children, in the anterolateral thigh. The vaccines achieve 94 to 98 immunogenicity among adults 20 to 39 years of age, 1 to 2 months after the third dose. Adults older than 40 years of age reach 89 immunogenicity. Infants, young children, and adolescents achieve 96 to 99 immunogenicity.

Human Cancers

Finally, the hepatitis virus B (HBV) can be understood as an intermediate between a DNA virus and a retrovirus. It is certainly a co-carcinogenic agent in a substantial fraction of human liver cancers ( 16.3). It causes cancer by a mixture of direct effects of viral proteins and indirect effects resulting from chronic inflammation elicited by the viral infection. The same can be said of the RNA hepatitis C virus (HCV), which causes another substantial fraction of human liver cancers ( 16.1).

General Discussions

Regional differences and the potential of unknown infective agents must be included in any discussions of the future prospect of blood substitutes. Also to be included is the degree of regulatory requirements. Blood substitutes are urgently needed in regions of the world where there are severe shortages of donor blood because of cultural or religious beliefs that cause people to be less willing to donate blood. They are also urgently needed in regions with higher incidences of infective agents like HIV and thus a higher potential for contaminated donor blood. It is less urgent in regions with a lower incidence of HIV and where costly screening tests are being used to screen out infective agents in donated blood. On the other hand, it is important to remember the past unexpected outbreaks of HIV and hepatitis C and the resulting contaminated donated blood that persisted for years until proper screening tests are developed. If this should happen again with some yet unknown agents, (e.g....


While most of the recent reports of viral knockdowns using Morpholinos have used Morpholinos conjugated to CPPs (see later), papers have described viral knockdown or studies of viral components using unconjugated Morpholinos with and without other delivery strategies. Replication of the hepatitis C virus has been knocked down in tissue culture by electroporating the cultures to deliver Morpholinos that targeted internal ribosomal entry sites on viral RNA.17,31 Morpholinos targeting various sites on Vesivirus RNA caused sequence-specific responses, including increase or decrease of viral titers relative to controls in cultured cells.32 The ability of the hepatitis C virus helicase to unwind various substrates was investigated. Oligos of peptide nucleic acid (PNA), Morpholino, phosphorothioate or DNA were duplexed with a nucleic acid strand. DNA duplexed with DNA, phosphorothioate or Morpholino unwound with similar rates, while PNA-DNA heteroduplexes unwound 25 times more slowly and...


Ecstasy Ecstasy (methylenedioxymethamfetamine, MDMA) may cause severe reactions, even at doses that were previously tolerated. The most serious effects are delirium, coma, convulsions, ventricular arrhythmias, hyperthermia, rhabdomyolysis, acute renal failure, acute hepatitis, disseminated intravascular coagulation, adult respiratory distress syndrome, hyperreflexia, hypotension and intracerebral haemorrhage hyponatr-aemia has also been associated with ecstasy use.


The Australian Adverse Drug Reaction Advisory Committee received 11 reports of adverse reactions associated with echinacea use between July 1996 and September 1997. There were three reports of hepatitis, three of asthma, one of rash, myalgia, and nausea, one of utricaria and one of anaphylaxis. There are other published reports of echinacea associated with contact dermatitis and anaphylaxis.78


Rash is the most frequent side effect and is seen in 18-36 (1998g Para et al., 1996). The rash is usually self-limited, occurs within 1-4 weeks of initiation of therapy, and is often pruritic and maculopapular eruptions over the upper half of the body. Rarely, hepatitis and neutropenia have been associated with delavirdine therapy.


Rash is again the most common side effect and is seen in up to 35 of patients (D'Aquila et al., 1996 Montaner et al., 1998a Carr et al., 1996 1998l). Like delavirdine, nevaripine's rash usually occurs in the first 6 weeks of therapy, is maculopapular, and is distributed over the torso and upper extremities. In clinical trials, 7 of patients stopped taking nevirapine because of the rash. Stevens-Johnson occurs in only 0.3 . Hepatitis occurs in 1 .