Search PubMed⌕ Search

Biomedical subjects

G Lake-Bakaar

Publications and source records attributed to G Lake-Bakaar.

At least 19 recordsLinked to original sources
PubMed2003

Current and future therapy for chronic hepatitis C virus liver disease.

Therapy with recombinant human interferon alpha remains pivotal to the treatment for chronic hepatitis C virus liver disease. Semi-synthetic protein-polymer conjugates of interferon with polyethylene glycol have also been recently developed. These conjugates protect the protein from degradation; reduce the immunogenicity; and prolong exposure to drug by a sustained absorption, restricted volume of distribution and sustained high serum concentration. Therapy with pegylated interferons is associated with significantly greater sustained virological response rates (SVR) compared to the non-pegylated formulation. Ribavirin is a guanosine analog with minimal antiviral activity against HCV. It demonstrates significant clinical synergism when administered in combination with interferon. Amantadine blocks entry of influenza A virus into cells. Used in combination with ribavirin and interferon as triple therapy, it may have some benefit compared to dual or monotherapy. Current treatment with pegylated interferons combined with weight-based ribavirin, provides the highest sustained virological response rates. In the absence of suitable animal models, HCV dynamic studies in man have been helpful in defining the mechanisms of action of interferon in chronic HCV liver disease. Novel therapeutic agents are being developed as the replication cycle of HCV is being understood. However, their safety and efficacy remain to be established and availability for clinical use is unlikely within the next 3 to 5 years. This review describes current antiviral therapy in chronic HCV liver disease, addresses the potential role of viral dynamics in elucidating the mechanisms of action of the drugs and discusses future potential therapeutics agents.

Antiviral Agents↗
PubMed2001

Differential effects of nucleoside analogs on oxidative phosphorylation in human pancreatic cells.

Although nucleoside analogs as a group inhibit mtDNA replication, individually they target specific organs for toxicity. For example, dideoxyinosine (ddI) is most closely associated with clinical pancreatitis and dideoxycytosine (ddC) with peripheral neuropathy. Comparison of the differential effects of these analogs on mitochondrial function in relevant human cell lines could provide general clues as to the mechanisms of their differential toxicity. We compared the effects of ddI [and its intracellular metabolite dideoxyadenosine (ddA)], with other nucleoside analogs ddC, Azidothymidine (AZT) and didehydrodeoxythymidine (d4T) on mtDNA elongation, cytotoxicity, oxidative phosphorylation, and cellular ATP concentration in a human pancreatic cell line, Capan-1 cells. AZT, like all the other analogs tested, altered mtDNA elongation, but had no other effect on these cells. Both ddC and d4T, but not ddI (20 microm and 50 microM), reduced total dish protein (a measure of cell numbers) in cells grown to confluence. The effect of ddA was intermediate. All (except AZT) increased lactate concentration in the cell culture medium. Dideoxycytosine (ddC) and d4T did not significantly affect cell oxygen consumption, expressed as a fraction of total dish protein. By contrast, ddI and ddA reduced basal and/or FCCP-stimulated oxygen consumption. Dideoxycytosine (ddC) but not ddI or ddA (50 microM) was cytotoxic to cells after six days of growth. Nevertheless, the ATP content (expressed as a fraction of surviving cells) for ddC-, ddI-, and ddA-treated cells was similar to control cells. Cytotoxicity was apparent for ddI, ddA, as well as ddC after seven days. Paradoxically, cell ATP content was now significantly higher than control cells. Electron microscopy of cells treated with ddI confirmed significant ultrastructural changes affecting the inner mitochondria membrane and cristae. In conclusion, these data suggest that nucleoside analogs uniformly induce damage to mtDNA. However, the mitochondrial phenotypic damage induced by ddI and ddA appear to result in less Capan-1 cytotoxicity than ddC and d4T. The link between these differential effects and ddI pancreatitis is unclear.

Antimetabolites↗
PubMed2001

Nitric oxide and chronic HCV and HIV infections.

High concentrations of nitric oxide (NO) are generated by the inducible form of the enzyme nitric oxide synthase (iNOS), which is expressed in activated macrophages and in hepatocytes. Increased expression of iNOS in hepatocytes or macrophages might be expected in chronic HCV liver disease and HIV infections. This might in turn be reflected in increased serum NO levels in these two conditions. In view of the discrepant findings in published reports, we measured serum NO levels in a large number of chronic HCV-infected patients and patients with chronic HIV infections with or without AIDS-related opportunistic infection. We also localized HCV and iNOS antigens by immunohistochemistry, in liver biopsy tissue from patients with chronic HCV-related hepatitis, HCV-related cirrhosis, and HCV-related hepatocellular carcinoma. A group of 121 subjects with serological evidence of HCV with or without HIV infection were studied. These were compared with 14 controls without HIV or HCV disease (group A). Among the subjects with HCV, 35 were negative for HIV (group B), 66 were HIV positive (group C), and 20 had AIDS-related opportunistic infection (group D). The serum NO concentration was determined by the Brucine method. A well-characterized commercially available antibody (HCV88) directed against a synthetic NS3 peptide fragment of HCV, which localizes to the hepatocyte nuclei, and an antibody to human macrophage iNOS, were both used to detect these proteins in liver biopsy tissue by immunohistochemistry. Mean serum NO values in HIV negative/HCV negative control patients (group A) (54.6+/-12 microM) were similar to those in HIV negative/HCV positive patients (group B) (55.0+/-13 microM) and HIV positive without AIDS-related disease/HCV positive patients (group C) (47.2+/-25 microM). By contrast, the mean serum NO (70.1+/-24 microM) was significantly increased in HCV-positive patients with AIDS-related infection (group D) compared to controls (P = 0.02). HCV NS3 and iNOS antibody staining hepatocytes were not detected in any of the control non-HCV-infected biopsy samples. In early chronic HCV hepatitis (fibrosis scores F0-F2), HCV NS3 antigen localized focally to only a small number of hepatocytes. In cirrhosis (fibrosis score F4) with or without hepatocellular carcinoma, the majority of hepatocyte nuclei stained positively with HCV NS3 antibody. The majority of hepatocytes in chronic HCV hepatitis expressed iNOS, irrespective of histological disease severity. The staining was present uniformly in the cytoplasm. In chronic HCV and HIV coinfection, the pattern and number of iNOS staining cells were similar to that in patients with chronic HCV infection alone. In conclusion, there is widespread expression of iNOS in hepatocytes in chronic HCV liver disease, irrespective of liver disease stage. However, elevated NO levels in serum were related only to active AIDS-related bacterial, protozoan, and fungal infections, rather than to chronic viral infection with HCV or HIV alone. NO may play a role in the local control of chronic viral infections at tissue level, but this is not reflected in serum levels.

AIDS-Related Opportunistic Infections↗
PubMed1996

Changes in parietal cell structure and function in HIV disease.

The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric mucosa were evaluated in patients with early and late HIV infection (AIDS) and compared to non-HIV-infected controls. Immunolocalization of HIV-related antigens in gastric mucosa was also examined. Fasting gastric juice pH and intrinsic factor (IF) concentration in AIDS and HIV infected subjects were significantly different from controls (P = 0.012 and P = 0.025, respectively for pH, and 0.029 and 0.035 for IF; ANOVA LSD test). By contrast, maximal acid output (MAO) was significantly lower in AIDS, but not HIV-infected subjects (P = 0.043 and P = 0.322, respectively). Similarly, Schilling test phases 1 and 2 results were significantly lower in AIDS, but not HIV-infected subjects. Varying degrees of vacuolar degeneration of parietal cells were seen on light microscopy. On electron microscopy (EM), tubulovesicles were reduced and intracellular canaliculi dilated with striking loss of microvilli. Immunofluorescent staining with antibodies to gp120, gp41, p24, and p17 demonstrated positive punctate signals in the cytoplasm of gastric glands, which includes parietal cells. Immunogold EM with anti-gp120, localized predominantly to the microvilli of intracellular canaliculi in parietal cells. Abnormal secretory function of parietal cells occurs early in HIV disease, affects acid as well as intrinsic factor secretion, and is associated with morphological changes in the acid secretory apparatus.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Alcohol abuse and stage of HIV disease in intravenous drug abusers.

Our objective was to identify factors that might correlate with human immunodeficiency virus (HIV) disease stage in intravenous drug abusers (IVDA). Particular attention was given to alcohol abuse. We accordingly explored in a cross-sectional study the relation between stage of HIV disease and age, sex, needle sharing, ethnicity, self-reported history of alcohol consumption and CAGE scores. IVDA from a single municipal hospital were subdivided into three groups according to HIV disease status. Group 1 comprised 42 individuals with AIDS; group 2 comprised 114 who were HIV positive but without AIDS; and group 3 comprised 52 who were HIV negative. Information on alcohol consumption and CAGE responses were obtained by questionnaire and interview. Discriminant analysis indicated that alcohol abuse, assessed either by self-reported consumption or by CAGE scores, was significantly more common in the AIDS group than in either the HIV positive or the HIV negative groups, when controlled for age, sex, and needle sharing status. The relative risk of AIDS was 3.8 times higher in the heavy drinkers than in moderate drinkers. Needle sharing was also more common in the AIDS group than in the HIV positive or HIV negative groups when the other factors were controlled for. AIDS was more common in black than white IVDA, and this increased frequency did not appear related to alcohol consumption since the distribution of heavy drinkers within each category of HIV disease did not differ within the ethnic groups. These data indicate that a history of heavy alcohol consumption is more common in IVDA with AIDS than in IVDA at earlier stages of HIV disease.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Dose-dependent effect of continuous subcutaneous verapamil infusion on experimental acute pancreatitis in mice.

Calcium antagonists may limit experimental tissue injury by membrane stabilization. We studied the effects of verapamil on pancreatic ultrastructure and zymogen extraction during diet-induced acute pancreatitis. Acute pancreatitis was induced in female Swiss-Webster mice by feeding a choline- and methionine-deficient diet (CD) supplemented with 1% ethionine (CDE). Varying doses of verapamil in normal saline were infused continuously at a rate of 0.5 microliter/hr for 96 hr through subcutaneously implanted osmotic pumps. The pancreata were examined blindly by light microscopy and by electron microscopy. Zymogen extracted from pancreatic tissue was measured and expressed per gram of protein. Mean histological scores, calculated according to a formula that incorporates the extent of necrosis, inflammation, acidophilia, and edema, were 14.1 +/- 4, 10.3 +/- 2, 9.9 +/- 4, 5.9 +/- 7, 12.5 +/- 4, and 12.7 +/- 4 for CDE-fed animals receiving 0, 0.14, 0.28, 0.56, 0.84, and 1.12 microM verapamil daily, respectively. Animals fed normal diet or CD had scores of 0 +/- 0. Histological scores were significantly lower in animals treated with 0.56 microns verapamil compared to animals who received no verapamil (p < 0.05) and was associated with reduced dissolution of the zymogen granule membrane on EM. Mean extracted trypsinogen and chymotrypsinogen content were reduced in the CD- and CDE-fed mice. The reduction in mean trypsinogen content reached statistical significance in CDE-fed mice treated with verapamil 0.56 microM daily. Mean chymotrypsinogen content was also significantly reduced CD-mice and in mice treated with 0.56 microns and 0.84 microM of verapamil daily. Increasing doses of verapamil protect against diet-induced pancreatitis in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

The effect of HIV disease on serum markers of hepatitis delta infection in intravenous drug abusers.

The prevalence of serum markers of delta hepatitis was determined prospectively in 82 intravenous drug abusers at various stages of human immunodeficiency virus (HIV) disease. Seventeen were HIV negative, 30 were HIV positive without acquired immunodeficiency syndrome (AIDS) and 35 had been diagnosed as having AIDS. Antihepatitis D virus (HDV) in serum was measured by a commercially available enzyme-linked immunosorbent assay (ELISA) and also by solid phase capture radioimmunoassays (RIAs) for immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-HDV. HDV antigen and hepatitis B virus (HBV) DNA were also measured. Hepatitis B surface antigen (HBsAg) and anti-HBs were determined by using a commercially available RIA. Anti-HDV (RIA) was only detected in serum that contained HBsAg. These anti-HDV (RIA) positive samples also tested positive with the commercial anti-HDV electroimmunoassay. In addition, the commercial anti-HDV ELISA detected anti-HDV in some serum samples that were negative for HBsAg; these anti HDV-positive HBsAg-negative samples were frequently lipemic or contained rheumatoid factor. The prevalence of HBsAg and anti-HBs did not differ significantly with the stage of HIV disease. HBsAg was detected in 3 of 13 (23%) HIV-negative, 5 of 29 (17%) HIV-positive, and 4 of 18 (22%) patients with AIDS. IgG and IgM anti-HDV (RIA) was positive in 2 of 3 HIV-negative and 4 of 5 HIV-positive pre-AIDS HBsAg-positive subjects. However, none of 4 AIDS patients had anti-HDV. The difference between AIDS and non-AIDS patients was statistically significant (Fisher's exact test, p = 0.03). HDV antigen was detected in serum from one AIDS patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Cytomegalovirus colitis in patients with acquired immunodeficiency syndrome.

The spectrum of presentation of complications in patients with human immunodeficiency virus (HIV) disease is changing, in line with their improved survival. Infection of the colon with cytomegalovirus (CMV) is now more commonly encountered in clinical practice. We have reviewed the medical records of eleven patients with clinical and pathological evidence of CMV colitis. The clinical presentation, endoscopic and histological findings, and simultaneous infection of other organs with CMV are discussed. Diarrhoea in association with abdominal pain is the most frequent symptom complex in these patients and should raise the clinical index of suspicion for CMV colitis.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Route of access of secretin into rabbit duodenal lumen during acid perfusion.

The route of entry of immunoreactive secretin into the duodenal lumen during acid perfusion is unknown. Possible sites include paracellular diffusion from the extracellular space, transapical secretion from S cells, or leaching from cells damaged by the perfusate. Antisecretin in the extracellular space and interstitium should reduce access due to paracellular diffusion from the interstitium without significantly affecting secretion or leaching. We therefore studied the effect of intravenous antisecretin antibody on luminal secretin output. Two groups of rabbits received either intravenous normal rabbit serum (controls) or antisecretin antibody, before perfusing a closed segment of duodenum with hydrochloric acid. Preliminary experiments established that duodenal perfusion with HCl concentrations below 0.025N produced no apparent mucosal damage on electron microscopy. HCl concentrations above this significantly damaged the mucosa. In the control group, perfusion with 0.01N, 0.0125N, and 0.025N hydrochloric acid resulted in a dose-dependent increase in secretin in the perfusate. Secretin output was markedly reduced in the group injected with secretin antibody. Antisecretin antibody significantly reduced bile flow at all levels of HCl concentration in the duodenal perfusate. These data suggest that luminal secretin is probably derived from the interstitium and travels to the lumen across narrow paracellular channels.

Animals↗
PubMed1988

Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS).

STUDY OBJECTIVE: To correlate oral ketoconazole absorption with gastric acid secretion in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Prospective measurement of maximal acid output and oral ketoconazole absorption with and without 0.1-N hydrochloric acid. SETTING: Hospital in-patients in university medical center. PATIENTS: Ten consecutive male patients with AIDS. INTERVENTION: Maximal acid output was determined after pentagastrin stimulation in all patients. Serum ketoconazole levels were measured the day after ingestion of a 200-mg ketoconazole tablet in the fasted state. On the final day, ketoconazole was ingested with 200 mL of 0.1-N hydrochloric acid. MEASUREMENTS AND MAIN RESULTS: Maximal acid output was below 15 mEq/h in 7 of 10 patients. In all 7, the area under the serum ketoconazole concentration-time curve was below normal (1.4 +/- 0.9 mg/h.L; mean +/- SE), and absorption was normalized by hydrochloric acid (9.9 +/- mg/h.L). Two of three patients with maximal acid outputs above 15 mEq/h had normal ketoconazole absorption (15.1 +/- 6.7 mg/h.L). CONCLUSIONS: The bioavailability of oral ketoconazole is reduced in patients with AIDS, largely as a result of gastric hypochlorhydria. Ketoconazole tablets should therefore be given with acid in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Hepatic reactions associated with ketoconazole in the United Kingdom.

Ketoconazole was introduced in the United Kingdom in 1981. By November 1984 the Committee on Safety of Medicines had received 82 reports of possible hepatotoxicity associated with the drug, including five deaths. An analysis of the 75 cases that had been adequately followed up suggested that 16, including three deaths, were probably related to treatment with the drug. Of the remainder, 48 were possibly related to treatment, five were unlikely to be so, and six were unclassifiable. The mean age of patients in the 16 probable cases was 57.9, with hepatotoxicity being more common in women. The average duration of treatment before the onset of jaundice was 61 days. None of these well validated cases occurred within the first 10 days after treatment. The results of serum liver function tests suggested hepatocellular injury in 10 (63%); the rest showed a mixed pattern. In contrast, the results of histological examination of the liver often showed evidence of cholestasis. The characteristics of the 48 patients in the possible cases were similar. Allergic manifestations such as rash and eosinophilia were rare. Hepatitis was usually reversible when treatment was stopped, with the results of liver function tests returning to normal after an average of 3.1 months. In two of the three deaths probably associated with ketoconazole treatment the drug had been continued after the onset of jaundice and other symptoms of hepatitis. Clinical and biochemical monitoring at regular intervals for evidence of hepatitis is advised during long term treatment with ketoconazole to prevent possible serious hepatic injury.

Adolescent↗
PubMed1987

Biliary immunoreactive trypsin in man.

Small, but significant amounts of immunoreactive trypsin/trypsinogen (IRT) are excreted in bile, obtained via percutaneous transhepatic catheter in patients with complete distal bile duct obstruction, and thus uncontaminated with pancreatic juice. The major serum proteolytic enzyme inhibitors alpha 2-macroglobulin and alpha 1-antitrypsin are also present in very small amounts in bile. The bile-to-serum ratios of these inhibitors are much lower (approximately two orders of magnitude) than that for IRT. The role of these inhibitors and their relative importance in biliary proteolytic enzyme inhibition is unknown.

Adenoma, Bile Duct↗