Experience with lamivudine against hepatitis B virus

After several nucleoside analogues have been tested against chronic hepatitis B virus (HBV) infection with minimal success, lamivudine seems to be a highly effective new therapeutic option. This review focuses on nucleoside metabolism and on the molecular action of lamivudine as well as on results of clinical studies for several indications. We report on results of trials on the use of lamivudine for chronic HBV infection, chronic HBV under immunosuppression and prophylaxis or treatment of HBV reinfection before or after orthotopic liver transplantation. Aspects of combination therapy of different nucleoside analogues as well as on combination of lamivudine with interferon are also highlighted. Although lamivudine seems to be highly effective in most patients at the start of therapy, development of resistance by mutations in the viral polymerase is a significant clinical problem. The mode of resistance development is compared with the situation in HIV infection. Possible cross-resistance with other nucleoside analogues and the perspectives of lamivudine therapy are also considered.     

Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations

Since its introduction in 1987, zidovudine monotherapy has been the treatment of choice for patients with HIV infection. Unfortunately it has been established that the beneficial effects of zidovudine are not sustained due to the development of resistant viral strains. This has led to the strategy of combination therapy, and in 1995 treatment with zidovudine plus didanosine, or zidovudine plus zalcitabine, was demonstrated to be more effective than zidovudine monotherapy in preventing disease progression and reducing mortality in patients with HIV disease. Recent work demonstrates an even greater antiviral effect from triple therapy with 2 nucleosides, zidovudine plus zalcitabine with the addition of saquinavir, a new protease inhibitor drug. The HIV protease enzyme is responsible for the post-translational processing of gag and gag-pol polyprotein precursors, and its inhibition by drugs such as saquinavir, ritonavir, indinavir and VX-478 results in the production of non-infectious virions. As resistance may also develop to the protease inhibitors they may be used in combination, and future strategies may well include quadruple therapy with 2 nucleoside analogues plus 2 protease inhibitors. Administration of protease inhibitors alone or in combination with other drugs does raise a number of important pharmacokinetic issues for patients with HIV disease. Some protease inhibitors (e.g. saquinavir) have kinetic profiles characterised by reduced absorption and a high first pass effect, resulting in poor bioavailability which may be improved by administrating with food. Physiological factors including achlorhydria, malabsorption and hepatic dysfunction may influence the bioavailability of protease inhibitors in HIV disease. Protease inhibitors are very highly bound to plasma proteins (> 98%), predominantly to alpha 1-acid glycoprotein. This may influence their antiviral activity in vitro and may also predispose to plasma protein displacement interactions. Such interactions are usually only of clinical relevance if the metabolism of the displaced drug is also inhibited. This is precisely the situation likely to pertain to the protease inhibitors, as ritonavir may displace other protease inhibitor drugs, such as saquinavir, from plasma proteins and inhibit their metabolism. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes present in the liver and small intestine. In vitro studies suggest that the most influential CYP isoenzyme involved in the metabolism of the protease inhibitors is CYP3A, with the isoforms CYP2C9 and CYP2D6 also contributing. Ritonavir has an elimination half-life (t1/2 beta) of 3 hours, indinavir 2 hours and saquinavir between 7 and 12 hours. Renal elimination is not significant, with less than 5% of ritonavir and saquinavir excreted in the unchanged form. As patients with HIV disease are likely to be taking multiple prolonged drug regimens this may lead to drug interactions as a result of enzyme induction or inhibition. Recognised enzyme inducers of CYP3A, which are likely to be prescribed for patients with HIV disease, include rifampicin (rifampin) [treatment of pulmonary tuberculosis], rifabutin (treatment and prophylaxis of Mycobacterium avium complex), phenobarbital (phenobarbitone), phenytoin and carbamazepine (treatment of seizures secondary to cerebral toxoplasmosis or cerebral lymphoma). These drugs may reduce the plasma concentrations of the protease inhibitors and reduce their antiviral efficacy. If coadministered drugs are substrates for a common CYP enzyme, the elimination of one or both drugs may be impaired. Drugs which are metabolised by CYP3A and are likely to be used in the treatment of patients with HIV disease include the azole antifungals, macrolide antibiotics and dapsone; therefore, protease inhibitors may interact with these drugs. (ABSTRACT TRUNCATED)     

Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies

Nucleoside analogues used in cancer and anti-viral therapies interfere with nucleotide metabolism and DNA replication, thus inducing their pharmacological effects. A long-awaited goal in the understanding of the pharmacological properties of these molecules, that is the molecular characterization of nucleoside plasma-membrane transporters, has been achieved very recently. These carrier proteins are encoded by at least two gene families and new isoforms remain to be identified. Direct demonstration of translocation of these drugs by nucleoside transporters has already been provided and most of them can inhibit natural nucleoside transport, probably in a competitive manner. The expression of these genes is clearly tissue-specific and might depend on the differentiated status of a cell. This is relevant because the sensitivity of a cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might modulate nucleoside carrier expression. In this article, Mar?al Pastor-Anglada, Antonio Felipe and Javier Casado discuss recent studies on the regulation of nucleoside carrier expression and of the molecular determinants of substrate specificity. Better knowledge of these will contribute to an improved design of therapies based on nucleoside derivatives.     

Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

BACKGROUND: The efficacy of highly active antiretroviral treatment (HAART) in HIV-1 disease may vary between nucleoside-naive and experienced patients as well as between patients with different viral phenotypes and in different stages of disease. OBJECTIVE: To investigate variables of importance for successful long-term viral suppression by analysing virological, clinical and immunological characteristics at initiation of protease inhibitor treatment on suppression of HIV RNA over 1 year. DESIGN: An open, non-randomized, observational clinical study. SETTING: Venh?lsan, Department of Dermatovenereology, S?der Hospital, Stockholm, Sweden. PATIENTS: A total of 147 unselected advanced patients with known HIV-1 infection for a mean of 7 years, of whom 37% had AIDS and who started treatment with a protease inhibitor during 1996. INTERVENTIONS: All patients received HAART with at least two nucleoside analogues in combination with either indinavir (81%) or ritonavir (19%). The majority (77%) had been previously treated with nucleoside analogues for a mean of 39 months. MEASUREMENTS: CD4+ lymphocyte count, plasma HIV-1 RNA, viral phenotype and HIV-1 coreceptor CCR-5 genotype at baseline. Viral load and CD4+ lymphocyte count were determined every 3 months. RESULTS: Patients were analysed on an intention-to-treat basis. The mean CD4+ lymphocyte count at baseline was 170 x 10(6)/l and the median viral load was 68 600 copies/ml. Heterozygosity for the delta32 deletion of the CCR-5 gene (delta32/wt) was found in 27%. MT-2 positive virus (syncytium-inducing) was isolated in 46%. Logistic regression revealed that nucleoside analogue experience and baseline log10 HIV-1 RNA were the only factors independently related to plasma HIV-1 RNA levels below 500 copies/ml after 1 year of treatment, which was found in 69%. CONCLUSION: The virological outcome after 1 year of HAART was strongly correlated to prior treatment history and baseline viral load, whereas CD4+ lymphocyte count, CCR-5 genotype and viral biological phenotype had less influence. The long-term antiviral efficacy of HAART was lowest in individuals with previous nucleoside analogue treatment and a high baseline viral load. In these individuals an even more aggressive treatment should be considered.     

Current status of anti-HBV chemotherapy

In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-alpha and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the mainstay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomew et al., 1997; Tipples et al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed.     

Value of digoxin in heart failure and sinus rhythm: new features of an old drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.     

The role of oxidative imbalance in progression to AIDS: effect of the thiol supplier N-acetylcysteine

In this study we investigate the redox profile of HIV+ patients at different stages of disease with regard to immunological parameters, i.e., the number of circulating CD4+ and CD8+ lymphocytes. For this purpose, peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, HIV+ patients in the asymptomatic phase, long-term nonProgressors (LTNPs), and AIDS patients have been considered. Cells have been exposed in vitro to the prooxidizing agent menadione, which is able to induce superoxide anion formation, and the susceptibility of the cells to the induced oxidative stress was estimated. Moreover, the possibility that the susceptibility of the cells to oxidative stress might be reduced by preexposing them to the antioxidizing agent N-acetylcysteine (NAC) has also been analyzed. The results obtained can be summarized as follows: (1) treatment with the prooxidant agent is capable of inducing massive morphological alterations in PBMCs. In particular, a significant correlation was found between the decrease in number of CD4+ lymphocytes in patients at different stages of disease and the susceptibility of their PBMCs to oxidative stress; (2) preincubation with NAC was able to preserve partially the ultrastructural characteristics of PBMCs isolated from HIV+ patients. In particular, a direct relationship was found between the efficacy of NAC protection and CD4 counts; (3) evaluation of the plasma index of peroxidation and the number of circulating CD4 lymphocytes indicates the existence of a positive correlation between "systemic" oxidative imbalance and stage of the disease; and (4) cells from LTNPs display either oxidative susceptibility or oxidative markers similar to those of healthy donor cells. Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial.     

Intron-exon structure of the MET gene and cloning of an alternatively-spliced Met isoform reveals frequent exon-skipping of a single large internal exon

BACKGROUND AND AIMS: the purine nucleoside analogues cladribine (CdA), fludarabine (F-Ara-AMP) and pentostatin (dCf), are effective therapy for a range of T- and B-cell lymphoid malignancies. The effects upon nucleotide metabolism in human CCRF-CEM T-cell leukaemia and Raji B-cell lymphoma cell lines of these drugs have been compared to assess possible mechanisms of cytotoxicity. METHODS: Leukaemia cells were exposed to a purine nucleoside analogue and perchloric acid extracts were analysed by HPLC for 2'-deoxynucleoside-5'-triphosphates (dNTPs), nucleoside-5'-triphosphates (NTPs) and drug metabolites. RESULTS: After addition of a purine nucleoside analogue, CdA-TP and F-Ara-ATP accumulate in cells while the levels of dCf-TP formed were not detectable by ultra-violet absorbance. In response to accumulating concentrations of drug triphosphate, the cellular levels of dNTPs initially decrease (0-4 h), then accumulate above their initial levels (4-10 h) before slowly declining beyond 10 h. NTPs also accumulate during the period 4-10 h before declining at later times. CONCLUSION: The temporal effects on the levels of dNTPs and NTPs of the 3 purine nucleoside analogues are similar against CCRF-CEM and Raji cells. However, CdA induces major depletions of dTTP, dGTP and dATP in CCRF-CEM cells and F-Ara-A induces a major accumulation of dATP in Raji cells.     

A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers

The different therapeutic options available for the treatment of chronic leukemias and myelofibrosis are discussed. In reference to chronic myeloid leukemia (CML), the choice of the most appropriate treatment must take into account not only the clinical condition but also the age of the patient. While subjects under 50 might benefit from the options offered by alpha-interferon, bone marrow and peripheral stem cell transplant, in older age groups treatment of the chronic phase must still rely on standard treatment. Chronic lymphocytic leukemia (CLL) and its variants is a disease of mostly middle and late life, with a variable clinical course. Patients show wide differences in morbidity and mortality. Many features have been shown to influence the prognosis, and the most important ones are incorporated into the staging systems currently in use. The results obtained from the study of large trials support the concept that treatment of patients with stable stage A CLL should be postponed until progression of disease. Treatment relies principally on alkylating agents, corticosteroids and radiation therapy; the new nucleoside analogues, such as fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value in improving overall survival. With regard to myelofibrosis, the histological and biological features that influence the natural course of the disease are described, as well as the choice of the most appropriate treatment, which ranges from the use of alkylating agents and androgens, to splenectomy and splenic irradiation.     

Structure to 1.9 A resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non-substrate inhibitor: X-ray crystallographic comparison with binding of aciclovir

Treatment of herpes infections with nucleoside analogues requires as an initial step the activation of the compounds by thymidine kinase. As an aid to developing more effective chemotherapy, both for treatment of recurrent herpes infection and in gene therapy systems where thymidine kinase is expressed, two high-resolution X-ray structures of thymidine kinase have been compared: one with the relatively poor substrate aciclovir (Zovirax), the other with a synthetic inhibitor having an N2-substituted guanine. Both compounds have similar binding modes in spite of their size difference and apparently distinct ligand properties.     

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team

BACKGROUND: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.     

MR imaging

MRI is a tool of unprecedented capabilities for evaluating arthritis and its progression. Not only can it non-invasively delineate the anatomy of all components of a joint with unparalleled clarity, MRI is also capable of probing important functional and compositional parameters of disease in these tissues. Particularly intriguing is MRI's potential for identifying very early changes of joint disease when clinical symptoms may be minimal or absent. Early detection of patients who are at risk for developing progressive disease may allow appropriate treatment to be initiated earlier, when there may be a greater chance of favourable outcome. MRI can, furthermore, provide objective and quantitative measures of disease progression and treatment response. Certain parameters, such as articular cartilage volume, have been validated cross-sectionally; however, their longitudinal performance has yet to be established. Further work is, therefore, necessary to thoroughly validate and optimize some of these measures so that they can begin to be used in more powerful ways to explore the pathophysiology and potential therapies of arthritic disorders.     

Calcium antagonists and renal protection: emerging perspectives

During the past two decades, major investigative interest has focused on the determinants of chronic renal disease and interventions that retard the inexorable progression to end-stage renal disease. Recent studies have provided a theoretic framework for anticipating that angiotensin-converting enzyme (ACE) inhibitors, and possibly calcium antagonists, may preferentially retard the progression of renal disease. Whereas the majority of available clinical trials have assessed the effects of ACE inhibitors in patients with insulin-dependent diabetes mellitus, relatively few long-term studies have evaluated the renoprotective effects of ACE inhibitors and calcium antagonists in patients with nondiabetic renal disease. Recent observations suggest that the two classes of drugs act in a complementary manner to countervail pathogenetic mechanisms at the level of the mesangium. Such observations recently prompted randomized prospective studies that compare the renoprotective effects of calcium antagonist versus ACE inhibitor monotherapy in both diabetic patients and patients with nondiabetic renal disease.     

Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?

The interaction of pregnancy and the rheumatic diseases varies, ranging from life-threatening conditions such as thromboembolic events and progressive renal disease in some autoimmune disorders, to minor flares of peripheral arthritis in inflammatory rheumatic disease. As a consequence, treatment strategy will vary according to the maternal or fetal compromise expected. All nonsteroidal anti-inflammatory drugs (NSAIDs), including high dose aspirin (acetylsalicylic acid), can cause adverse effects during pregnancy related to the inhibition of prostaglandin synthesis. Prolongation of gestation and labour, constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding are risks of third trimester exposure of pregnant women to all inhibitors of cyclo-oxygenase. Most of these adverse effects can be prevented by discontinuing NSAIDs 8 weeks prior to delivery. Low dose aspirin has not been associated with fetal or neonatal toxicity. Some corticosteroids such as prednisone and prednisolone do not readily cross the placenta and can be safely used during pregnancy as immunosuppressive drugs. Maternal complications related to corticosteroids may occur and close monitoring is therefore mandatory. There is limited information on the safety of disease-modifying antirheumatic drugs including gold, antimalarials, penicillamine (D-penicillamine), sulfasalazine and cyclosporin. Of these agents, sulfasalazine has the best record for tolerability and can be used by pregnant patients. Gold compounds and penicillamine should be discontinued when pregnancy is recognised. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine in patients requiring treatment with antimalarials. Use of cyclosporin may be an alternative to other therapy in pregnant patients with severe rheumatic disease. Indications for treatment with colchicine during pregnancy are few, except for familial Mediterranean fever. Azathioprine can be used when the maternal condition requires a cytotoxic drug during the first trimester. Cyclophosphamide, chlorambucil and methotrexate are contraindicated during pregnancy because of their teratogenic potential. Their use may be considered in late pregnancy if the mother has a life-threatening condition.     

Anesthesia for patients with carcinoid syndrome

Carcinoid syndrome, although rare, can create serious problems to the anesthetist, both by the nature and variability of clinical manifestations and by the complications that can occur peroperatively. Recent research has led to a better understanding of the pathophysiology of the disease process. However, modern medicine is far from unraveling the precise nature and physiological effects of all the peptide mediators produced by these tumors. The severity of symptoms does not predict the severity of perioperative complications, so that patients with minor preoperative symptoms may have significant intraoperative complications. While urinary 5-HIAA levels provide a good indicator of disease progression, they cannot predict the degree or type of physiological response to intraoperative tumor manipulation. Indeed, urinary 5-HIAA may be normal both in the presence of a clinical diagnosis of carcinoid syndrome and in the face of a peroperative carcinoid crisis. The keys to successful anesthetic management of patients with carcinoid syndrome are good communication between endocrinologist, anesthetist, and surgeon and preoperative optimization of the patient. This includes appropriate investigation and treatment of the effects of carcinoid peptides and the prevention of their release from tumors. If possible, advice should be sought from centers with experience at managing this group of patients. Octreotide has largely replaced the use of other drugs both for symptomatic control and acute treatment of the symptoms associated with carcinoid syndrome. However, other drugs, such as aprotinin, still have a significant place in the symptomatic control and treatment of peroperative complications, as serotonin is only one of a large variety of peptides responsible for the clinical effects of this disease. Anesthetic technique should be aimed at minimizing carcinoid mediator release, in response to stress it induction of anesthesia and tracheal intubation and during tumor manipulation. It is equally important to prepare for carcinoid crisis by, for example, ordering drugs, which are otherwise uncommonly used in the theater setting, ahead of time. Cardiovascular instability, particularly hypotension, is common, so that full monitoring and vigilance is vital to predict its onset. The current surgical view of management is that, while curative resection of carcinoid tumors less than 2 cm in diameter with no evidence of invasion or metastatic spread is appropriate, patients with disseminated disease should be medically managed unless symptom control is poor. The exceptions to this are those patients with early and correctable carcinoid cardiac disease and those who require palliative procedures such as defunctioning obstructed bowel. Survival rates in patients following excision of gastric and appendical carcinoid tumors approach those of the general population as a whole and the chance of metastasis is extremely low. Only two series have been published in the anesthetic literature on anesthesia for patients with carcinoid syndrome, although there are many single-case reports. Despite the rarity of this syndrome, further formal studies into the anesthetic management of this condition should be encouraged.     

A study on thallium-201 SPECT in brain metastases of lung cancer: with special reference to tumor size and tumor to normal brain thallium uptake ratio

The activity of prolyl endopeptidase (PEP), a serine proteinase, has been found to be significantly lower in the blood of patients with major depression than in normal volunteers. The present study investigates plasma PEP activity in 25 major depressed, 10 manic, and 14 schizophrenic subjects versus 30 normal volunteers. It also examines the effects of antidepressants, valproate, and neuroleptic drugs on plasma PEP activity. PEP activity was significantly lower in major depressed subjects than in normal volunteers and in patients with mania and schizophrenia. In depressed subjects, plasma PEP activity was significantly increased during treatment with antidepressant drugs, such as fluoxetine. Plasma PEP activity was significantly increased in manic and schizophrenic subjects compared with normal volunteers. In manic subjects, short-term treatment with valproate had a significant suppressive effect on PEP activity. No significant effects of neuroleptics on PEP activity could be found in the schizophrenic patients. The results support the hypothesis that lower PEP activity could play a role in the pathophysiology of major depression, while increased PEP activity may be related to psychotic conditions, such as mania and schizophrenia.