Rational pharmacotherapy and correction of immunity disorders in children with chronic hepatitis (clinical review)

The data on the efficacy of antivirals and their impact on the virologic and immunologic indices in HCV- and HBV-infected children are presented. The best therapeutic effect in the management of children with chronic virus hepatitis was provided by combined antiviral therapy of different action. In the treatment of babies the drugs of choice could be viferon or cycloferon, for the 2-year older children with chronic hepatitis B the combination of viferon + cycloferon should be recommended and for those with chronic hepatitis C the combination of interal + cycloferon could be used. The cycloferon combination with interferons-a makes it possible to generate the Th1 cellular immune response, to minimize the side effects of interferons and chemotherapeutics and to improve their tolerability. The complex therapy of patients with chronic hepatitis B and lambliasis, using cycloferon and macmiror, provided stable effect, less frequent relapses oflambliasis and minimum side effects of the specific therapy. The repeated isolation of lamblia within a 1-year observation period was recorded only in 16.6% of the children treated with cycloferon vs. the control (40.0%).     

Current concepts in glucocorticoid resistance

Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease.     

Emergency Cardiopulmonary Resuscitation—A Fifteen-Month Experience in a General Hospital

Results under a resuscitation program in a general hospital in which the entire house staff is capable of functioning as a team in emergency, bear out the effectiveness of prompt action in cardiopulmonary or other life-threatening emergencies. Such a program remains important in spite of the salutary trend toward coronary care units. Both emergency and definitive therapy must be accomplished without delay. A house staff is necessary for an effective emergency resuscitation program. Paramedical personnel must be instructed to recognize an emergency and immediately institute life-sustaining therapy. Definitive therapy must be applied as soon as possible.The entire house staff, rather than a specially organized team, should be trained in the techniques of definitive therapy.Consideration should be given to immediate defibrillation following diagnosis of cardiac arrest as an early step in definitive therapy.     

Synergy of small molecular inhibitors of hepatitis C virus replication directed at multiple viral targets

Chronic hepatitis C virus (HCV) infection is a significant worldwide health problem with limited therapeutic options. A number of novel, small molecular inhibitors of HCV replication are now entering early clinical trials in humans. Resistance to small molecular inhibitors is likely to be a significant hurdle to their use in patients. A systematic assessment of combinations of interferon and/or novel anti-hepatitis C virus agents from several different mechanistic classes was performed in vitro. Combinations of inhibitors with different mechanisms of action consistently demonstrated more synergy than did compounds with similar mechanisms of action. These results suggest that combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.     

Establishment of Hepatitis C Virus RNA-Replicating Cell Lines Possessing Ribavirin-Resistant Phenotype

BackgroundRibavirin (RBV) is a potential partner of interferon-based therapy and recently approved therapy using direct acting antivirals for patients with chronic hepatitis C. However, the precise mechanisms underlying RBV action against hepatitis C virus (HCV) replication are not yet understood. To clarify this point, we attempted to develop RBV-resistant cells from RBV-sensitive HCV RNA-replicating cells.Conclusions/SignificanceThese newly established HCV RNA-replicating cell lines should become useful tools for further understanding the anti-HCV mechanisms of RBV.     

Chemotherapy of schistosomiasis: present and future

Schistosomiasis is a chronic parasitic disease in tropical and subtropical regions and is associated with a variety of clinical syndromes that may lead to severe morbidity. Over the past 25 years, therapy and control of schistosomiasis has come to rely heavily on one drug, praziquantel (PZQ). This reliance is of concern should widespread treatment failure arise, particularly as measures are being undertaken to increase PZQ's availability. This review summarizes the use, possible modes of action and limitations of PZQ, and recent attempts to derive synthetic analogs. Alternative artemisinin-based chemotherapies that have shown applicability in certain disease settings are also similarly examined. Looking forward, the review highlights some of the more experimental anti-schistosomals being evaluated (e.g. the trioxolanes), including those where knowledge of the parasite target (e.g. cysteine proteases and hemozoin formation) is more defined.     

Ultra-short acting beta-blockers: a proposal for the treatment of the critically ill patient

Beta-blockade is of proven value in the therapy of acute myocardial infarction but, unfortunately, may produce cardiac failure by removal of needed sympathetic support. The long duration of action of available blockers (hours) makes reversal of failure a complicated problem and precludes rapid modification of therapy to match changing autonomic conditions. To improve the safety and efficacy of beta-blockade in this setting we have developed the concept of ultra-short beta-blockade and have identified a novel beta-blocker (ASL-8052) which possesses a duration of action less than 15 minutes. This compound is cardioselective and possesses efficacy in an animal model of acute myocardial infarction. It, therefore, appears to be suitable for rapid attainment of controlled levels of beta-blockade via intravenous infusion and rapid recovery from beta-blockade if required by the clinical situation. The compound should, therefore, be useful for safe therapy in critically ill cardiac patients.     

NONSPECIFIC ANTI-INFLAMMATORY AGENTS—Some Notes on Their Practical Application,Especially in Rheumatic Disorders

A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented.Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases.Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages.Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.     

The pain of "chronic Lyme disease": moving the discourse in a different direction

About 30% of the population of the United States suffers from acute or chronic pain, often of unknown cause. Among this group might be included patients with symptoms claimed to be caused by a poorly defined condition called "chronic Lyme disease" in which chronic pain is a major contributor. Since there is no evidence to indicate that chronic Lyme disease is due to a persistent infection and that extended antibiotic therapy is beneficial and safe, this condition should not be viewed solely as an infectious disease problem. Rather, it should be considered within the context of a broad-based, multidisciplinary approach to determining the cause of chronic pain per se and developing more effective strategies for its treatment as outlined in a recent report on pain issued by the Institute of Medicine.     

Herbogenomics: from traditional Chinese medicine to novel therapeutics

Traditional Chinese medicine (TCM) has a long history of development and application and has demonstrated on evidence basis its efficacy in the treatment of many diseases affecting multiple organ systems. In particular, TCM is effective in the prevention and treatment of chronic diseases and metabolic syndromes. However, the value of TCM has not been fully recognized worldwide due to the lack of definitive information of active ingredients in almost any TCM preparation. Novel functional genomics and proteomics approaches provide alternate perspectives on the mechanism of action of TCM. The target molecules on which TCM either activates or inactivates can be identified by functional genomics and proteomics, thus the affected critical signaling pathway cascades leading to effective recovery of chronic diseases can be studied. Several TCM preparations have been available for the treatment of liver fibrosis and cirrhosis, even advanced liver cirrhosis that has been shown to be irreversible and has no US-FDA approved therapy. In the TCM-treated livers with fibrosis and cirrhosis, some critical molecules that are significantly involved in the recovery can be identified through functional genomics and proteomics studies. These molecules become novel targets for drug discovery and development and candidates for the development of gene therapy. Gene therapy developed based on this strategy for the treatment of advanced liver fibrosis and cirrhosis in animal models has obtained promising results. This process thus establishes a herbogenomics approach to understand mechanisms of action of TCM and to identify effective molecular targets for the discovery and development of novel therapeutics.     

GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal

Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.     

Staphylococcal infections

All the forms of staphylococcal infections require cooperation among microbiologists, immunologists and clinicians. In case of any acute staphylococcus process, the curative tactics is based on an effective chemotherapy sometimes completed by a radical surgical intervention. In case of chronic forms, however, the antibiotics therapy is considered to be problematic. It is the specific immunotherapy by means of specific vaccine with polyvalent action, containing all pathogenetically significant antigens, that is considered by the authors to be a reliable base of the therapy of chronic staphylococcus infections. The specific polyvalent phage lysate is used for local application. It has to be pointed out that this therapy requires a complex curative regimen, i.e. regulation of the deficiency of serum immunoglobulines, administration of antibiotics, amelioration of the tissue trophism of the area concerned, suitable therapy by means of vitamines and diet. If necessary, surgical technique and tactics are an important part of the entire complex curative method.     

Strategies for breast cancer therapy with antiestrogens

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.     

Beneficial effect of S-adenosyl-L-methionine in lead intoxication. Another approach to clinical therapy

Five patients with chronic lead intoxication were treated with S-adenosyl-L-methionine (12 mg/kg body weight, daily), given intravenously, over a period of 22 days. A significant recovery of erythrocytic ALA-D was observed in all cases, after therapy. Blood lead content significantly pathologic at the beginning of SAM administration, rapidly decreased within 24-48 h of initiating treatment, reaching nearly control values at the end of the trial. A good correlation between recovery of ALA-D activity and decreased concentration of lead in RBC was found. GSH content in blood was diminished in lead poisoned patients, increasing to normal levels after SAM administration. Other biochemical parameters such as Deaminase activity in RBC, ALA, PBG, porphyrins and lead in urine and serum gamma-GT were measured, showing no important deviations from control values before, during or after treatment. Both biochemical and clinical improvement was observed, indicating that SAM therapy is beneficial in the treatment of lead intoxication. No untoward signs were observed. The mechanism of action of SAM is not yet clear; however, a chelating effect could be excluded, and very likely its action can be attributed to glutathione availability.     

A crucial role for CD44 in inflammation

Current therapies for chronic inflammatory diseases typically act through the nonspecific downregulation of immune cell activation. However, it is becoming increasingly evident that parenchymal cells are also active participants in the inflammatory process. Future prospects for the treatment of inflammation should therefore include the targeting of specific inflammatory pathways in both immune cells and parenchymal cells. CD44, a cell-adhesion molecule that is ubiquitously expressed on leukocytes and parenchymal cells, has been implicated, together with its ligand hyaluronan (HA), in several inflammatory diseases. The mechanisms of action of CD44-HA interactions in inflammation might provide potential targets for therapy.     

Decreased Creatine Kinase Activity Caused by Electroconvulsive Shock

Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy to minimize side effects of this treatment, little progress has been made in understanding its mechanism of action. Creatine kinase is a crucial enzyme for brain energy homeostasis, and a decrease of its activity has been associated with neuronal death. This work was performed in order to evaluate creatine kinase activity from rat brain after acute and chronic electroconvulsive shock. Results showed an inhibition of creatine kinase activity in hippocampus, striatum and cortex, after acute and chronic electroconvulsive shock. Our findings demonstrated that creatine kinase activity is altered by electroconvulsive shock.     

Toxicology of vanadium compounds in diabetic rats: The action of chelating agents on vanadium accumulation

The possible use of vanadium compounds in the treatment of diabetic patients is now being evaluated. However, previously to establish the optimal maximum dose for diabetes therapy, it should be taken into account that vanadium is a highly toxic element to man and animals. The toxic effects of vanadium are here reviewed. The tissue vanadium accumulation, which would mean an additional risk of toxicity following prolonged vanadium administration is also discussed. Recently, it has been shown that coadministration of vanadate and TIRON, an effective chelator in the treatment of vanadium intoxication, reduced the tissue accumulation of this element, decreasing the possibility of toxic side effects derived from chronic vanadium administration without diminishing the hypoglycemic effect of vanadium. However, previously to assess the effectiveness of this treatment in diabetic patients, a critical reevaluation of the antidiabetic action of vanadium and its potential toxicity is clearly needed.     

Pharmacokinetic requirements for successful site-directed targeting of drugs

Targeted drugs can be defined as those in which features of the molecule, additional to those required for receptor interaction, substantially improve the concentration ratio of active substance at the site of action compared to the site where side-effects occur.These requirements for successful targeting of systemically administered drugs can be determined by pharmacokinetic modeling. The requirements depend on the mechanism of targeting and on whether targeting is to be achieved for continuous therapy or for acute treatment. For continuous therapy (lasting several days) the success of targeting using a prodrug which is locally activated and has linear pharmacokinetics is proportional to the clearance of active drug from the body and inversely proportional the rate constant for leaving the site of action and to the volume of the tissue. The relationship can be mapped graphically and typical values for these parameters are considered so that situations where targeting can be successful can be identified. The prodrug must also have properties which result in sufficient concentration of drug being formed at the site of action. These properties can also be described by simple proportionality relationships and the conditions for success illustrated graphically.Kinetic considerations are also important for targeting. For continuous therapy it is desirable that steady drug concentrations should be reached rapidly. This is best achieved by using molecules which rapidly exchange between body compartments and have low tissue binding. For acute therapy the rules for targeting can be quite different and an example is given where binding can be responsible for a form of targeting.The results emphasise the need for careful consideration of the properties of targeted system taking into account transport, binding and clearance of both prodrug and drug. Specific details of the disease are also critical both in terms of local tissue properties and the desired time course of drug action.     

Stem cells for the treatment of heart failure

Stem cell-based therapy is currently tested in several trials of chronic heart failure. The main question is to determine how its implementation could be extended to common clinical practice. To fill this gap, it is critical to first validate the hypothesis that the grafted stem cells primarily act by harnessing endogenous repair pathways. The confirmation of this mechanism would have three major clinically relevant consequences: (i) the use of cardiac-committed cells, since even though cells primarily act in a paracrine manner, such a phenotype seems the most functionally effective; (ii) the optimization of early cell retention, rather than of sustained cell survival, so that the cells reside in the target tissue long enough to deliver the factors underpinning their action; and (iii) the reliance on allogeneic cells, the expected rejection of which should only have to be delayed since a permanent engraftment would no longer be the objective. One step further, the long-term objective of cell therapy could be to use the cells exclusively for producing factors and then to only administer them to the patient. The production process would then be closer to that of a biological pharmaceutic, thereby facilitating an extended clinical use.     

The cardiovascular amplifiers in human primary hypertension and their role in a strategy for detecting the underlying causes

The present review considers evidence that in chronic hypertension, hypertrophy of the muscles of the resistance vessels and left ventricle (LV) accounts for their intrinsic properties as haemodynamic amplifiers. In spontaneously hypertensive rats (SHR) there is early hypertrophy of both vessels and LV, suggesting that they may initiate hypertension; slow development of alpha-adrenoceptors may contribute to the early preponderance of the LV amplifier. In human hypertension LV hypertrophy occurs in most patients, including a high proportion of mild hypertensives. In Goldblatt one-kidney hypertension the stenosis resistance, which is the initiating cause, accounts for 25% of the rise in blood pressure throughout, with 75% initially due to systemic constrictor action of angiotensin II and later due to the amplifier properties of the hypertrophied heart and vessels. The cardiovascular amplifiers must be important in all chronic hypertension, so that if hypertrophy can be reversed, detection of the initiating mechanism should be easier. Studies in patients indicate that drug therapy can reverse hypertrophy and that subsequent redevelopment of hypertension is markedly slowed. We postulate an intrinsic disturbance of muscle performance in all primary hypertension, which may be triggered through the sympathetic nervous system in some patients and through altered cation transport in others.