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Current Drug Therapy (v.1, #2)

Beta-Blocker Therapy for Septic Cardiac Shock: Fiction Or Realism? by Karim Bendjelid (pp. 131-133).
Beta-blockers, previously considered contraindicated in heart failure are today amongst the most important drugs in heart failure. They improve survival and retard the need for cardiac transplantation. Since most clinical trials demonstrating the benefits of beta-blockers have been done in patients with mild to moderate heart failure, the use of these agents in patients with advanced heart failure remains contraindicated. In this brief review, the author theorizes that due to their immunomodulatory effects, beta-blockers may also play a helpful role in patients presenting cardiogenic shock related to septic shock. However, intensivists should keep in mind that no clinical data are available so far on the role of beta-blockers in septic cardiac shock. Thereby, because the use of beta-blockers in this setting is not established, nor recommended, it should only be applied under controlled trial conditions.

Recombinant Tissue-Type Plasminogen Activator (Alteplase) in the Management of Acute Ischemic Stroke: A Review of its Pharmacological Properties, Efficacy, Safety and Pharmacoeconomic Aspects by Naveed Akhtar, Dirk Deleu, Sadaat Kamran (pp. 135-146).
Ischemic stroke ranks as one of the major leading cause of death and the most common cause of acquired neurological disability in adults. The treatment of acute ischemic stroke remains one of the most challenging areas in medicine today. Timely recognition and treatment is imperative to reduce its morbidity and mortality. So far, intravenous recombinant tissue-type plasminogen activator (rt-PA or alteplase) is the only approved thrombolytic by the European Agency for the Evaluation of Medicinal Products (EMEA) and Food and Drug Administration (FDA) for treating acute ischemic stroke within three hours of onset of symptoms. Though encouraging, the data for a larger therapeutic window between 3 and 6 hours remains controversial. Other treatment strategies (using intra-arterial alteplase combined intravenous/intra-arterial alteplase, other thrombolytic agents, mechanical disruption of clot and ultrasonic augmentation of thrombolysis) although still under investigation, have shown beneficial in selected conditions. Still thrombolytic therapy has not been widely adopted and practiced. This limited implementation may be because of many factors including clinical and time criteria, and most of all lack of public and professional education for understanding stroke as acute emergency. The objective of this paper is to provide an updated overview of the use of alteplase in acute ischemic stroke in all its aspects: mechanism of action, pharmacokinetics, drug interactions, efficacy and tolerability via different routes of administration in the anterior and posterior circulation, and last but not least the pharmacoeconomic issues. The rationale for thrombolytic therapy and its limits will be addressed. Educating the general public, training emergency caregivers and allied health professionals, and addressing long-term cost savings to health institutions will make stroke management optimized and widely available.

Consequences of Secondary Hyperparathyroidism on Vascular Calcification and Cardiovascular Mortality: Potential Benefit of Calcimimetics by Emanuel Zitt, Alexander Rosenkranz (pp. 147-155).
Chronic kidney disease and especially end-stage renal disease (ESRD) are regularly associated with profound disturbances in the mineral metabolism characterized by secondary hyperparathyroidism (SHPT), hyperphosphatemia, hypercalcemia, elevated calcium-phosphorus product and renal osteodystrophy. These metabolic changes are either the result of the disease itself or due to toxicity from current therapeutic options. There is growing evidence that besides the classical cardiovascular risk factors, non-traditional uremia-specific risk factors, including abnormal mineral metabolism and SHPT, play a key role in the excessively increased cardiovascular mortality and morbidity in these patients. Calcimimetics represent an innovative new therapeutic compound in the treatment of SHPT, acting as allosteric activators of the calcium-sensing receptor. In this review we will discuss the consequences of SHPT in ESRD patients on vascular calcification, its impact on cardiovascular morbidity and mortality and the potential role of calcimimetics in preventing the cardiovascular consequences of SHPT.

Statins: Are They All the Same? by Walter Riesen (pp. 157-172).
Statins are a diverse group of drugs, which share the ability to inhibit HMG CoA reductase and thereby the conversion of acetoacetyl CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. By inhibiting mevalonate production statins inhibit the pathway leading to the generation of farnesylpyrophosphate and geranylgeranyl pyrophosphate, two pyrophosphates that are critical for the induction of a variety of signal transduction pathways, which promote a cascade of events leading to endothelial dysfunction, inflammation, proliferation, apoptosis and other effects important for atherogenesis. Even though statins share a common mode of action they differ by several features like chemical structure, affinity towards HMG CoA reductase and their relative lipophilicity. These features translate into marked differences in LDL cholesterol lowering efficacy, pharmacokinetic properties and differences in lipophilicity associated with different tissue affinity and penetration. Rosuvastatin and atorvastatin produce the greatest percentage change in LDL cholesterol. Fluvastatin and pravastatin are less prone to drug interactions, because they are not metabolized through the CYP450 3A4 system. The hydrophilic pravastatin does not inhibit proliferation and migration of vascular smooth muscle cells. Data from clinical trials with statins suggest that the efficacy in LDL cholesterol lowering plays the overriding role in cardiovascular event reduction.

Treatment of Infections Caused by Extended-Spectrum β-Lactamase- Producing Enterobacteriaceae by Kevin Laupland, Johann Pitout (pp. 173-179).
The Enterobacteriaceae, most notably Escherichia coli and Klebsiella pneumoniae, are among the most important causes of serious nosocomial and community-acquired bacterial infections of humans. These organisms may produce extended-spectrum β-lactamases (ESBLs) that result in broad spectrum resistance to the β-lactam antibiotics, a major class of anti-bacterial agents. The majority of ESBL enzymes in Enterobacteriaceae are encoded on large plasmids typically with other antibiotic resistance genes that are transmissible among different strains and species. Although there is considerable geographic variation, the rate of infections due to ESBL-producing Enterobacteriaceae is rising and these infections have been increasingly recognized to occur in community-based patients. As a result of their broad spectrum resistance profile, empiric treatment failure is common with ESBL-producing Enterobacteriaceae infections. Largely because of their resistance to both hydrolysis and the innoculum effect, the carbapenem class of antibacterials have become widely accepted as the agents of choice for the treatment of serious infections due to ESBL-producing Enterobacteriaceae. However, the superiority of carbapenems over other classes of active agents in the treatment of these infections is inconsistently supported by observational studies and there is a lack of clinical trial data. Future prospective studies are needed to determine the optimal management of these important infections.

Is There a Place for Nebulized Magnesium Sulfate in the Treatment of Acute Asthma? A Systematic Review by Gustavo Rodrigo, Luis Nannini (pp. 181-185).
Objective: To evaluate the use of aerosolized magnesium sulfate (MgSO4) in combination with inhaled betaagonists compared to inhaled beta-agonists alone in the treatment of acute asthma. Methods: Published (1966-2005) randomized controlled trials were retrieved using different databases, bibliographic reviews of primary research, review articles, and citations from texts. The primary outcome measure was pulmonary function. Results: Five out of 16 potentially eligible studies met criteria for inclusion in the meta-analysis. They included 187 adults and 62 children who were treated in an emergency department. Patients that received MgSO4 showed non-significant improvement in pulmonary function (SMD = -0.21, 95%CI:-0.52 to 0.10, p = 0.18). The advantage of the use of MgSO4 was demonstrated only in patients with life-threatening acute asthma (baseline FEV1 or PEF < 30% predicted) (SMD = - 1.10; 95%CI: -1.80 to -0.39, p = 0.002; I2 = 0%). Nebulized MgSO4 with beta-agonists showed a marginal significant reduction in admission rate compared to beta-agonists alone (RR = 0.63, 95% CI: 0.39 to 1.01, p = 0.06, I2 = 0%). Conclusions: Data suggests that MgSO4 presents a beneficial effect in terms of pulmonary function only in the subgroup of life-threatening acute asthma patients. However, the small number of studies selected, the standard treatment used in all trials, and the beta-agonist delivery method restricts this conclusion.

Cholinergic Treatment of Traumatic Brain Injury by Olli Tenovuo (pp. 187-209).
In spite of affecting the life of millions of people, chronic traumatic brain injury (TBI) has not been hitherto treatable with effective pharmacological tools. This review gives a comprehensive summary of the theoretical data supporting the pharmacological manipulation of the cholinergic system in TBI, pointing out the most urgent targets for further studies. The published clinical evidence of cholinergic treatment in TBI is critically reviewed, with emphasis on modern available cholinergic agents. The lessons from these studies are converted to detailed suggestions for further clinical testing. In addition, the treating clinicians are provided with practical advice, based on personal experience of the cholinergic treatment in over 350 TBI patients. It is concluded that cholinergic agents offer several very promising potentials for the treatment of TBI. However, the final breakthrough requires further well-conducted studies and the potential caveats of the treatment have to be acknowledged.

The Use of Progesterone in Clinical Practice: Evaluation of its Efficacy in Diverse Indications Using Different Routes of Administration by Vittorio Unfer, Gian di Renzo, Sandro Gerli, Maria Casini (pp. 211-219).
Introduction: Progesterone is a hormone of paramount importance in the reproductive physiology. Its multiple physiological roles and pharmacology have been extensively studied throughout the years. However, the use of progesterone in the pathophysiology of pregnancy as well as in its other indications remains arguable for diverse reasons. One of these reasons concerns the fact that there have been few large randomised controlled trials, which are not easily comparable because of the different dosages, populations and routes of administration used. Regarding this last issue, the route of progesterone administration may have a strong influence on the efficacy of the treatment since the distribution and concentration of the hormone at the tissutal level varies considerably. Objective: To review the literature concerning the efficacy of progesterone in its diverse indications in correlation to the different routes of administration used. Methods: The search strategy included a literature search of PubMed, MEDLINE and the Cochrane Database from 1949 to April 2005, as well as a review of reference lists of identified studies and a hand search of relevant textbooks and reference works. Search terms used included: progesterone, pregnancy, preterm birth, preterm labor, threatened miscarriage, recurrent miscarriage, menopause, contraception, pharmacology, route of administration. Study designs included experimental studies, observational studies, case control studies, reviews, letters, and editorials. Results: The search on MEDLINE identified approximately 3800 articles. We found only limited literature relating to some of the administration route of progesterone (transnasal, transdermic, sublingual, rectal). Conclusion: Many routes of progesterone administration have been studied, but the only routes of administration used in the clinical practice are the i.m., oral and vaginal one. Among these options, the intramuscular administration is the only one that ensures adequate and verifiable plasmatic levels of progesterone.

Novel Therapeutic Agents for Hyperuricemia in Patients with Gout by Geoffrey Wall, Carrie Koenigsfeld, Kristin Meyer (pp. 221-229).
Objective: To review the current literature concerning the treatment of hyperuricemia in patients with gout with novel agents not primarily used for this condition. Data Sources: Computerized MEDWATCH and International Pharmaceutical Abstracts search engines were utilized with the following terms: gout, uric acid, losartan, fenofibrate, sevelamer, febuxostat, and treatment. Bibliographies from key articles were also searched, and all pertinent articles were procured and reviewed. Data Extraction: All available primary literature accounts in English of hyperuricemia treatment with the agents listed above were considered for this review. Pertinent review articles were also utilized. Data Synthesis: Although several drugs effectively treat hyperuricemia in gout, existing agents may not always be effective or well tolerated. Losartan, fenofibrate, and sevelamer have been shown to exert a hypouricemic effect and may be effective adjunct agents for gout, especially in patients with concomitant co-morbid conditions. Additionally, febuxostat, a novel non-purine hypouricemic agent, will soon become available for the treatment of this disorder. Conclusion: As the incidence of gout increases in Western countries the availability of several effective medications for lowering uric acid levels will be necessary. The agents described in this review can be considered in patients with gout, especially if current drugs are ineffective or not tolerated.

Current Outcomes and Future Perspectives of Cochlear Implants by Zanetti Diego, Guida Maurizio (pp. 231-239).
Cochlear implants (CI) are semi-implantable devices for the rehabilitation of profound deafness due to loss of sensory hair cells in the cochlea. They have enabled more than 60,000 deaf people with no benefit from traditional acoustic amplification to restore a functional hearing. Although individual performance is variable, most adults with postverbal onset of deafness can talk on the phone in a quiet environment. Children born deaf who receive a CI before the age of two years can develop normal language perception and production, and the majority can attend the mainstream schools. Technological advances and positive outcomes have expanded the CI candidacy. Current areas of clinical research are: 1) the sparing of residual hearing in the low frequencies in order to allow the combined use of an hearing aid; 2) the use of perimodiolar electrodes which minimize the spread of neural excitation and the battery consumption; 3) new hardware, such as the behind-the-ear speech processors, and more flexible speech processing strategies; 4) binaural implantation, for stereophonic sound processing. The present paper reviews expected performances in different categories of subjects undergoing cochlear implantation. Future developments such as the totally implantable device and the delivery of pharmacologic agents to the inner ear via an adjunctive channel are discussed.
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