Current Clinical Pharmacology - Volume 4, Issue 2, 2009

Introduction: Following the landmark observations on the relevance of adequate analgesia and sedation in neonates, neonatologists are in search for short acting agents for procedural sedation. Propofol (2,6 di-isopropylphenol) is considered to be a short acting anaesthetic that is both rapid in onset and short in duration after cessation, but data on pharmacokinetics and metabolism in neonates were absent. Methods: In 3 consecutive studies, data on propofol pharmacokinetics and metabolism were collected in neonates after single intravenous (3 mg/kg) bolus administration. Results: Median propofol clearance (19.6 mL kg-1 min-1) is significantly lower and interindividual variability (range 3.7- 78 mL kg-1 min-1) in propofol clearance in neonates is extensive. Simultaneous introduction of postmenstrual and postnatal age as covariates resulted in a reduction of this interindividual clearance from 322 to 84 %. Finally, differences in clearance are due to limited capacity for glucuronidation in neonates, only in part compensated by hydroxylation. Conclusions: Clinicians should remain careful with propofol in neonates because of the reduced clearance and extensive interindividual variability. We strongly dissuade the use of continuous or repeated intermittent administration of propofol in the first weeks of life and suggest to study the pharmacodynamics of single bolus administration of propofol in neonates.

BNP or NT-proBNP testing has dramatically changed the management of acute heart failure patients by aiding in early recognition, prognostication and treatment. Furthermore, recent studies have shown that natriuretic peptide testing may guide the therapy of the stable chronic heart failure patients in out-patient setting. We will review the understanding of utilizing natriuretic peptide testing to guide heart failure therapy, including present and future directions for this exciting area.

Drug toxicity is a common cause of liver injury and kidney failure. This study was designed to elucidate whether administration of high doses of Ceftriaxone or Vancomycin induce oxidative stress in liver as well as kidney, and to investigate the protective effects of VRP 1020 with fixed dose combination of ceftriaxone-vancomycin (Immunox-V). Twenty four Mus musculus mice (weighing 30 ± 5 g) were divided into four groups containing six mice in each group. The activities of antioxidant enzymes such as superoxide dismutase, catalase and the level of malonaldialdehyde, as an marker of lipid per oxidation, were measured to evaluate oxidative stress in homogenates of the liver and renal tissue. Ceftriaxone or vancomycin administration significantly increased malonaldialdehyde levels (p < 0.001) but significant decreased in superoxide dismutase (p<0.01) and catalase (p<0.001) activities. Co-administration of VRP 1020 with FDC of Immunox-V injections caused significantly decreased malonaldialdehyde levels (p< 0.001) and increased superoxide dismutase (p<0.01) and catalase (p<0.001) activities in liver and renal tissue when compared with other treated groups. Similarly, the levels of extracellular antioxidant (Creatinine and Uric acid) were found to be significant lowered in Immunox-V treated group when compared to ceftriaxone or vancomycin alone treated group. These results indicate that chemical mediated technology of VRP 1020 with fixed dose combination of Immunox-V can prevent drug induced nephrotoxicity and oxidative stress which protects liver injury as well as renal tissue damage by reducing reactive oxygen species which improve the activities of free radical scavenging enzymes.

Recent years have seen improvements in strategies to treat pancreatic cancer. Pancreatic cancer is a leading cause of cancer-related death in the world, and is characterised by rapid disease progression, highly invasive tumour phenotype and resistance to chemotherapy. Patient prognosis is extremely grim, with a one-year survival rate of just 10% and only a 5% chance of surviving beyond five years. There has been little change in the treatment regimen, with 5-FU-based therapies being the usual route. Gemcitabine has also offered some relief over the past two decades, with modest improvements in median survival. This lack of choice has increased the call for new treatments, and indeed, novel drugs are now being investigated for their use in pancreatic cancer. These include those agents classically applied to other indications such as doxycycline and doxorubicin, as well as dietary components such as curcumin and genistein. Each of these drugs possesses different levels of activity both as single agents and in combinatorial approaches with gemcitabine. This review will discuss the difficulties in treating pancreatic cancer, and will summarise the progress and latest development in drugs used within this field of cancer.

Anaphylaxis is an acute and often severe systemic allergic reaction. The prevalence of food allergy has been increasing and is currently estimated at ∼3.5%. Food allergic reactions account for one-third to one-half of anaphylaxis cases worldwide. It is estimated that approximately 30,000 food-related anaphylactic reactions are treated in United States emergency departments (ED) every year resulting in ∼ 2000 hospitalizations and 150 deaths. The increasing rate of foodinduced anaphylactic episodes in the last few decades underlines the existence of major challenges. This review will critically appraise current guidelines for the diagnosis as well as the acute and long-term management of food-induced anaphylaxis (FIA). Importantly, it will outline existing challenges and suggest measures to improve outcomes in patients with FIA. We propose that the discovery of novel diagnostic (i.e. biomarkers and predictors) and therapeutic approaches is a major challenge that may be overcome as the mechanisms underlying FIA are better delineated. We further propose that better dissemination, implementation and compliance with the consensus management guidelines are urgently needed. This will require education of ED personnel, patient empowerment as well as effective multilateral communication among patients, emergency and family physicians, allergists and specialized volunteer organizations.

K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a nonspecific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca2+ release from the sarcoplasmic reticulum, suppression of spontaneous Ca2+ sparks and Ca2+ waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.

Long-acting nitrates are effective antianginal drugs during initial treatment. However, their therapeutic value is compromised by the rapid development of tolerance during sustained therapy, which means that their clinical efficacy is decreased during long-term use. Sublingual nitroglycerin (NTG), a short-acting nitrate, is suitable for the immediate relief of angina. In patients with stable angina treated with oral long-acting nitrates, NTG maintains its full anti-ischemic effect both after initial oral ingestion and after intermittent long-term oral administration. However, NTG attenuates this effect during continuous treatment, when tolerance to oral nitrates occurs, and this is called cross-tolerance. In stable angina long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid the development of tolerance. Nitrates vary in their potential to induce the development of tolerance. During long-lasting nitrate therapy, except pentaerythritol tetranitrate (PETN), one can observe the development of reactive oxygen species (ROS) inside the muscular cell of a vessel wall, and these bind with nitric oxide (NO). This leads to decreased NO activity, thus, nitrate tolerance. PETN has no tendency to form ROS, and therefore during long-term PETN therapy, there is probably no tolerance or cross-tolerance, as during treatment with other nitrates.

In systemic autoimmune rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), the interaction between hyperactive T cells and B cells causes a dysregulated production of autoantibodies that can lead to tissue damage, with subsequent impaired organ function and disability. The available information on the immune cells that participate in this process has led to the development of several approaches that can influence disease course. One of these approaches uses immunomodulatory peptides that mimic selected sequences involved in the interaction between T and B cells. Preclinical studies in animal models have given encouraging results, and synthetic peptidebased intervention in human autoimmune rheumatic diseases is now approaching translational work into clinical settings.

Progesterone (P4) is defined as a steroid female hormone that exerts a wide variety of biologic effects in the human organism. One of the key roles of P4 is in the female reproductive system, pregnancy and mammary development. However, it also acts in many other organs, including cardiovascular and central nervous systems. The wide range of biologic effects of this steroid hormone is associated with the presence of several progesterone receptor isoforms, both in the nucleus and in the cytoplasm, as well as the huge number of molecular mechanisms, namely target gene transcription or phosphorylation cascade signaling pathways, evoked by their stimulation. In addition, synthetic progestins are widely used among the female gender, either as contraceptive agents or hormone replacement therapy. Since P4 has been linked to several pathological stages, including several types of cancer, care must be taken regarding the general employment of this hormone. Herein, we review the role of progesterone and their target signaling pathways in physiological and pathological conditions.

Background: The most frequent intervention after Comprehensive Geriatric Assessment (CGA) is adjustment of medications. Adherence to recommendations is often incomplete. Patients at high risk of non-adherence should be identified. Objective: To explore if changes in drug-use after CGA are carried out by the patient. To identify factors influencing nonadherence. Methods: Co-morbidity and medication use were recorded. Patients, and when cognitively impaired, a caregiver, were questioned about advised changes. Drug-use before and after CGA was assessed. Patients were asked whether they would discontinue their drugs either with or without consulting their physician. Univariate logistic regression analysis to identify factors influencing non-adherence, was performed with SPSS. Results: Forty patients were included. Of the changes in medication advised, 90 % were reported to be carried out. 65 % of the patients were compliant. Only the presence of a caregiver was associated with reported complete adherence to drug therapy. Most patients can't describe for how long they will have to continue taking the drugs that are prescribed to them. Conclusion: Most geriatric patients carry out changes in medication made after CGA. Supervision by caregivers may explain a high rate of reported adherence despite the presence of polypharmacy and cognitive decline. Practice Implications: In the absence of caregivers special attention should be paid to adherence to medication changes. Information about intended duration of drug therapy should be improved.

Optical properties of gold and silver nanoparticles are considered. Processes of preparation of these particles are described. The data presented about application of these nanoparticles in immunoagglutination assays. The features of these metals in immunoagglutination assays are compared. Application of gold nanoparticles in DNA hybridization assays is presented. Application of these metals in cell imaging and therapy is considered. Other prospective metal and semiconductor composites for application in these area are considered.