Current Clinical Pharmacology - Volume 11, Issue 4, 2016

Background: Xenon (Xe) in many respects is an ideal anaesthetic agent. Its blood/gas partition coefficient is lower than that of any other anaesthetic, enabling rapid induction of and emergence from anaesthesia. While the whole body kinetics during wash-in of inhalational anaesthesia is well known, data describing the pharmacokinetics of xenon in the cerebral compartment at the site of action are still largely missing. Methods: In order to illuminate xenon’s cerebral pharmacokinetics, we anaesthetised five pigs and measured arterial, mixed- and sagittal sinus-venous blood, as well as end-expiratory gas concentrations of xenon by gas chromatography-mass spectrometry (GCMS) up to 30 minutes after starting the anaesthetic gas mixture. Results: Despite xenon’s fast onset of effect the half-time for equilibration between xenon concentration in arterial blood and at the site of action is measured to be 1.49 ± 0.04 minutes versus 3.91 ± 0.1 minutes. Successful loading of xenon in the brain during inhalational anesthesia was accomplished after approximately 15 minutes although the end-expiratory xenon concentration reached a plateau after 7 minutes. Thus cerebral xenon uptake rate is only moderate, xenon's fast onset of action being largely due to its extremely fast alveolar uptake. Conclusions: To ensure safety and precise control during anaesthesia we need a profound knowledge about to what extent the measured end-tidal concentrations reflect the drug concentrations in the target tissue. The results of this study expand our knowledge about the temporal characteristics of xenon´s pharmacokinetics at its site of action and provide the basis for appropriate clinical protocols and experimental designs of future studies.

The increased risk of bleeding observed in patients on oral anticoagulant therapy (OAT) undergoing outpatient oral surgical procedures has been reported in the literature and remains a major concern in the care of these patients. This is still of great concern to dental surgeons that discontinuing OAT medication increases the risk of thromboembolism, while maintaining the therapeutic dose increases the risk of hemorrhage. Several local hemostatic measures have been used to control bleeding in patients on OAT. However, the effectiveness of these measures has not been thoroughly investigated. The aim of this study is to evaluate the efficacy of local hemostatic measures in patients taking oral anticoagulants. Various databases were searched using the key terms. Selection criteria included publications in English, Spanish, or Portuguese within the last 20 years. The titles and abstracts of papers were initially screened, and reports of 18 clinical trials were selected for a critical review and scored according to CONSORT 2010 guidelines. The data extracted from these trials represented 1821 patients receiving OAT, 4116 tooth extractions, and 144 cases of postoperative bleeding. In most studies, there were no differences in the effectiveness of various local hemostatic measures, and only tranexamic acid was proven effective as compared with a placebo group. The reported INR values varied widely among studies; the lowest INR value was 0.9 and the highest was 5.0. All local hemostatic methods showed low rates of bleeding; and when bleeding occurred, the use of these methods was essential for controlling postoperative bleeding. While local hemostatic measures appear to be effective in controlling postoperative bleeding, additional controlled randomized clinical trials are needed to assess the true effectiveness of these measures in patients taking OAT.

Ivabradine, acting on the funny channel (If) in the sino-atrial node, reduces myocardial oxygen demand without inducing hypotension. It was developed as a specific bradycardic agent in the 1980s, avoiding the adverse effects of more traditional antianginal agents (beta-blockers and calcium channel antagonists). This has seen significant interest in this first-in-class treatment, and is perceived as a promising drug in the management of ischaemic heart disease and heart failure. There has been much clinical research conducted exploring its role in these fields, to try to elucidate potential benefits and target patient group. The side effect profile of ivabradine ensures it is well tolerated, and consistently leads to a reduction in heart rate. This review discusses the drug development and trial data in ischaemic heart disease and chronic left ventricular systolic dysfunction. Key clinical trials and observational studies are discussed in depth to examine potential explanations of unexpected or diverging results. The emerging role of ivabradine in acute decompensated heart failure is explored with recent trial data, providing a potential novel treatment avenue in this difficult to manage patient cohort. The role of intravenous ivabradine, as a beneficial tool in the acute hospital setting, when oral medication is not ideal, or where fast onset of action is required, in cardiac computerised tomography for example, is also discussed. Future directions for research are highlighted, including options for further elucidating unexplained results from previous studies.

Metformin is a biguanide used in the treatment of type 2 diabetes mellitus and obesity. The main mechanism of action is to decrease the intestinal glucose absorption and the hepatic glucose production, however, it does not influence insulin secretion. Metformin also increases the affinity of the insulin receptor, reduces high insulin levels and improves insulin resistance. Additionally, it promotes weight loss. Metformin is a pleiotropic compound but acts, largely, by activating 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK). Data suggest that the therapeutic effects of this compound are mediated, at least in part, through an upregulation of paraoxonase-1 (PON1) synthesis. PON1 is a thiolactonase that degrades lipid peroxides, and downregulates the chemokine (C-C motif) ligand 2 (CCL2) which is a pro-inflammatory chemokine that stimulates the migration of monocytes to areas of inflammation where they differentiate into macrophages. However, the prescription of metformin in patients with liver disease is controversial since, in some cases, this drug causes worsening of liver function. Patients with chronic liver disease have decreased hepatic PON1 activity. A study in mice deficient in PON1 showed that in this experimental model, metformin administration increased the severity of steatosis, increased CCL2 expression, did not activate AMPK, and increased the expression of the apoptosis marker caspase-9. These results suggest that PON1 is essential for the successful activation of AMPK in the liver, and for metformin to demonstrate its therapeutic function.

A growing interest exists in documenting the role of paraoxonase 1 (PON1) in different human diseases including, cardiovascular disease, obesity, diabetes mellitus, cancers, aging, and several neurological disorders. Three aspects of PON1 have attracted the attention of researchers: (1) hydrolyzing and detoxifying of toxic organophosphorous compounds such as nerve gases; (2) antioxidative activity in hydrolyzing oxidized phospholipids in high-density lipoprotein (HDL) and low-density lipoprotein (LDL); (3) interaction with various drugs. Drugs and nutrients which can increase the activity of paraoxonases contribute to reduce atherosclerosis and other disorders. There were contradictory reports on the interactions of PON1 with various drugs. These findings may be a reflection of differences in the dosage and type of drug, length of treatment, genetic variations, particularly loss-of-function polymorphisms, and the model used (cultured cells, animal studies or human studies). In addition, it should be noted that the regulatory effects of a drug on the enzyme protein may be important because a drug may induce the PON1 gene while having inhibitory effects on its enzymatic activity. Due to the association of PON1 with various human diseases, this review is focused on the pharmacological aspects of PON1 and the study of interactions between the enzyme and various drugs that may potentially assist to better understand the role of PON1 in drug metabolism, as well as the effects of drugs on PON1 status (activity and gene expression). In general, increasing our knowledge about the antioxidant and antiatherogenic enzyme will assist in determining efficient preventive and therapeutic strategies in the management of human disorders, particularly vascular diseases and those which are associated with negative regulation of PON1.

Background: Visceral leishmaniasis (VL) is a zooanthroponosis affecting both rural and periurban areas, and can also spread into urban areas. VL has emerged in many countries in the world, presenting new cases in new countries of occurrence. Thus, studies concerning epidemiological aspects in different world regions are very meaningful. Methods: With this purpose, this study analyzed 89 cases of VL, treated between June 2006 and June 2014 at Eduardo de Menezes Hospital (HEM), a Reference Center of Infectious Diseases situated in Belo Horizonte, in Minas Gerais state, Brazil. Results: According to the results, it was observed that males are mostly infected (84%/n=75) and the most affected age range was 20-49 years old (83%/n=74). The treatment liposomal amphotericin B (33%/n=29) was mostly used. Recurrences were more frequent in patients treated with Glucantime® (17%/n=9). No side effects were reported among the 29 patients treated with liposomal amphotericin B. On the other hand, there were 23 cases related to the occurrence of acute renal failure (ARF) and the use of conventional amphotericin B, both when it was administered alone or in combination with other drugs. Additionally, we observed a close relationship between the VL and HIV infection, observing a coinfection rate of 28.1% (n=25). Conclusion: From the survey data, it was possible to conclude that the majority of VL patient treated at HEM is male, classified as brown racial group, economically active, and may be drug addicts, chronic alcoholics and/or smokers. They may present some Non-communicable diseases (NCD), such as hypertension, diabetes mellitus, dyslipidemia and/or obesity and, predominantly present a great chance of being a carrier of the Human Immunodeficiency Virus, associated or not with tuberculosis. As symptoms, these patients possibly will present hepatosplenomegaly, fever and pronounced weight loss.

Background: Charles Bonnet Syndrome (CBS) is a rare clinical condition which is characterized by complex hallucinations in visually impaired patients. The pathophysiology of this disorder remains largely unknown, and there is still no proven treatment for this disease. In our study, we aimed to investigate the neural activity through Electroencephalography (EEG) power and evaluate the effect of rivastigmine in combination with alpha-lipoic acid on hallucination in two CBS patients with diabetic retinopathy. Methods: EEG data was recorded with standard routine EEG protocols for both patients in our electrophysiological research laboratory (REMER Clinical Electrophysiology and Neuromodulation Research and Application Laboratory) with Brain Vision Recorder (Brainproduct, Munich, Germany). All spectral analyses were processed by BrainVision Analyzer 2 (Brainproduct, Munich, Germany, 2.0.4 Version) in 128 Hz sample rates and the EEG recording and analysis was performed before the administration of rivastigmine (4.5 mg/daily and five patch daily for the first and second patients, respectively) in combination with alpha-lipoic acid (600 mg/daily) for both patients while they were not hallucinated during the time period recordings. Based on our measurement protocol, we have compared the patients in the study group with the three control subjects who were found to be normal except of visual disturbances secondary to significant diabetic retinopathy. Results: Highest theta power values were found in right occipital and left temporo-parietal regions for first and second CBS patients, respectively. Additionally, power spectra were lower in two cases as compared to their control groups in the alpha band for all electrodes. We have also shown that acid rivastigmine in combination with alpha-lipoic exerted significant anti-hallucinatory efficiency. Conclusion: Our present findings could support the hypothesis that increased activation of specific areas in the source monitoring system plays an important role in the pathogenesis of CBS. In addition, rivastigmine in combination with alpha-lipoic acid could be a new valuable option for CBS patients.

Objective: Maternal drug abuse may influence neonatal outcomes. We compared neonatal outcomes of patients with urine screened positive for commonly abused drugs (CAD) versus those who were screened negative, and reviewed the pattern of drugs detected at a university teaching hospital. Methods: Urine samples collected from babies with suspected illicit drug exposure who were admitted to the neonatal unit were sent for comprehensive drug screen (CDS) performed by liquid chromatographytime- of-flight mass spectrometry (LC-TOF/MS). The screening library can detect more than 300 drugs and their metabolites. Fluorescence polarization immunoassay (FPIA) was also used to screen for cannabinoids which were not detected by the present LC-TOF/MS method. Symptoms suggestive of drug exposure and history of maternal substance misuse were recorded. Results: Commonly abused drugs (CAD) including methadone, morphine, codeine, methamphetamine, ketamine, midazolam and heroin were present in the urine specimens of 46 (24.2%) of 190 neonates. Eighty-one (42.6%) urine samples screened positive for other drugs, which include antibiotics, lidocaine and pethidine administered during delivery. Drugs were undetectable in 33.2% samples. Urine positive for CAD was independently associated with maternal history of substance misuse (p<0.0001), birth-weight <2.5 kg (OR 2.9, p<0.01), neonatal withdrawal symptomatology (OR=8.89, p<0.0001); but not with risk of preterm delivery. Logistic regression demonstrated that neonates with maternal history of substance misuse and CAD positivity were 5.99 (p=0.021) and 5.91 (p<0.0005) times more likely to have withdrawal symptoms. Conclusions: CADs are isolated in the CDS of nearly one-fourth of neonates. Neonates with maternal history of CAD exposure as evidenced by positive urine CDS are associated with low birth weight, and symptoms of drug withdrawal.

Background: Lamotrigine and topiramate are well-known agents with their antiepileptic and mood stabilizing effects. Their therapeutic effect is associated with significant alteration of brain metabolism. In our study, we aimed to investigate the neurometabolic correlates of the therapeutic effects of both agents in a depressive patient with anxiety symptoms and cognitive decline. Methods: In addition to structural Cranial Magnetic Resonance Imaging, we also have performed Neuropsychometric evaluation and FDG-PET Brain fludeoxyglucose positron emission tomography (F18) (FDG PET-CT) FDG-PET before and after the treatment. Brain fludeoxyglucose positron emission tomography (F18) (FDG PET-CT) images were taken before and after the treatment using Philips Gemini TF PET/CT equipped with 16 slice CT. The raw FDG-PET data was processed using NeuroQ software (Version 3,5. Syntermed, Inc Atlanta. USA). Results: Topiramate and lamotrigine additively reduced the neuropsychiatric symptoms and test scores which were associated with the improvement of cerebral glucose metabolism. Conclusion: Our present findings support that the therapeutic effect of lamotrigine and topiramate involves a modulatory effect on the glucose metabolism in cortico-subcortical network and suggests the functional role of a bi-directional hippocampal-cingulate connectivity.

Background: The current study was performed to evaluate the anti-urolithiatic activity of Argemone mexicana L. leaves extracts as natural remedy to over come side effects problem due to the usage of modern synthetic medicine. Methods: In vitro experiments (nucleation, aggregation and microscopic assay’s) were performed to test the anti-urolithiasis activity of A. mexicana extracted using the four different solvents i.e. petroleum ether, chloroform, methanol, and water. These extracts were tested at increasing concentration of 25, 50, 75 and 100 mg/ml and compared with the standard drug cystone. Result and Discussion: The extracts were tested for the inhibition percentage of anti-urolithiasis potential against preformed calcium oxalate crystal. The results of A. mexicana extracts on nucleation assay were found to be significant and the methanol leaf extract showed considerable inhibition (72.26%) compared to standard cystone drug (62.96%) and in aggregation assay also the methanol leaf extract of A. mexicana showed significant inhibition (77.24%) compared to cystone (69.33%) at 100 mg/ml concentration. The microscopic assay clearly indicated that A. mexicana leaves extracts are capable to dissolve the calcium oxalate crystals. Conclusion: The methanol extract of A. mexicana leaves contains anti-urolithiatic potentials by in vitro at a dose level of 100 mg/ml. The methanol extract of A. mexicana leaves can be further exploited as a potential anti-urolithiasis drug.