Effect of Smoking on Pharmacokinetics of Clopidogrel, an Antiplatelet Drug

Purpose: To assess the influence of smoking cigarettes on the pharmacokinetics of the antiplatelet drug, clopidogrel.Methods: Thirty four male patients, mean age and weight of 59.3 years and 81.1 kg, respectively, who underwent percutaneous coronary intervention (PCI), took part in the study. Each subject received an oral loading dose of 600 mg clopidogrel eight tablets, each 75 mg). Clopidogrel carboxylate plasma level was measured and non-compartmental analysis was used to determine peak plasma concentration (Cmax), time to achieve peak plasma concentration (Tmax), elimination half-life (t1/2e), and area under the curve (AUC0-∞). Other parameters measured include gamma-glutamyltransferase enzyme (GGT), low density lipoprotein cholesterol (LDL-cholesterol), blood urea nitrogen (BUN) and platelet count.Results: Nineteen patients were smokers (55.9 %). Smokers had higher levels of GGT compared to non-smokers (31.73 ± 14.42 vs. 21.63 ± 11.41 IU/L, p = 0.08) as well as higher levels of LDL-cholesterol (116.79 ± 42.08 vs. 87.07 ± 27.34 mg/dl, p = 0.041, respectively). Smokers had shorter half-life (smokers: 3.47 ± 1.9 h vs. non-smokers: 5.83 ± 4.09 h, p = 0.012). Smoking behavior had no influence on Cmax (p = 0.16), AUC0-∞ (p = 0.65) or Tmax (p = 0.91). In general, the pharmacokinetic parameters were characterized by considerable inter-individual variation (Cmax = 23.2 ± 8.79 μg/ml, coefficient of variation (CV) = 37.9 %), (Tmax = 1.71 ± 1.15 h, CV = 67.2 %), (AUC0-∞ = 120.97 ± 44.4 μg.h/ml, CV = 36.7 %) and (t1/2e = 4.57 ± 3.15 h, CV = 68.9 %).Conclusion: Smoking behavior may not be a significant determinant of the pharmacokinetics of clopidogrel following oral administration of 600 mg dose in patients undergoing PCI.Keywords: Antiplatelet, Clopidogrel, Pharmacokinetics, Smoking, Cigarett

Production of parthenolide in organ and callus cultures of Tanacetum parthenium (L.)

The in vitro micropropagation of the seeds of Tanacetum parthenium (L.) Schultz-Bip. family Asteraceae was performed on half strength Murashige and Skoog (MS) medium containing 0.2% gibrellic acid. Theexplants were in vitro cultured on MS-medium using different plant growth regulators, culture media ingredients and carbon sources. Parthenolide content in the different established cultures was studiedand compared with that present in the open field herb. Results revealed that using half strength MSmedium containing 50 g/l glucose or fructose as a carbon source and 0.5 mg/l benzyl aminopurine(BAP) resulted in significantly higher parthenolide content than that present in the open field herb. In addition, bud sprouting ability, number and length of shootlets and number of leaves of differentexplants under different treatments were studied. The in vitro callus formation was conducted on MSmedium using different plant growth regulators and culture media ingredients. Parthenolide wasdetected in callus culture for the first time in only two different hormonal treatments which were MS medium containing 0.5 mg/l BAP or 0.5 mg/l naphthalene acetic acid (NAA). In addition, callusing capacity and weight of callus of different explants under different treatments were also determined. Parthenolide content was determined in the explants as well as in callus using RP-HPLC on Luna C18 column and SPD-10A UV detector. The mobile phase used was acetonitrile: water (55 : 45) and the flow rate was 1.5 ml/min at the ambient temperature

Innovative solutions in last mile delivery: concepts, practices, challenges, and future directions

In the last decade, e-commerce has been growing consistently. Fostered by the covid pandemic, online retail has grown exponentially, particularly in industries including food, clothing, groceries and many others. This growth in online retailing activities has raised critical logistic challenges, especially in the last leg of the distribution, commonly referred to as the Last Mile. For instance, traditional truck-based home delivery has reached its limit within metropolitan areas and can no longer be an effective delivery method. Driven by technological progress, several other logistic solutions have been deployed as innovative alternatives to deliver parcels. This includes delivery by drones, smart parcel stations, robots, and crowdsourcing, among others. In this setting, this paper aims to provide a comprehensive review and analysis of the latest trends in last-mile delivery solutions from both industry and academic perspectives (see Figure 1 for overview). We use a content analysis literature review to analyse over 80 relevant publications, derive the necessary features of the latest innovation in the last mile delivery, and point out their different maturity levels and the related theoretical and operational challenges

Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer

By using the positional cloning gene approach, we were able to identify a novel gene encoding for a serine/arginine-rich protein, which appears to be the human homologue of the rat A1 gene. We named this new gene SR-A1. Members of the SR family of proteins have been shown to interact with the C-terminal domain (CTD) of the large subunit of RNA polymerase II and participate in pre-mRNA splicing. We have localized the SR-A1 gene between the known genes IRF3 and RRAS on chromosome 19q13.3. The novel gene spans 16.7 kb of genomic sequence and it is formed of 11 exons and 10 intervening introns. The SR-A1 protein is composed of 1312 amino acids, with a molecular mass of 139.3 kDa and a theoretical isoelectric point of 9.31. The SR-A1 protein contains an SR-rich domain as well as a CTD-binding domain present only in a subset of SR-proteins. Through interactions with the pre-mRNA and the CTD domain of the Polymerase II, SR proteins have been shown to regulate alternative splicing. The SR-A1 gene is expressed in all tissues tested, with highest levels found in fetal brain and fetal liver. Our data suggest that this gene is overexpressed in a subset of ovarian cancers which are clinically more aggressive. Studies with the steroid hormone receptor-positive breast and prostate carcinoma cell lines ZR-75-1, BT-474 and LNCaP, respectively, suggest that SR-A1 is constitutively expressed. Furthermore, the mRNA of the SR-A1 gene in these cell lines appears to increase by estrogens, androgens and glucocorticoids, and to a lesser extend by progestins. © 2001 Cancer Research Campaign http://www.bjcancer.co

Antinociceptive activity of Mentha piperita leaf aqueous extract in mice

Mentha piperita L. (Labiatae) is an herbaceous plant, used in folk medicine for the treatment of several medical disorders.In the present study, the aqueous extract of Mentha piperita leaf, at the i.p doses 200 and 400 mg/kg, showed significant analgesic effects against both acetic acid-induced writhing and hot plate-induced thermal stimulation in mice, with protection values of 51.79% and 20.21% respectively. On the contrary, the Mentha piperita leaf aqueous extract did not exhibit anti-inflammatory activity against carrageenan induced paw oedema.These findings indicate that Mentha piperita has a potential analgesic effect that may possibly have mediated centrally and peripherally, as well as providing a pharmacological evidence for its traditional use as a pain reliever

Obesity and nutrition behaviours in Western and Palestinian outpatients with severe mental illness

Extent: 7p.Background: While people with severe mental illness have been found to be more overweight and obese in Western nations, it is unknown to what extent this occurs in Middle Eastern nations and which eating behaviours contribute to obesity in Middle Eastern nations. Method: A total of 665 responses were obtained from patients with serious mental illness attending out-patient clinics in Western developed countries (Germany, UK and Australia; n = 518) and Palestine (n = 147). Patients were evaluated by ICD-10 clinical diagnosis, anthropometric measurements and completed a self-report measure of frequencies of consuming different food items and reasons for eating. Nutritional habits were compared against a Western normative group. Results: More participants from Palestine were overweight or obese (62%) compared to Western countries (47%). In the Western sample, obese patients reported consuming more low-fat products (OR 2.54, 95% CI 1.02-6.33) but also greater eating due to negative emotions (OR 1.84, 95% CI 1.31-2.60) than patients with a healthy body-mass index. In contrast, obese patients from Palestine reported increased consumption of unhealthy snacks (OR 3.73 95% CI 1.16-12.00). Conclusion: Patients with mental illness have poorer nutritional habits than the general population, particularly in Western nations. Separate interventions to improve nutritional habits and reduce obesity are warranted between Western nations and Palestine.David Jakabek, Frances Quirk, Martin Driessen, Yousef Aljeesh and Bernhard T Baun

Validity and reliability of Arabic version of the ID Pain screening questionnaire in the assessment of neuropathic pain

Diagnosis of neuropathic pain (NP) can be challenging. The ID Pain (ID-P) questionnaire, a screening tool for NP, has been used widely both in the original version and translated forms. The aim of this study was to develop an Arabic version of ID-P and assess its validity and reliability in detecting neuropathic pain. The original ID-P was translated in Arabic language and administered to the study population. Reliability of the Arabic version was evaluated by percentage observed agreement, and Cohen’s kappa; and validity by sensitivity, specificity, correctly classified, and receiver operating characteristic (ROC) curve. Physician diagnosis was considered as the gold standard for comparing the diagnostic accuracy. The study included 375 adult patients (153 [40.8%] with NP; 222 [59.2%] with nociceptive pain). Overall observed percentage agreement and Cohen’s kappa were >90% and >0.80, respectively. Median (range) score of ID-P scale was 3 (2–4) and 1 (0–2) in the NP group and NocP group, respectively (p<0.001). Area under the ROC curve was 0.808 (95% CI, 0.764–0.851). For the cut-off value of ≥2, sensitivity was 84.3%, specificity was 66.7%, and correct classification was 73.9%. Thus, the Arabic version of ID-P showed moderate reliability and validity as a pain assessment tool. This article presents the psychometric properties of the Arabic version of ID Pain questionnaire. This Arabic version may serve as a simple yet important screening tool, and help in appropriate management of neuropathic pain, specifically in primary care centers in the Kingdom of Saudi Arabia

Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.</p> <p>Methods</p> <p>A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00841139">NCT00841139</a></p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN2887836">ISRCTN2887836</a></p

Genome-Wide Analysis of the Emerging Infection with Mycobacterium avium Subspecies paratuberculosis in the Arabian Camels (Camelus dromedarius)

Mycobacterium avium subspecies paratuberculosis (M. ap) is the causative agent of paratuberculosis or Johne's disease (JD) in herbivores with potential involvement in cases of Crohn's disease in humans. JD is spread worldwide and is economically important for both beef and dairy industries. Generally, pathogenic ovine strains (M. ap-S) are mainly found in sheep while bovine strains (M. ap-C) infect other ruminants (e.g. cattle, goat, deer), as well as sheep. In an effort to characterize this emerging infection in dromedary/Arabian camels, we successfully cultured M. ap from several samples collected from infected camels suffering from chronic, intermittent diarrhea suggestive of JD. Gene-based typing of isolates indicated that all isolates belong to sheep lineage of strains of M. ap (M. ap-S), suggesting a putative transmission from infected sheep herds. Screening sheep and goat herds associated with camels identified the circulation of this type in sheep but not goats. The current genome-wide analysis recognizes these camel isolates as a sub-lineage of the sheep strain with a significant number of single nucleotide polymorphisms (SNPs) between sheep and camel isolates (∼1000 SNPs). Such polymorphism could represent geographical differences among isolates or host adaptation of M. ap during camel infection. To our knowledge, this is the first attempt to examine the genomic basis of this emerging infection in camels with implications on the evolution of this important pathogen. The sequenced genomes of M. ap isolates from camels will further assist our efforts to understand JD pathogenesis and the dynamic of disease transmission across animal species

Identification of Pharmacological Modulators of HMGB1-Induced Inflammatory Response by Cell-Based Screening

High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein, is released into the circulation during sterile inflammation (e.g. arthritis, trauma) and circulatory shock. It participates in the pathogenesis of delayed inflammatory responses and organ dysfunction. While several molecules have been identified that modulate the release of HMGB1, less attention has been paid to identify pharmacological inhibitors of the downstream inflammatory processes elicited by HMGB1 (C23-C45 disulfide C106 thiol form). In the current study, a cell-based medium-throughput screening of a 5000+ compound focused library of clinical drugs and drug-like compounds was performed in murine RAW264.7 macrophages, in order to identify modulators of HMGB1-induced tumor-necrosis factor alpha (TNFα) production. Clinically used drugs that suppressed HMGB1-induced TNFα production included glucocorticoids, beta agonists, and the anti-HIV compound indinavir. A re-screen of the NIH clinical compound library identified beta-agonists and various intracellular cAMP enhancers as compounds that potentiate the inhibitory effect of glucocorticoids on HMGB1-induced TNFα production. The molecular pathways involved in this synergistic anti-inflammatory effect are related, at least in part, to inhibition of TNFα mRNA synthesis via a synergistic suppression of ERK/IκB activation. Inhibition of TNFα production by prednisolone+salbutamol pretreatment was also confirmed in vivo in mice subjected to HMGB1 injection; this effect was more pronounced than the effect of either of the agents administered separately. The current study unveils several drug-like modulators of HMGB1-mediated inflammatory responses and offers pharmacological directions for the therapeutic suppression of inflammatory responses in HMGB1-dependent diseases. © 2013 Gerö et al