Pharmacological Basis Of Therapeutics Research Articles

Advances and challenges in the clinical practice of respiratory tract pharmacology and pharmacotherapy

This paper addresses the advances and challenges in the clinical practice of respiratory tract pharmacology and pharmacotherapy. Respiratory pharmacology has evolved significantly, offering a wide range of medications for the treatment of conditions such as asthma and chronic obstructive pulmonary disease (COPD). Bronchodilators, inhaled corticosteroids, and risk factor modification strategies, such as smoking cessation, are key to improving lung function and reducing exacerbations. The use of modern drugs, as highlighted in "Goodman & Gilman's: The Pharmacological Basis of Therapeutics", is complemented by updated guidelines, such as those of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Brazilian Society of Pulmonology and Phthisiology. These guidelines aim not only to relieve symptoms but also to promote an integrated approach that improves patients' quality of life. Effective implementation of these strategies requires not only up-to-date scientific knowledge, but also public health policies that promote the rational use of medicines and educational interventions. Therefore, this study underscores the importance of a multidisciplinary approach to address the complex challenges associated with chronic respiratory diseases.

PS-C36-9: A REVIEW OF THE PHARMACOKINETIC PROFILES OF THE 40 MOST COMMONLY PRESCRIBED CARDIOMETABOLIC MEDICATIONS

Objective: To collate the pharmacokinetic (PK) parameters of the 40 most commonly prescribed cardiometabolic medications from published literature to provide a useful reference source for clinicians when interpreting results of chemical adherence testing. Design and Methods: Non-adherence to medication is a prime cause of treatment failure and costs the UK health system approximately £500 million annually. A recent meta-analysis on adherence to 7 cardiovascular drug classes revealed a non-adherence rate of 43%. Chemical adherence testing (CAT) by liquid chromatography tandem mass spectrometry (LC-MS/MS) is an objective method for testing patient adherence to medication and has been proven to be effective in managing disease progression. To improve result interpretation, factors including dose time, sample collection, and PK need to be better understood. The list of the most commonly prescribed drugs was obtained using the NHS Prescription Cost Analysis 2020/2021. Data on the pharmacokinetic parameters was collected from original papers from the following sources: Lexicomp: Medical Library Goodmans & Gilmans: The pharmacological basis of therapeutics, 13th edition Clarks analysis of drugs and poisons 4th edition Martindale: The complete drug reference All original manuscripts were reviewed, filtered and graded, following a robust criteria. The collected PK parameters focused on the bioavailability, volume of distribution, peak concentration, minimum plasma concentration, time to peak concentration, half-life, clearance and urine excretion. Results: A total of 3004 papers were initially screened for pharmacokinetic data, of which, 274 papers were relevant. These papers were further filtered, a total 84 papers adhered to the criteria for grading. Propranolol was one of the most prescribed cardiometabolic drugs with 6,124,180 prescriptions issued in the UK between 2020–2021. The half-life for Propranolol 80 mg (3.5 h), the peak time (1.5 h), the peak concentration (49 ± 8 ng/mL). Edoxaban was prescribed 1,584,638 times in the time period selected. Mean PK parameters for steady state levels of Edoxaban were: bioavailability (99.7%), urine excretion (44.7 ± 14.8%), clearance (535 ± 15.5 mL/min), volume of distribution (426 ± 30.7 L), half-life (9.2 ± 30.5 h), peak time (2 ± 1.03) and peak concentration (507 ± 17.3 ng/mL). Conclusions: This is one of the first studies to utilise a criteria for collecting and grading of PK parameters from published literature for common cardiometabolic medications. Medications have diverse pharmacokinetic profiles hence; systematic collection of these parameters will be a useful reference for clinicians when interpreting results of CAT for medication presence in patient samples.

The "Square Box": Therapeutic Equivalence as a Foundation of the WHO Model List of Essential Medicines.

Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Model List often includes a single medicine as representative of a group of equivalent and interchangeable medicines. The representative medicine of that group is listed with an accompanying ‘square box’ symbol. The intended purpose of the square box is to highlight pharmacological classes or groups of medicines for which countries, institutions and health professionals can assume homogeneous therapeutic efficacy and safety and select the most appropriate single medicine based on price, local availability, and acceptability. Though this concept of therapeutic equivalence within a therapeutic class has been endorsed by most authoritative textbooks of pharmacology since Goodman & Gilman’s The Pharmacological Basis of Therapeutics and evidence-based guidelines, marketing forces have often made claims on individual drugs to distinguish them beyond relevant differences shown by reliable evidence: this has generated the concept of “me-too drugs” with its double meaning—i.e., market latecomers differing minimally from products preceding them and whose marketing budgets have significant opportunity costs, or medicines which may be useful to substitute for equivalent products in the event of shortages. The square box concept is applied in the context of a comprehensive list: therapeutic equivalence or interchangeability cannot always be easily established. Different interpretations have been applied to different groups of medicines over the 40+ year history of the Model List. This paper presents the concept of the square box, provides key examples and guidance on how square box listings should be practically interpreted in the development and implementation of national essential medicine lists, considers the applicability of a square box listing concept to biologic medicines and proposes that an updated review of the square box concept and listings is warranted.

A qualitative and quantitative comparison of adverse drug reaction data of anti-epileptic drugs in various sources of drug information

Background: It is essential to spread awareness about known adverse drug reactions (ADRs) for identification, prevention and their proper management. The aim of this study is to assess disparities in documented ADRS of antiepileptic drugs in various sources of drug information.Methods: An observational, cross sectional study was done to compare different drug information sources for ADRs. Six sources of information namely: National Formulary India (2011), Drug Today (2018), Current index of medical specialties (CIMS), and some textbooks like Lippincott’s illustrated reviews: Pharmacology (2012), Brenner and Stevens' Pharmacology (2018) and George and Goodman and Gilman's (GG): The pharmacological basis of therapeutics (2018) were critically analysed for ADRs of a total of 34 drugs. Prototype drugs and most commonly prescribed antiepileptic drugs, were chosen for study. They were categorized according to therapeutic classification and guidelines by Indian Society of Epilepsy. ADRs were categorized according to various body systems, and serious and life threatening ADRs, then were tabulated and compared. Qualitative and quantitative analysis of this data was also done.Results: None of analysed sources mentioned all antiepileptic drugs. GG contained information for maximum number of drugs studied (76.4%) and National Formulary of India gave information for (52.9%) drugs only. There was wide variability among various resources while listing ADRs. CIMS listed maximum number of ADRs (85.5%) while minimum was included in Brenner and Stevens' Pharmacology (13%) for all antiepileptic drugs. The quality of data though limited was relatively better in CIMS, but none of sources studied were found to be complete.Conclusions: No source of information provided complete information about adverse effects of all 34 anti-epileptic drugs. Academicians and policymakers can work towards providing complete ADR information in all sources of information and updating it from time to time. Thus, making drug use safer in patients of epilepsy.

A Quantitative and Narrative Evaluation of Goodman and Gilman's Pharmacological Basis of Therapeutics.

Goodman and Gilman’s The Pharmacological Basis of Therapeutics (GGPBT) has been a cornerstone in the education of pharmacists, physicians, and pharmacologists for decades. The objectives of this study were to describe and evaluate the 13th edition of GGPBT on bases including: (1) author characteristics; (2) recency of citations; (3) conflict of interest (CoI) disclosure; (4) expert evaluation of chapters. Contributors’ (N = 115) sex, professional degrees, and presence of undisclosed potential CoI—as reported by the Center for Medicare and Medicaid’s Open Payments (2013–2017)—were examined. The year of publication of citations was extracted relative to Katzung’s Basic and Clinical Pharmacology (KatBCP), and DiPiro’s Pharmacotherapy: A Pathophysiologic Approach (DiPPAPA). Content experts provided thorough chapter reviews. The percent of GGPBT contributors that were female (20.9%) was equivalent to those in KatBCP (17.0%). Citations in GGPBT (11.5 ± 0.2 years) were significantly older than those in KatBCP (10.4 ± 0.2) and DiPPAPA (9.1 ± 0.1, p < 0.0001). Contributors to GGPBT received USD 3 million in undisclosed remuneration (Maximum author = USD 743,718). In contrast, DiPPAPA made CoI information available. Reviewers noted several strengths but also some areas for improvement. GGPBT will continue to be an important component of the biomedical curriculum. Areas of improvement include a more diverse authorship, improved conflict of interest transparency, and a greater inclusion of more recent citations.

MON-355 Recurrent Adrenal Crisis Secondary to Rifampin-Induced Hepatic Microsomal Enzyme Metabolism

Rifampin is a widely known antibiotic used to treat several types of bacterial infections including tuberculosis (TB) in a combination therapy setting. Rifampin is also known to have a profound drug-drug interaction profile. We describe here a case of rifampin induced hepatic microsomal enzyme causing accelerated hydrocortisone metabolism in a patient with panhypopituitarism resulting in multiple admissions with adrenal crisis. This is a 73-year-old male with a history of pituitary sarcoidosis since the 1980s with subsequent panhypopituitarism requiring replacement with levothyroxine, testosterone, desmopressin, and hydrocortisone in a stable dose pattern of 15 mg in the morning and 5 mg in the evening. He had been recently started on multi-drug therapy for military TB in the setting of an iliopsoas abscess. Initial therapy consisted of the following drug combination: rifampin, isoniazid, pyrazinamide, and ethambutol. After initiation of TB therapy, he presented with signs and symptoms of adrenal crisis that included: fatigue, hypotension, hyponatremia, hyperkalemia, and metabolic acidosis. Despite attempts at increasing the hydrocortisone dose over multiple hospital admissions, the patient had recurrent admissions for adrenal crisis episodes. These events occurred despite changes in his TB therapy regimen (therapy changed to rifampin and levofloxacin followed by the addition of meropenem, Augmentin and cycloserine for suspected resistant TB). Eventually, a stable dose of hydrocortisone 80 mg daily divided into 40/40 mg in the morning and evening stabilized the patient with no further adrenal crisis episodes. Rifampin is considered to be the most powerful known inducer of the hepatic cytochrome P450 enzyme system. It is known to increase the metabolism of many drugs that leads to those drugs being partially or totally ineffective. The list of drugs influenced by this mechanism includes: warfarin, contraceptive pills, anti-retroviral therapy, statins and many more.1 In addition, case reports have been described of hypothyroid patients requiring significantly higher doses of thyroid hormone replacement while on rifampin as compared to their original weight-based dosing requirements. However, in the literature, rifampin inducing increased steroid replacement therapy requirements in adrenally insufficient patients has been rarely reported. This case illustrates the need for increased awareness of higher steroid dose requirements, namely hydrocortisone, in patients on steroid replacement therapy with concomitant use of rifampin to avoid the sequelae of adrenal crisis which can be life threatening. 1. Hardman, Joel G., Lee E. Limbird, and Alfred G. Gilman, eds. "Rifampin." The Pharmacological Basis of Therapeutics. 10th ed. United States of America: The McGraw-Hill Companies, 2001. pp. 1277-1279.

A Quantitative Analysis of Undisclosed Conflicts of Interest in Pharmacology Textbooks.

BackgroundDisclosure of potential conflicts of interest (CoI) is a standard practice for many biomedical journals but not for educational materials. The goal of this investigation was to determine whether the authors of pharmacology textbooks have undisclosed financial CoIs and to identify author characteristics associated with CoIs.Methods and FindingsThe presence of potential CoIs was evaluated by submitting author names (N = 403; 36.3% female) to a patent database (Google Scholar) as well as a database that reports on the compensation ($USD) received from 15 pharmaceutical companies (ProPublica’s Dollars for Docs). All publications (N = 410) of the ten highest compensated authors from 2009 to 2013 and indexed in Pubmed were also examined for disclosure of additional companies that the authors received research support, consulted, or served on speaker’s bureaus. A total of 134 patents had been awarded (Maximum = 18/author) to textbook authors. Relative to DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, contributors to Goodman and Gilman’s Pharmacological Basis of Therapeutics and Katzung’s Basic and Clinical Pharmacology were more frequently patent holders (OR = 6.45, P < .0005). Female authors were less likely than males to have > 1 patent (OR = 0.15, P < .0005). A total of $2,411,080 USD (28.3% for speaking, 27.0% for consulting, and 23.9% for research), was received by 53 authors (Range = $299 to $310,000/author). Highly compensated authors were from multiple fields including oncology, psychiatry, neurology, and urology. The maximum number of additional companies, not currently indexed in the Dollars for Docs database, for which an author had potential CoIs was 73.ConclusionsFinancial CoIs are common among the authors of pharmacology and pharmacotherapy textbooks. Full transparency of potential CoIs, particularly patents, should become standard procedure for future editions of educational materials in pharmacology.

Comparative Survey on Retention of Clinical Pharmacology Knowledge among Students who Have Completed the Second Year at a Medical College of Central Nepal

Objective: The present study was conducted to evaluate and compare the retention of clinical pharmacology knowledge among the students who had completed the Integrated Basic Medical Sciences program. Methods: This was a cross-sectional study carried out among the 2nd year exit students of National Medical College, Birgunj, Nepal during the month of September 2013. Students’ responses were collected through a survey questionnaire prepared on the basis of renowned pharmacology text books including Katzung’s Basic and Clinical Pharmacology, Bennett and Brown’s Clinical Pharmacology, Goodman and Gilman’s the Pharmacological Basis of Therapeutics and Rang and Dale’s Pharmacology. The questionnaire was distributed among the participants and they were requested to tick the correct response independently. Data were entered in SPSS version 11.5 and evaluated for descriptive and inferential analyses using the Chi square test and Paired samples t test. Results: About 58% of the students were males and more than 66% of the total students were from different parts of India. The mean scores ± standard deviations from the syllabus of first and second years were 9.08 ±3.34 and 11.67 ±3.54 respectively; and the scores were positively and significantly correlated (r=0.542, p<0.001). The difference in means of scores was 2.59 (95% CI: 2.02 to 3.15). Conclusions: The retention of clinical pharmacology knowledge is significantly lower from the first year syllabus than that from the second year which clearly indicates a decline in clinical pharmacology knowledge with passage of time.

In Vitro Liberation of Indomethacin from Chitosan Gels Containing Microemulsion in Different Dissolution Mediums

The objective of this research is to outline the liberation of indomethacin from different chitosan gels containing O/W microemulsion. The influence of surfactant, sodium lauryl sulfate, in two concentrations (0.5% and 0.75%, w/w) was determined in dissolution medium on the release of indomethacin, which was used as poor water-soluble model drug. Chitosan gels were prepared in four different concentrations of chitosan-1%, 1.5%, 2%, and 3% (w/w). Microemulsion enhanced the liberation of the indomethacin from chitosan gels into all dissolution mediums. Adding the surfactant into phosphate-buffered saline decreased the amount of liberated indomethacin from microemulsion, gel mixture, but increased the drug liberation from pure chitosan gels. It was detected that with the increased concentration of chitosan in the samples, the amount of indomethacin liberated (p < 0.05) also increased. A conclusion was drawn that the liberation of indomethacin from chitosan gels was influenced by increased pH of the samples. The high viscosity induced a higher release of indomethacin from 3% (w/w) chitosan hydrogel at pH 5.8 as compared with 3% (w/w) chitosan hydrogel at pH 3.8. The highest percentage of released indomethacin was determined when a mixture of microemulsion gel with higher chitosan content was used.

From mechanism to empiricism: the evolution of heterogeneity of treatment effects.

Journal of Comparative Effectiveness ResearchVol. 3, No. 5 CommentaryFrom mechanism to empiricism: the evolution of heterogeneity of treatment effectsNewell E McElwee & Cynthia J GirmanNewell E McElweeUS Outcomes Research, Center for Observational & Real-world Evidence, Merck & Co., Inc., Whitehouse Station, NJ, USASearch for more papers by this author & Cynthia J GirmanData Analytics & Observational Methods, Center for Observational & Real-world Evidence, Merck & Co., Inc., Whitehouse Station, NJ, USASearch for more papers by this authorPublished Online:28 Oct 2014https://doi.org/10.2217/cer.14.49AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: heterogeneity of treatment effectindividualization of drug therapypersonalized medicinesub-group analysisReferences1 Brenneman SK, Shen W, Brekke L et al. Field-testing the ENSEMBLE minimum data set: performance of an instrument to address heterogeneity of treatment effects. J. Comp. Eff. Res. 3(5), 463–472 (2014).Link, Google Scholar2 PCORI. Patient-Centered Outcomes Research Definition Revision: Response to Public Input. www.pcori.org/content/research-we-support Google Scholar3 Lesko LJ, Schmidt S. Individualization of drug therapy: history, present state, and opportunities for the future. Clin. Pharmacol. Ther. 92(4), 458–466 (2011).Google Scholar4 Goodman L, Gilman A (Eds). Chapter 1: general principles. In: The Pharmacological Basis of Therapeutics. Macmillan, NY, USA (1941).Google Scholar5 Koch-Weser J. Serum drug concentrations as therapeutic guides. N. Engl. J. Med. 287(5), 227–231 (1972).Crossref, Medline, CAS, Google Scholar6 Temple R. Enrichment of clinical study populations. Clin. Pharmacol. Ther. 88(6), 774–778 (2010).Crossref, Medline, CAS, Google Scholar7 Kravitz RL, Duan N, Braslow J. Evidence based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q. 82(4), 661–687 (2004).Crossref, Medline, Google Scholar8 Kent DM, Hayward RA. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA 198(10), 1209–1212 (2007).Crossref, Google Scholar9 Gabler NB, Duan N, Liao D et al. Dealing with heterogeneity of treatment effects: is the literature up to the challenge? Trials 10, 1–12 (2009).Crossref, Medline, Google Scholar10 PCORI. The PCORI Methodology Report. www.pcori.org/content/pcori-methodology-report Google Scholar11 Kent DM, Rothwell PM, Ionnidis JPA, Altman DG, Hayward RA. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 11, 85 (2010).Crossref, Medline, Google Scholar12 Greenfield S, Kravitz R, Duan N, Kaplan SH. Heterogeneity of treatment effects: implications for guidelines, payment and quality assessment. Am. J. Med. 120(4 Suppl. 1), 53–59 (2007).Google ScholarFiguresReferencesRelatedDetails Vol. 3, No. 5 Follow us on social media for the latest updates Metrics Downloaded 48 times History Published online 28 October 2014 Published in print September 2014 Information© Future Medicine LtdKeywordsheterogeneity of treatment effectindividualization of drug therapypersonalized medicinesub-group analysisFinancial & competing interests disclosureNewell E McElwee and Cynthia J Girman are employees of Merck & Co., Inc and own stock in Merck & Co, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Redistribution of voltage-gated sodium channels after nerve decompression contributes to relieve neuropathic pain in chronic constriction injury

Nerve decompression is an important therapeutic strategy to relieve neuropathic pain and promote the peripheral nerve regeneration. To address these issues, we investigated the effects of nerve decompression on relief of neuropathic pain behaviors, redistribution of voltage-gated sodium channels (VGSCs), and skin reinnervation with chronic constriction injury (CCI). At post-operative week (POW) 4, animals were divided into a decompression group, in which the ligatures were removed, and a CCI group, in which the ligatures remained. Thermal hyperalgesia and mechanical allodynia at POW 8 had distinct reductions in decompression group compared to CCI group. At that time in CCI group, morphological evidence of pan VGSCs (Pan Nav) and isoforms of VGSCs (Nav1.6, Nav1.9, except for Nav1.8) were shown the widely distribution along the injured sciatic nerve. All of the VGSCs in decompression group became clustering around the node of Ranvier, similar to the pattern of control sciatic nerve at POW 8. Skin reinnervation was demonstrated by epidermal nerve density (END) for protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) nerve fibers and a significant difference between groups only at POW 24 (p=0.01). Growth-associated protein 43 (GAP-43) is participated in the nerve fiber growth and sprouting, a difference in END for GAP-43-IR nerve fibers at POW 24 between groups were also significant (p=0.02). These observations demonstrated that nerve decompression was accompanied with the disappearance of neuropathic pain behaviors after CCI. Morphological studies provided the evidence that redistribution of VGSCs along the injured sciatic nerve but still with an incomplete skin reinnervation. These significant findings demonstrated a role of VGSCs in the pathogenesis of neuropathic pain, and gave an approaching in pharmacological basis of therapeutics.

Management of Poisonings: Core Curriculum 2010

Management of Poisonings: Core Curriculum 2010

Polyethylene Terephthalate: Sax Responds

In his letter Vasami reminds readers that phthalates are not used in the manufacture of PET. Indeed, I emphasized precisely this point in my commentary (Sax 2010), for example, when I stated that “phthalates are not used as substrates or precursors in the manufacture of PET.” Vasami also asserts that “it is not chemically plausible for PET to produce these phthalate esters”; however, I never suggested that virgin PET gives rise to phthalate esters via degradation of PET itself. I did cite multiple studies in which phthalates were recovered from the contents of PET bottles—as contaminants leaching from the PET bottle wall. How did the phthalates come to be there? As I noted, one possibility is that some of the PET used in manufacturing the bottles may have been recycled PET, and some of this recycled PET might have been contaminated with phthalates. Again, as I noted in my commentary, PET is commonly used for bottling a variety of products (e.g. shampoo) that are known to contain phthalates; these phthalates can then sorb into the PET bottle. Other researchers have previously documented that various organic substances readily migrate into PET (e.g., Komolprasert and Lawson 1997). Indeed, previous investigators have documented the presence of phthalates in PET bottles marketed for consumer use (e.g., Kim et al. 1990); Nerin et al. (2000) reported that the concentration of phthalates was much higher in recycled PET material than in virgin PET. There are good environmental arguments for recycling plastics rather than disposing of them in landfills. The potential for tension between the desire to recycle plastics, on the one hand, and the desire to protect human health, on the other hand, has long been recognized (e.g., Castle 1994). Reconciling these two objectives requires a better understanding of the origin of endocrine disruptors in PET. Vasami notes that although Choe et al. (2003) reported antimony chloride as showing high estrogenicity, “antimony oxides—not antimony chloride—are used as catalysts in the manufacture of PET.” Although Vasami asserts that antimony oxides “are chemically and toxicologically distinct from antimony chlorides,” the toxicological literature does not provide strong support for this assertion. Antimony chloride, when combined with water, readily forms antimony oxide (National Research Council 2000), and both antimony chloride and antimony oxide ionize in vivo. Merski et al. (2008) reported that when animals were fed ground PET, antimony was recovered from their urine in a dose-dependent fashion. Toxicologically, what seems to matter is the antimony and its oxidation state [trivalent (III) or pentavalent (V)], not the anion (chloride or oxide). Antimony(III) is the ionization state in the antimony oxide used in the production of PET; the same ionization state (III) is found in antimony chloride. Using X-ray spectrometry, Martin et al. (2010) confirmed that the antimony in PET bottle walls is in fact trivalent antimony. The toxicological literature clearly establishes that trivalent antimony is far more toxic to humans than is pentavalent antimony (e.g., Chulay et al. 1988; De Boeck et al. 2003; Phillips and Stanley 2006). Vasami’s implication that antimony(III) oxide, when ingested, might be free of the risks demonstrated for antimony(III) chloride, is without evidentiary basis. Vasami concludes by reminding readers that PET bottles meet all applicable safety requirements. However, he neglects to note that these safety requirements were developed largely in the 1980s and 1990s, when the chief concern about antimony and other metalloids had to do with carcinogenicity (e.g., De Boeck et al. 2003) and organ toxicity (e.g., Poon et al. 1998). The standards were developed based on doses believed to be carcinogenic and/or directly toxic. The ability of inorganic metalloids such as antimony to act as xenoestrogens has only recently been recognized (Darbre 2006). More research is needed to determine whether the regulatory requirements for antimony in foods and beverages should be adjusted in order to minimize the risk of endocrine-disrupting effects. Certainly there is a paucity of research on the endocrine-disrupting effects of antimony. But surely the remedy for this deficiency is more research, not a stubborn insistence that what we don’t know can’t hurt us.

Epitope-tagged Receptor Knock-in Mice Reveal That Differential Desensitization of α2-Adrenergic Responses Is because of Ligand-selective Internalization

Although ligand-selective regulation of G protein-coupled receptor-mediated signaling and trafficking are well documented, little is known about whether ligand-selective effects occur on endogenous receptors or whether such effects modify the signaling response in physiologically relevant cells. Using a gene targeting approach, we generated a knock-in mouse line, in which N-terminal hemagglutinin epitope-tagged alpha(2A)-adrenergic receptor (AR) expression was driven by the endogenous mouse alpha(2A)AR gene locus. Exploiting this mouse line, we evaluated alpha(2A)AR trafficking and alpha(2A)AR-mediated inhibition of Ca(2+) currents in native sympathetic neurons in response to clonidine and guanfacine, two drugs used for treatment of hypertension, attention deficit and hyperactivity disorder, and enhancement of analgesia through actions on the alpha(2A)AR subtype. We discovered a more rapid desensitization of Ca(2+) current suppression by clonidine than guanfacine, which paralleled a more marked receptor phosphorylation and endocytosis of alpha(2A)AR evoked by clonidine than by guanfacine. Clonidine-induced alpha(2A)AR desensitization, but not receptor phosphorylation, was attenuated by blockade of endocytosis with concanavalin A, indicating a critical role for internalization of alpha(2A)AR in desensitization to this ligand. Our data on endogenous receptor-mediated signaling and trafficking in native cells reveal not only differential regulation of G protein-coupled receptor endocytosis by different ligands, but also a differential contribution of receptor endocytosis to signaling desensitization. Taken together, our data suggest that these HA-alpha(2A)AR knock-in mice will serve as an important model in developing ligands to favor endocytosis or nonendocytosis of receptors, depending on the target cell and pathophysiology being addressed.

Sympathetic (Adrenergic) Innervation Modulates But Does Not Generate Basal Tone in the Internal Anal Sphincter Smooth Muscle

Sympathetic (Adrenergic) Innervation Modulates But Does Not Generate Basal Tone in the Internal Anal Sphincter Smooth Muscle

Salicylates Trigger Protein Synthesis Inhibition in a Protein Kinase R-like Endoplasmic Reticulum Kinase-dependent Manner

The non-steroidal anti-inflammatory drug aspirin and its metabolite, sodium salicylate, have profound effects on cellular protein synthesis and cell physiology. However, the underlying mechanism by which they cause these responses remains unclear. We show here that salicylates induce phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha), resulting in the inhibition of mRNA translation in cells. Exposure of cells to acetyl salicylic acid resulted in strong activation of eIF2alpha stress-activated protein kinase R-like endoplasmic reticulum kinase (PERK). Analysis of fibroblasts with a targeted deletion of the perk gene revealed that PERK is indispensable for triggering the phosphorylation of eIF2alpha as well as the inhibition of protein synthesis induced by salicylates. Although salicylate treatment did not trigger activation of inositol-requiring enzyme 1, there was an increased expression of the pro-apoptotic transcription factor CHOP-(gadd153), a downstream event to eIF2alpha phosphorylation known to mediate endoplasmic reticulum stress-mediated responses. Thus, salicylates selectively trigger an endoplasmic reticulum stress-responsive signaling pathway initiated through activation of PERK to induce their cellular effects.

High-Dose Oral Erythromycin Decreased the Incidence of Parenteral Nutrition-Associated Cholestasis in Preterm Infants

Background & Aims: Feeding intolerance because of functional gastrointestinal dysmotility and parenteral nutrition-associated cholestasis (PNAC) are common problems in preterm, very-low-birth-weight (VLBW) infants. This double-blind, randomized, placebo-controlled study aimed to assess the effectiveness of “high-dose” oral erythromycin as a prokinetic agent in decreasing the incidence of PNAC. Two secondary end points, including the time to achieve full enteral feeding and the duration of parenteral nutrition, were also evaluated. Methods: Infants consecutively admitted to the neonatal unit were randomized to receive erythromycin (12.5 mg/kg/dose every 6 hours for 14 days) or an equivalent volume of normal saline (placebo) if they attained less than half the total daily fluid intake (<75 mL/kg/day) as milk feeds on day 14 of life. Results: Of 182 VLBW infants enrolled, 91 received erythromycin. The incidence of PNAC was significantly lower in erythromycin-treated infants (18/91) compared with placebo infants (37/91; P = .003). Treated infants achieved full enteral nutrition significantly earlier (mean, 10.1; SE, 1.7 days; P < .001), and the duration of parenteral nutrition was also significantly decreased by 10 days (P < .001). Importantly, fewer infants receiving erythromycin had 2 or more episodes of septicemia (n = 4) compared with placebo patients (n = 13, P = .03). No serious adverse effect was associated with erythromycin treatment. Conclusions: High-dose oral erythromycin can be considered as a rescue measure for VLBW infants who fail to establish adequate enteral nutrition and in whom anatomically obstructive pathologies of the gastrointestinal tract have been excluded.

Nonsteroidal Anti-inflammatory Drugs and Abdominal Pain

1. David N. Collier, MD, PhD 1. Brody School of Medicine at East Carolina University Greenville, NC 1. Cassie Billings, PharmD 1. Pitt County Memorial Hospital Greenville, NC Acute Renal Failure Associated with Non-Steroidal Anti-Inflammatory Drugs in Healthy Children. Krause I, Cleper R, Einstein B, Davidovits M. Pediatr Nephrol. 2005;20 :1295– 1298[OpenUrl][1][CrossRef][2][PubMed][3] Analgesic-antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:687– 731 Non-steroidal Anti-inflammatory Drugs and Exacerbations of Asthma in Children. Body R, Potier K. Emerg Med J. 2004;21 :713– 724[OpenUrl][4][Abstract/FREE Full Text][5] The Effectiveness of Five Strategies for the Prevention of Gastrointestinal Toxicity Induced by Non-steroidal Anti-inflammatory Drugs: Systematic Review. Hooper L, Brown TJ, Elliot RA, et al. BMJ. 2004;329 :948[OpenUrl][6][Abstract/FREE Full Text][7] The Safety of Acetaminophen and Ibuprofen Among Children Younger Than Two Years Old. Lesko SM, Mitchell AA. Pediatrics. 1999;104 :e39[OpenUrl][8][Abstract/FREE Full Text][9] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically heterogeneous group of compounds that have analgesic, antipyretic, and anti-inflammatory properties. These effects are mediated primarily through inhibition of the cyclooxygenase enzymes (COX-1 and COX-2), which are involved in the production of prostaglandins (PGs) and thromboxanes (TXs). The COX-1 isoform is produced constitutively in a variety of tissues and organs, including the kidney, vascular endothelium, and gastric mucosa. In many tissues, expression of the COX- 2 isoform is induced by inflammatory mediators, but COX-2 also is produced constitutively in the brain, uterus, and kidneys. PGI2 and prostaglandins of the E family (PGEs) reduce the pain threshold of nociceptors, resulting in hyperalgia (the sensitization of afferent nerve endings to the effects of mechanical or chemical stimulation). 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