Can We Justify Ipratropium Therapy as Initial Management of Acute Exacerbations of COPD?

Although inhaled ipratropium is commonly accepted as the drug of choice for long-term management of chronic bronchitis and emphysema, little evidence is available to promote its administration in conjunction with a beta2-agonist as part of initial management of exacerbations of chronic obstructive pulmonary disease (COPD) in the acute care setting. Reasons for its widespread acceptance for acutely ill patients may include its status as a first-line agent for long-term therapy, its relative safety, and attempts to provide optimal patient care. Since inhaled ipratropium is beneficial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these findings to treatment of COPD. Review of available studies reveals wide variability in methodologies and results. Although some studies reported improvement in pulmonary function tests, no clinically significant differences in patient outcomes, including shorter hospitalization, were evident. In patients who fail traditional therapies, inhaled ipratropium is reasonable. Double-blind, randomized, placebo-controlled trials in patients receiving emergency department care and in hospitalized patients that reveal shorter length of stay or other improved outcomes, are necessary to establish routine addition of inhaled ipratropium to beta2-agonists in the initial management of acute COPD.     

The Future of Hormesis: Where Do We Go from Here?

Although the occurrence of U-shaped dose responses in toxicology (i.e., hormetic effects) have been known for more than a century, the concept of hormesis has long been marginalized under the belief that such observations could be explained by a combination of poor study designs and normal variability. However, recent efforts have established that numerous highly reliable studies demonstrating hormetic effects exist and that such findings appear to be highly generalizable across species, endpoint measures, and class of agents assessed. In light of such a long and complicated history, and its significant biomedical/toxicological implications, this article explores the unique challenges that the concept of hormesis confronts in both the experimental and institutional domains with respect to assessing its scientific foundations and validity and the impediments to its intstitutional acceptance and use with society. This perspective is then immediately critiqued by five authors in subsequent articles.     

ADME of Biologics—What Have We Learned from Small Molecules?

Thorough characterization and in-depth understanding of absorption, distribution, metabolism, and elimination (ADME) properties of a drug candidate have been well recognized as an important element in small molecule (SM) drug discovery and development. This has been the area of focus for drug metabolism and pharmacokinetics (DMPK) scientists, whose role has been evolving over the past few decades from primarily being involved in the development space after a preclinical candidate was selected to extending their involvement into the discovery stage prior to candidate selection. This paradigm shift has ensured the entry into development of the best candidates with optimal ADME properties, and thus has greatly impacted SM drug development through significant reduction of the failure rate for pharmacokinetics related reasons. In contrast, the sciences of ADME and DMPK have not been fully integrated into the discovery and development processes for large molecule (LM) drugs. In this mini-review, we reflect on the journey of DMPK support of SM drug discovery and development and highlight the key enablers that have allowed DMPK scientists to make such impacts, with the aim to provide a perspective on relevant lessons learned from SM drugs that are applicable to DMPK support strategies for LMs.     

A new producer of mevastatin

Mevastatin (compactin)was isolated form culture broth of a fungal strain SIIA-F3933,The strain SIIA-F3933 was isolated from a soil sample collected in Putuo mountain,Zhejiang Province,P,R.China,It was identified as Penicillium janczewskii Zaleski based on its cultural and morphological characteristics and was regarded as a new producer of mevastatin，。     

A series of outbreaks of food poisoning?

A series of independently occurring episodes which were notified individually as 'food poisoning' were, after investigation, linked to a common source water supply.     

The Measurement of Small Quantities of Amorphous Material—Should We Be Considering the Rigid Amorphous Fraction?

Pharmaceutical Research -     

Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A₂A adenosine receptor

Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. d-Amino acid conjugates were generally more potent than l-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles.     

A rheological study of semisolid preparations of Eudragit ®

The present work studies the rheology of semisolid preparations of acrylic polymers of Eudragit^©, specifically RS 30 D, RL 30 D and NE 30 D. The parameters of shear deformation were obtained from experimental data and those of compression deformation were determined using previously obtained linear equations relating shear and compression stresses. The results, which were statistically significant, show a linear relationship between the coefficient of regression of these equations and the apparent viscosities of the different semisolid preparations, and between the independent term and the consistency index of each, and corroborate the previously demonstrated linear relationship between shear and compression stresses. The effect of the volume of the spindle used in the viscosimeter was observed in all cases. The equations relating both types of stress, obtained from semisolid preparations of Carbomer^® 940, can be used to determine the compression stresses of other semisolid preparations in this case, Eudragit^®.     

Health Effects of Low Level Radiation: When Will We Acknowledge the Reality?

The 1986 April 26th Chernobyl event was the worst nuclear power accident--it killed 31 people. Its significance was exaggerated immensely because of the pervasive fear of ionizing radiation that has been indoctrinated in all of humanity. In reality, our environment includes radiation from natural sources, varying widely in intensity, to which all living things have adapted. The effect of radiation on organisms is primarily on their damage control biosystem, which prevents, repairs and removes cell damage. Low doses stimulate this system, while high doses inhibit it. So low doses decrease the incidences of cancer and congenital malformations; high doses have the opposite effect. Efforts by radiation protection organizations to lower exposures to (human-made) radiation to as low as reasonably achievable (ALARA) provide no benefit. They only create inappropriate fear-barriers to very important applications of nuclear technology in energy production and medicine.     

A new producer of cyclosporin C

从真菌ＳＩＡ－Ｆ４８２９（Ｇｌｉｏｍａｓｔｉｘｌｕｚｕｌａｅ（Ｆｕｃｋｅｌ）ＭａｓｏｎｅｔＨｕｇｈｅｓ）的发酵液中，分离出一种具有抗真菌活性的化合物ＳＩＡ－Ｃ４８２９Ａ，经理化性质鉴别，证明ＳＩＡ－Ｃ４８２９Ａ与环孢菌素Ｃ同质。这是首次从半知菌亚门、丝孢纲、丛梗孢目、暗色孢科的菌株中发现环孢菌素类化合物的产生菌。     

Design and characterization of optimized adenosine A₂A/A₁ receptor antagonists for the treatment of Parkinson's disease

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.