The aim of this study was to quantify the global prevalence of chronic obstructive pulmonary disease (COPD) by means of a systematic review and random effects meta-analysis. PubMed was searched for ...population-based prevalence estimates published during the period 1990-2004. Articles were included if they: 1) provided total population or sex-specific estimates for COPD, chronic bronchitis and/or emphysema; and 2) gave method details sufficiently clearly to establish the sampling strategy, approach to diagnosis and diagnostic criteria. Of 67 accepted articles, 62 unique entries yielded 101 overall prevalence estimates from 28 different counties. The pooled prevalence of COPD was 7.6% from 37 studies, of chronic bronchitis alone (38 studies) was 6.4% and of emphysema alone (eight studies) was 1.8%. The pooled prevalence from 26 spirometric estimates was 8.9%. The most common spirometric definitions used were those of the Global Initiative for Chronic Obstructive Lung Disease (13 estimates). There was significant heterogeneity, which was incompletely explained by subgroup analysis (e.g. age and smoking status). The prevalence of physiologically defined chronic obstructive pulmonary disease in adults aged > or =40 yrs is approximately 9-10%. There are important regional gaps, and methodological differences hinder interpretation of the available data. The efforts of the Global Initiative for Chronic Obstructive Lung Disease and similar groups should help to standardise chronic obstructive pulmonary disease prevalence measurement.
Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part ...of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient’s (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.
ABSTRACT
Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop ...codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double‐blind, placebo‐controlled study; males ≥5 years with nm‐dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N = 57); ataluren 20, 20, 40 mg/kg (N = 60); or placebo (N = 57) for 48 weeks. The primary endpoint was change in 6‐Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ = 31.3 meters, post hoc P = 0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm‐dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Muscle Nerve 50: 477–487, 2014
Cellular tumor suppressors p53 and Rb play an important role in controlling cell proliferation. Inactivation of these tumor suppressor proteins can occur by gene mutation or by association with ...oncoproteins from the small DNA tumor viruses. One function of p53 is in regulating cell cycle check-point control after DNA damage. To dissect the pathways by which p53 and Rb may act, the E6 and E7 oncogenes of human papillomavirus (HPV) types 6 and 16 were introduced into primary human epithelial cells by retroviral transfer vector, and cells were assayed for growth arrest after DNA damage induced by actinomycin D. The E6 or E7 oncogenes from the low-risk HPV6 had no affect on growth arrest, p53 protein levels increased, Rb protein levels decreased, and Rb was predominantly in the hypophosphorylated state similar to vector-infected cells. Either the E6 or the E7 oncogene from the high-risk HPV16 abrogated growth arrest. Cells expressing HPV16 E6 (16E6) were severely reduced in p53 protein levels that did not increase detectably after DNA damage, Rb protein levels did not decrease, and hyperphosphorylated Rb was present. After DNA damage in cells expressing 16E7 p53 levels increased, and Rb protein levels decreased; however, Rb was predominantly in the hyperphosphorylated state. Even though p53 protein levels increased in response to DNA damage in cells expressing 16E7, G1 growth arrest was bypassed. This suggests that the circuitry controlling the growth arrest signal after DNA damage may be interconnected between the p53 and Rb pathways.
In Kartagener's syndrome (KS), primary defects of the ciliary axoneme cause dyskinetic ciliary motion. Because ciliary motion is an important factor in normal ovum transport, ciliary dyskinesia may ...cause infertility. On the other hand, the existence of some ciliary activity, albeit abnormal, may account for fertility in some women with KS. In this case study, an infertile woman diagnosed with KS had normal results in all usual infertility tests. Biopsies of tubal mucosa were obtained at laparoscopy for ovum recovery during an in-vitro fertilization cycle. Ciliary activity, measured by laser light-scattering spectroscopy, was detected in all tubal specimens; however the majority of regions sampled showed no activity. In active regions, beat frequency ranged from 5 to 10 Hz, approximately 30% of normal. Electron microscopy showed similar morphological defects in both tubal and nasal mucosa. The number of cilia per cell was approximately 20% of normal. The major ultrastructural abnormality of cilia was an absence of the central microtubules. The only demonstrable explanation for this patient's infertility was primary ciliary dyskinesia associated with KS.
Greenbug, Schizaphis graminum (Rondani) (Hemiptera: Aphididae), was first discovered damaging seashore paspalum (Paspalum vaginatum Swartz) turfgrass in November 2003 at Belle Glade, FL. Inquiries to ...several golf courses with seashore paspalum turf across southern Florida indicated infestation was wide spread by April 2004. Damage symptoms progress from water soaked lesions surrounding feeding sites within 24 h to chlorosis and necrosis of leaf tips within 96 h. Problems caused by greenbug feeding were initially misdiagnosed as fertilizer, disease, other insects, or water management problems because aphids were not previously found on warm season turfgrasses. Greenbug development and fecundity studies were conducted on six seashore paspalum varieties: 'Aloha,' 'SeaDwarf,' 'SeaGreen,' 'SeaIsle,' 'SeaWay,' and 'SeaWolf.' Greenbug did not survive on 'SeaWolf.' Development rates (mean c SEM) ranged from 7.6 c 0.2 to 8.2 c 0.2 d on the remaining varieties. Greenbug longevity and fecundity on 'Aloha' were significantly less than on the other varieties. The estimated intrinsic rate of natural increase (rm) for greenbug ranged from 0.24 to 0.26 across tested varieties. Values for net reproductive rate (Ro) ranged from 12.3 on 'Aloha' to 40.4 on 'SeaWay.' In feeding trials on indicator plants, the Florida isolate of greenbug exhibited a unique biotypic profile most commonly found on noncultivated grass hosts. It was virulent on the wheat variety GRS1201 that is resistant to the principal agricultural biotypes attacking small grains and to all currently available resistant sorghum varieties.
Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, ...potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.
Greenbug, Schizaphis graminum (Rondani) (Hemiptera: Aphididae), was first discovered damaging seashore paspalum (Paspalum vaginatum Swartz) turfgrass in November 2003 at Belle Glade, FL. Inquiries to ...several golf courses with seashore paspalum turf across southern Florida indicated infestation was wide spread by April 2004. Damage symptoms progress from water soaked lesions surrounding feeding sites within 24 h to chlorosis and necrosis of leaf tips within 96 h. Problems caused by greenbug feeding were initially misdiagnosed as fertilizer, disease, other insects, or water management problems because aphids were not previously found on warm season turfgrasses. Greenbug development and fecundity studies were conducted on six seashore paspalum varieties: ‘Aloha,’ ‘SeaDwarf,’ ‘SeaGreen,’ ‘SeaIsle,’ ‘SeaWay,’ and ‘SeaWolf.’ Greenbug did not survive on ‘SeaWolf.’ Development rates (mean ± SEM) ranged from 7.6 ± 0.2 to 8.2 ± 0.2 d on the remaining varieties. Greenbug longevity and fecundity on ‘Aloha’ were significantly less than on the other varieties. The estimated intrinsic rate of natural increase (rm) for greenbug ranged from 0.24 to 0.26 across tested varieties. Values for net reproductive rate (Ro) ranged from 12.3 on ‘Aloha’ to 40.4 on ‘SeaWay.’ In feeding trials on indicator plants, the Florida isolate of greenbug exhibited a unique biotypic profile most commonly found on noncultivated grass hosts. It was virulent on the wheat variety GRS1201 that is resistant to the principal agricultural biotypes attacking small grains and to all currently available resistant sorghum varieties.
The development of alpha(1a)-adrenergic receptor (AR) subtype-selective antagonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms ...without causing undesirable side effects that may be due to vascular alpha(1)-AR blockade. The properties of four aryl piperazine compounds (RWJ-38063, RWJ-68141, RWJ-68157, and RWJ-69736) are described in this report and compared with the properties of tamsulosin, an alpha(1)-AR antagonist that is used in the treatment of BPH. Radioligand binding studies show that all four RWJ compounds have significantly higher affinity for the alpha(1a)-AR subtype than for the alpha(1b) or alpha(1d) subtype and display a higher level of receptor subtype selectivity than tamsulosin. The RWJ compounds were more potent in inhibiting (+/-)-norepinephrine-induced contractions of isolated rat prostate tissue than those of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity. RWJ-38063 and RWJ-69736 had the highest potency in the isolated prostate tissue assays of the four RWJ compounds, with pK(B) values of 8.24 and 9.26, respectively, and were 319- and 100-fold more potent in their effects on isolated prostate tissue than aorta tissue. The in vivo uroselectivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthetized dogs. Both RWJ compounds suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response; however, RWJ-69736 also caused a marked transient rise in heart rate. Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselective than tamsulosin in this canine model.
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