Bone biopsy in patients with osteoporosis

Although rarely used to diagnose and manage patients with osteoporosis, bone biopsies are performed to establish bone quality, including degree of mineralization and microarchitecture; to assess bone turnover and bone loss mechanisms; and to analyze treatment effects on bone structure and bone turnover. Bone biopsies are also the only method to diagnose mineralization defect or frank osteomalacia. Due to the availability of antiresorptive agents and anabolic drugs, determining bone turnover and bone-loss mechanisms is critical to appropriate treatment regimen selection. Bone biopsies establish the safety and efficacy of new therapeutic modalities. Further, new techniques such as molecular morphometry (in situ hybridization and immunohistochemistry) and analysis of bone content and crystal perfection have been applied to undecalcified bone and elucidated pathogenetic mechanisms or abnormalities in bone microstructure.     

Cortical folding patterns and predicting cytoarchitecture

The human cerebral cortex is made up of a mosaic of structural areas, frequently referred to as Brodmann areas (BAs). Despite the widespread use of cortical folding patterns to perform ad hoc estimations of the locations of the BAs, little is understood regarding 1) how variable the position of a given BA is with respect to the folds, 2) whether the location of some BAs is more variable than others, and 3) whether the variability is related to the level of a BA in a putative cortical hierarchy. We use whole-brain histology of 10 postmortem human brains and surface-based analysis to test how well the folds predict the locations of the BAs. We show that higher order cortical areas exhibit more variability than primary and secondary areas and that the folds are much better predictors of the BAs than had been previously thought. These results further highlight the significance of cortical folding patterns and suggest a common mechanism for the development of the folds and the cytoarchitectonic fields.     

Subglottic MALT lymphoma of the larynx--more attention to the glottis

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma of the larynx is a rare but well-documented entity which may arise from chronic inflammatory process. Supraglottic left regions are predominant due to unknown reason. CASE REPORT: We present the case of a 62-year-old man with a dry cough, stridor and developing exertional dyspnea. This subglottic almost circumferential MALT lymphoma showed a temporary distinct disappearance after cortisone administration during the diagnostic process. Bronchoscopy confirmed the diagnosis of a primary MALT lymphoma of the larynx. The patient received chemotherapy according to CHOP scheme plus rituximab. A reliable post-treatment care period of 15 months showed no sign of recurrence. CONCLUSION: MALT lymphoma of the larynx are believed to arise from preexisting or acquired lymphoid tissue of the upper airway. Acquired lymphoid tissue is documented in the supraglottic region and may be associated with a chronic inflammatory process. However, in subglottic cases it is unclear whether the chronic inflammation arises from a local or systemic process.     

AAPS-FDA Workshop White Paper: Microdialysis Principles, Application and Regulatory Perspectives

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development. The views expressed in this paper are those of the authors and do not necessarily reflect the opinions of their companies/institutions or the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred. The contents of this report were presented by the authors at the Microdialysis Workshop, Nashville, TN, Nov 4–5, 2005 organized by American Association of Pharmaceutical Scientists and Co-Sponsored with the US Food and Drug Administration.     

Diterpenoids from Turraeanthus mannii

Three new compounds, 15-acetoxy-12-hydroxy-16-methyl-labda-8(17),13E-diene (1), ent-labda-8(17),13-dien-15,16-olid-19-oic acid methyl ester (2), and 12-hydroxy-labda-8(17),13-dien-15,16-olide (3), together with two known compounds, 19-acetoxy-ent-labda-8(17),13-dien-15,16-olide (4), and 16-acetoxy-12,15-epoxy-15beta-hydroxy-labda-8(17),13(16)-diene (5) were isolated from the stem bark of Turraeanthus mannii (Meliaceae). The structures of compounds 1 - 3 were elucidated by analysis of the spectroscopic data. The crude methanol extract and compound 5 exhibited weak antibacterial and antifungal activity.     

Increased Absorption of Digoxin from the Human Jejunum Due to Inhibition of Intestinal Transporter-Mediated Efflux

BACKGROUND AND OBJECTIVES: The contribution of transport in the small intestine by the apically located efflux pump P-glycoprotein to variable drug absorption in humans is still poorly understood. We therefore investigated whether inhibition of intestinal P-glycoprotein-mediated efflux by quinidine leads to increased absorption of the P-glycoprotein substrate digoxin. METHODS: Using a multilumen perfusion catheter, we investigated the impact of P-glycoprotein inhibition on absorption of two compounds: the P-glycoprotein substrate digoxin and the marker for passive transcellular absorption antipyrine. Two 20cm adjacent jejunal segments were isolated with the multilumen perfusion catheter in seven healthy subjects. Unlabelled and deuterated digoxin and antipyrine, respectively, were simultaneously infused into either of the intestinal segments. One of the segments was additionally perfused with the P-glycoprotein inhibitor quinidine. Intestinal perfusates were collected for 3 hours, and drug concentrations were determined in the intestinal perfusates, plasma and urine. RESULTS: Quinidine did not affect the disposition of antipyrine. In contrast, coadministration of quinidine into one jejunal segment caused a considerable increase in the amount of digoxin absorbed from this segment compared with the absorption from the other quinidine-free segment (22.3 +/- 8.9% vs 55.8 +/- 21.2% of the dose; p < 0.05). Accordingly, the area under the plasma concentration-time curve and the maximum plasma concentration of digoxin were considerably higher when luminal quinidine was coadministered (p < 0.05 and p < 0.001, respectively). Differences in digoxin absorption from the two intestinal segments were also reflected by pronounced differences in urinary digoxin elimination (5.5 +/- 3.3% vs 19.2 +/- 8.1% of the dose; p < 0.01). CONCLUSIONS: P-glycoprotein inhibition in enterocytes increases systemic exposure of orally administered drugs that are P-glycoprotein substrates. These data highlight the importance of the small intestine as an active barrier against xenobiotics.     

Pharmacokinetic/pharmacodynamic modeling of in vitro activity of azithromycin against four different bacterial strains

The bacterial time-kill curves of azithromycin against four bacterial strains (Streptococcus pneumoniae/penicillin-intermediate, S. pneumoniae/penicillin-sensitive, Haemophilus influenzae and Moraxella catarrhalis) were determined by in vitro infection models. Eighteen different pharmacokinetic/pharmacodynamic models were fitted to the time-kill data using non-linear regression and compared for best fit. A simple, widely used E(max) model was not sufficient to describe the pharmacodynamic effects for the four bacterial strains. Appropriate models that gave good curve fits included additional terms for saturation of the number of bacteria (N(max)), delay in the initial bacterial growth phase and/or the onset of anti-infective activity (1-exp(-zt)) as well as a Hill factor (h) that captures the steepness of the concentration-response profile. Azithromycin was highly effective against S. pneumoniae strains and M. catarrhalis while the efficacy against H. influenzae was poor. Applications of these pharmacokinetic/pharmacodynamic models will eventually provide a tool for rational antibiotic dosing regimen decisions.     

The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking

OBJECTIVES: This study evaluated the associated comorbidities and patient satisfaction with treatment options for premature ejaculation (PE), a common sexual dysfunction. METHODS: A comprehensive, Internet-based survey (the PE Prevalence and Attitudes [PEPA] survey) was conducted among men ages 18-70 in the United States, Germany, and Italy (n=12,133). Men were classified as having PE based on self-report of low or absent control over ejaculation, resulting in distress for them or their sexual partner or both. RESULTS: The prevalence of PE was 22.7% (24.0% in the United States, 20.3% in Germany, and 20.0% in Italy) and did not vary significantly with age among men over age 24 yr. Men with PE were more likely to self-report other sexual dysfunctions (e.g., anorgasmia, low libido, erectile dysfunction) and psychological disturbances (e.g., depression, anxiety, excessive stress) than men without PE (p<0.05 for all). Men with PE were most aware of (>70%) and most likely to have used (>50%) special positions during sex, interrupted stimulation, masturbation, and having intercourse more often than usual to manage their PE. Only 9.0% of men with PE reported having consulted a physician for the condition; 81.9% had to initiate the conversation about PE and 91.5% reported little or no improvement as a result of seeking treatment. CONCLUSION: PE is a highly prevalent sexual problem, with significant sexual and psychological comorbidities. Most men with PE do not seek assistance from their physician, and most of those who do are not satisfied with the results.