Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that the therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.     

Comparison of the effects of chemical permeation enhancers on the lipoidal pathways of human epidermal membrane and hairless mouse skin and the mechanism of enhancer action

Previously, the effects of chemical permeation enhancers upon the permeability of the lipoidal pathway of hairless mouse skin (HMS) were investigated and a quantitative structure enhancement relationship was established. The present study was to study the effects of these enhancers on human epidermal membrane (HEM) using the same experimental method employed in the previous HMS studies. The effects of enhancers on the permeability coefficients of the lipoidal pathways of HEM and HMS for corticosterone were found to be essentially the same. In the equilibrium uptake studies of the enhancers and beta-estradiol, it was found that the amounts of enhancers taken up and the partitioning of beta-estradiol into the HEM stratum corneum (SC) intercellular lipid under the E = 10 conditions were different from those of HMS. Despite these differences, the HEM data show a correlation between the intercellular lipid/PBS partition coefficients of the enhancers and the enhancer n-octanol/PBS partition coefficients. This correlation is consistent with the observed chemical microenvironment of the site of enhancer action in the HMS SC in previous studies. Therefore, provided with proper experimental protocols, HMS can be a reliable model for the evaluation of the effects of skin permeation enhancers on the lipoidal pathway of HEM.     

Treatment of 161 Men with Symptomatic Late Onset Hypogonadism with Long-Acting Parenteral Testosterone Undecanoate: Effects on Body Composition,Lipids, and Psychosexual Complaints

IntroductionElderly men may suffer from late-onset hypogonadism (LOH). The long-term effects of long-acting testosterone undecanoate (TU) in a large number of LOH men have not yet been reported.AimsWe analyzed the effects of normalization of plasma testosterone (T) in LOH men.MethodsThe records of 161 men with LOH (baseline T < 300 ng/dL) were reviewed and 100 men had used parenteral TU for >12 months. The mean duration of treatment was 90.6 weeks (54 to 150 weeks).Main Outcome MeasuresBody mass index (BMI), waist circumference, percentage body fat, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, prostate-specific antigen (PSA), and hematocrit were measured. Further the Aging Male Symptoms' scale (AMS) and the International Index of Erectile Function (IIEF-5 and 15) were scored.ResultsT therapy was associated with a significant decline in waist circumference (P = 0.028) and percentage body fat (P < 0.001), but no change of BMI. Total cholesterol and LDL cholesterol declined significantly (P = 0.005 and P = 0.024, respectively), with no significant changes of HDL cholesterol and triglycerides. The scores of sub-scales of AMS (psychological, somotovegetative and sexual factors) decreased (P = 0.044, P = 0.200 and P = 0.071, respectively). The mean IIEF-5 (P = 0.011) and IIEF-15 scores (P = 0.021) improved significantly. Erectile function domain, orgasmic function domain, sexual desire domain, intercourse satisfaction domain, and overall satisfaction domain improved. Median PSA rose from 0.95 (0.640; 1.558) ng/mL to 1.480 (1.015; 2.275) ng/mL (P < 0.001), with 11 patients >4 ng/mL (4.01–13.21). On biopsy there was no evidence for malignancy. The mean hematocrit level increased significantly from 42.3 ± 3.4% to 47.1 ± 3.8%.ConclusionsNormalizing serum T in men with LOH resulted in improvement of the metabolic syndrome, mood and sexual functions and appeared acceptably safe. Permpongkosol S, Tantirangsee N, and Ratana-olarn, K. Treatment of 161 men with symptomatic late onset hypogonadism with long-acting parenteral testosterone undecanoate: Effects on body composition, lipids, and psychosexual complaints.     

Complications of 2,775 urological laparoscopic procedures: 1993 to 2005

PURPOSE: We assessed the complications associated with urological laparoscopic surgery at a single high volume center during a 12-year period. MATERIALS AND METHODS: A retrospective chart analysis was performed, focusing on complications associated with 2,775 laparoscopic surgeries occurring between 1993 and 2005. These included radical nephrectomy (549), partial nephrectomy (345), donor nephrectomy (553), simple nephrectomy (186), pyeloplasty (301), nephroureterectomy (105), retroperitoneal lymph node dissection (86), renal ablation (81), adrenalectomy (106) and radical prostatectomy (463). Complication data were tabulated according to case number, procedure type, patient age, the American Society of Anesthesiologists score, conversion status, length of hospitalization, Clavien classification system and annual complication rate during the study. Statistical analysis was performed with Fisher's exact and chi-square tests. RESULTS: A total of 614 complications (22.1%) occurred within each group, broken down into laparoscopic radical nephrectomy (20%), laparoscopic partial nephrectomy (28%), laparoscopic donor nephrectomy (28%), laparoscopic simple nephrectomy (15%), laparoscopic pyeloplasty (13.3%), laparoscopic nephroureterectomy (40.9%), laparoscopic retroperitoneal lymph node dissection (26.7%), laparoscopic renal tumor ablation (18.6%), laparoscopic adrenalectomy (25.4%) and laparoscopic radical prostatectomy (15%). Total intraoperative and postoperative complication rates were 4.7% and 17.5%, respectively. Vascular injuries were the most common intraoperative complications. Annual complication rates plateaued in the year 2000 and were not significantly different during the ensuing 4 years (p >0.05). Complications correlated with a greater American Society of Anesthesiologists score as well as a longer hospital stay (p <0.05). CONCLUSIONS: The data presented here help define the complication rates for laparoscopic urological procedures in experienced hands at a high volume institution.     

Feasibility of biowaiver extension to biopharmaceutics classification system class III drug products: cimetidine

BACKGROUND: The extension of biowaivers (drug product approval without a pharmacokinetic bioequivalence study) to drugs belonging to Class III of the Biopharmaceutics Classification System (BCS) is currently a subject of much discussion. OBJECTIVES: To assess the relationship between in vitro dissolution characteristics and in vivo absorption performance of immediate-release (IR) products containing cimetidine, a BCS Class III compound, in human subjects. To evaluate the feasibility and appropriateness of an extension of the biowaiver concept to BCS Class III compounds. STUDY DESIGN AND PARTICIPANTS: BCS-conform dissolution tests were carried out on ten marketed cimetidine products from Thailand and Germany, as well as cimetidine tablet formulations containing cimetidine 400mg manufactured by direct compression using methacrylate copolymer (Eudragit) RS PO) as a release-retarding agent to yield three batches with significantly different release profiles. Twelve healthy male subjects were enrolled in a randomised, open-label, single-dose schedule based on a five-way Williams' design balanced for carryover effects. Subjects received the following treatments, with 1-week washout periods between: (i) Tagamet 400mg tablet; (ii) 7.5% methacrylate copolymer cimetidine tablet; (iii) 15% methacrylate copolymer cimetidine tablet; (iv) 26% methacrylate copolymer cimetidine tablet; and (v) Tagamet (300 mg/ 2 mL) intravenous injection. The area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and AUC from time zero to infinity (AUC(infinity)), peak plasma concentration (C(max)), absolute bioavailability (F) and mean residence time (MRT) were evaluated and statistically compared among formulations. In vitro-in vivo correlation (IVIVC) analysis was then applied to elucidate the overall absorption characteristics of each tablet formulation. RESULTS: The release properties of the ten marketed cimetidine products were shown to comply with current US FDA criteria for rapidly dissolving drug products. As expected, the in vitro dissolution profiles of the cimetidine tablets containing different percentages of methacrylate copolymer differed considerably from one another. However, in vivo results showed no significant difference in AUC(12), AUC(infinity), C(max) and F between the tablets manufactured with methacrylate copolymer and the innovator. The MRT values obtained from 26% methacrylate copolymer tablets were significantly longer than for the other two methacrylate copolymer formulations and the Tagamet tablets. Furthermore, IVIVC analysis showed that the 26% methacrylate copolymer tablets exhibited dissolution rate-limited absorption, whereas the other formulations showed permeability rate-limited absorption. CONCLUSION: The results of the present study indicated that the absorption of cimetidine from IR tablets is, in general, limited by permeability rather than dissolution. IVIVC analysis demonstrated that only when the release was deliberately retarded (tablets containing 26% methacrylate copolymer), did the dissolution represent the rate-limiting step to drug absorption. On the in vitro side, it seems that 85% dissolution within 30 minutes, as currently required by the US FDA Guidance, is more than sufficient to guarantee bioequivalence of IR cimetidine products. For cimetidine and other BCS Class III drugs with a similar intestinal absorption pattern, application of the biowaiver concept seems to present little risk of an inappropriate bioequivalence decision.     

Leiomyomas of the kidney: emphasis on conservative diagnosis and treatment

Leiomyomas are benign mesenchymal tumors that rarely occur in the kidney. We present the reports of three renal leiomyomas diagnosed and treated at our institution during the past 10 years. On the basis of our experience, preoperative diagnosis may be possible through image-guided percutaneous biopsy, and conservative treatment with either expectant management or minimally invasive nephron-sparing surgery should always be considered.