Assessment of image quality of a standard and two dose-reducing protocols in paediatric pelvic CT

Background: Concerns exist regarding the effect of radiation dose from paediatric pelvic CT scans and the potential later risk of radiation-induced neoplasm and teratogenic outcomes in these patients. Objective: To assess the diagnostic quality of CT images of the paediatric pelvis using either reduced mAs or increased pitch compared with standard settings. Materials and methods: A prospective study of pelvic CT scans of 105 paediatric patients was performed using one of three protocols: (1) 31 at a standard protocol of 200 mA with rotation time of 0.75 s at 120 kVp and a pitch factor approximating 1.4; (2) 31 at increased pitch factor approaching 2 and 200 mA; and (3) 43 at a reduced setting of 100 mA and a pitch factor of 1.4. All other settings remained the same in all three groups. Image quality was assessed by radiologists blinded to the protocol used in each scan. Results: No significant difference was found between the quality of images acquired at standard settings and those acquired at half the standard mAs. The use of increased pitch factor resulted in a higher proportion of poor images. Conclusions: Images acquired at 120 kVp using 75 mAs are equivalent in diagnostic quality to those acquired at 150 mAs. Reduced settings can provide useful imaging of the paediatric pelvis and should be considered as a standard protocol in these situations.

Equine laminitis: loss of hemidesmosomes in hoof secondary epidermal lamellae correlates to dose in an oligofructose induction model: an ultrastructural study

Reasons for performing study: Light microscopical studies show that the key lesion of laminitis is separation at the hoof lamellar dermal-epidermal interface. More precise knowledge of the damage occurring in the lamellar basement membrane zone may result if laminitis affected tissue is examined with the transmission electron microscope. This could lead to better understanding of the pathogenesis of lesions and the means of treatment or prevention. Objectives: To investigate the ultrastructure of acute laminitis as disease of greater severity is induced by increasing oligofructose (OF) dosage. Methods: Three pairs of normal horses, dosed with OF at 7.5, 10 and 12.5 g/kg bwt via nasogastric intubation, developed laminitis 48 h later. Following euthanasia, their forefeet were processed for transmission electron microscopy. Lamellar basal cell hemidesmosome (HD) numbers and the distance between the basal cell plasmalemma and the lamina densa of the basement membrane were estimated and compared to control tissue. Results: Increasing OF dosage caused greater HD loss and more severe laminitis. The characteristic separation of the basement membrane, cytoskeleton failure and rounded basal cell nuclei results from combined HD dysassembly and anchoring filament failure. Conclusions: Without properly assembled HDs, dysadhesion between the lamina densa of the basement membrane (BM) and epidermal basal cells occurs, emphasising the fundamental importance of HDs in maintaining attachment at the lamellar interface. Medical conditions that trigger lamellar matrix metalloproteinase (MMP) activation and/or compromise entry of glucose into lamellar basal cells appear to promote loss and failure of HDs and, therefore, laminitis development. Potential relevance: A correlation between lameness severity and escalating loss of lamellar HDs now exists. Therapy aimed at protecting the lamellar environment from haematogenous delivery of MMP activators or from glucose deprivation may control laminitis development.

Disposition of MDMA and Metabolites in Human Sweat Following Controlled MDMA Administration

BACKGROUND: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. METHODS: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek (R) sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. RESULTS: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. CONCLUSIONS: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results. (C) 2008 American Association for Clinical Chemistry

PHBHV/PCL microspheres as biodegradable drug delivery systems (DDS) for photodynamic therapy (PDT)

Unloaded microspheres were prepared from polyhydroxybutyrate-co-valerate (PHBHV) and poly(epsilon-caprolactone) (PCL) polymers using the emulsification-solvent evaporation method (EE). The study was conducted to determine the ideal polymeric composition and ideal molecular weight for the microspheres preparation to be used as a Drug Delivery System (DDS) for cancer therapy. In this work, NzPC, a new photosensitizer, has been investigated when incorporated into microspheres of PHBHV/PCL evaluating its application for Photodynamic Therapy (PDT) of neoplastic tissue. The biodegradation studies were conducted to analyze the effects of the incorporation of the NzPC and also to determine the release profiles in vitro condition. We also evaluated the dark toxicity and the photobiological effect of the PHBHV-PCL microspheres in cutaneous melanoma cell line (B-16-A1) used as a biological neoplastic medium.

Pindolol potentiates the panicolytic effect of paroxetine in the elevated T-maze

Aims: The beta-adrenergic and 5-HT(1A) receptor antagonist pindolol has been used in combination with antidepressant drugs, to shorten the time of onset of clinical efficacy and/or increase the proportion of responders in depressive and anxiety disorders. The aim of this study was to examine the interaction between pindolol and the selective serotonin reuptake inhibitor (SSRI), paroxetine in rats submitted to the elevated T-maze (ETM). Main methods: For assessing the drug combination effect, rats were administered with pindolol before paroxetine, using oral or intraperitoneal (i.p.) routes of acute administration, and were submitted to the ETM model. Key findings: The highest dose of pindolol used (15.0 mg/kg, i.p.) increased both inhibitory avoidance and escape latencies in the ETM, probably due to nonspecific motor deficit, since locomotion in a circular arena was also significantly decreased. The highest dose of paroxetine (3.0 mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0 mg/kg, i.p.) with an ineffective dose of paroxetine (1.5 mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0 mg/kg) nor pindolol (5.0 mg/kg) alone were effective, but the combination treatment had a marked panicolytic effect, again indicating drug potentiation. Significance: The present results show that the combination of the ineffective doses of pindolol and paroxetine significantly increased escape latency, indicating a selective panicolytic effect. These findings give preclinical support for the use of this drug combination in the treatment of panic disorder (PD). (C) 2010 Elsevier Inc. All rights reserved.

The unconditioned fear produced by morphine withdrawal is regulated by mu- and kappa-opioid receptors in the midbrain tectum

We have recently shown that morphine withdrawal sensitizes the neural substrates of fear in the midbrain tectum structures-the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC). In the present study, we investigated the role of mu- and kappa-opioid receptors in the mediation of these effects. Periadolescent rats chronically treated with morphine (10 mg/kg; s.c.) twice daily for 10 days were implanted with an electrode glued to a guide-cannula into the dPAG or the IC. Forty-eight hours after the interruption of this treatment, the effects of intra-dPAG or intra-IC microinjections of [D-Ala(2) N-Me-Phe(4) Gly(5)-ol]-enkephalin (DAMGO; 0.6 and 1 nmol/0.2 mu l) - a selective mu-receptor agonist - or nor-binaltorphimine (BNI; 2.5 and 5 mu g/0.2 mu l) - a selective K-receptor antagonist with tardive action - on the freezing and escape thresholds determined by electrical stimulation of the dPAG and the IC were examined. For both structures, morphine withdrawal produced pro-aversive effects. DAMGO and BNI had antiaversive effects when injected into the dPAG and IC of non-dependent rats. In morphine-withdrawn rats, only BNI continued to promote antiaversive effects in both structures. Whereas DAMGO lost its antiaversive efficacy when injected into the dPAG, only its highest dose promoted antiaversive effects in the IC of morphine-withdrawn rats, suggesting the development of an apparent tolerance. Thus, the enhanced reactivity of the midbrain tectum in morphine-withdrawn periadolescent rats may be due, at least partially, to an impairment of the inhibitory influence of mechanisms mediated by mu-receptors on the neural substrates of fear in this region. (C) 2009 Elsevier B.V. All rights reserved.

Characterization of rat behavior in the elevated plus-maze using a directed graph

The elevated plus-maze is a device widely used to assess rodent anxiety under the effect of several treatments, including pharmacological agents. The animal is placed at the center of the apparatus, which consists of two open arms and two arms enclosed by walls, and the number of entries and duration of stay in each arm are measured for a 5-min exposure period. The effect of an anxiolytic drug is to increase the percentage of time spent and number of entries into the open arms. In this work, we propose a new measure of anxiety levels in the rat submitted to the elevated plus-maze. We represented the spatial structure of the elevated plus-maze in terms of a directed graph and studied the statistics of the rat`s transitions between the nodes of the graph. By counting the number of times each transition is made and ordering them in descending frequency we represented the rat`s behavior in a rank-frequency plot. Our results suggest that the curves obtained under different pharmacological conditions can be well fitted by a power law with an exponent sensitive to both the drug type and the dose used. (C) 2009 Elsevier B.V. All rights reserved.

BUPROPION/NALTREXONE FIXED-DOSE COMBINATION FOR THE TREATMENT OF OBESITY

The combination of bupropion and naltrexone is one of the most promising new possibilities for the treatment of obesity in an era of increasing prevalence of this disease and decreasing options for its pharmacological management. Although approved by FDA panel members, it was temporally rejected by the FDA afterwards, who demanded more cardiovascular safety data for its commercialization. This monograph will focus on the physiology involved in its mechanisms of action and results of clinical trials.

Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

Background Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. Methods This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs >= 50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. Findings 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11.4 mmol/L (SD 3.6) in the mipomersen group and 10.4 mmol/L (3.7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24.7%, 95% CI 31.6 to 17.7) than with placebo (-3.3%, 12.1 to 5.5; p=0.0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Interpretation Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.

Long-Term Pharmacotherapy for Obesity in Elderly Patients A Retrospective Evaluation of Medical Records from a Specialized Obesity Outpatient Clinic

Background: Obesity is a serious chronic disease and the prevalence of this condition is increasing among the elderly. Although the benefits of weight loss to improve control of associated diseases are well known in young adults, they are not in older patients. The use of anti-obesity drugs to promote weight loss is widespread in Brazil and other countries, and obesity specialists frequently prescribe medicines in doses and for durations previously unreported in the literature. Sibutramine, orlistat and amfepramone (diethylpropion) have been evaluated in clinical trials of more than 2 years` duration in adults, demonstrating safety and efficacy, but long-term studies in obesity treatment are absent for other drugs. The efficacy and safety of obesity pharmacotherapy among the elderly is unknown. Objective: To describe the experience of obesity pharmacotherapy in the elderly in a specialized obesity care setting in Brazil, with a focus on efficacy and safety. Methods: A retrospective evaluation was conducted on medical charts from an outpatient clinic of a specialized tertiary centre for the treatment of obesity. We included patients who had had at least one consultation between January and December 2007, were aged >= 60 years at the beginning of the treatment, had had at least 6 months of follow-up and had received a prescription of at least one potential weight-loss drug. Diagnoses reported on medical records were documented. Age, weight, height and body mass index (BMI) were recorded at admission, after 6, 12, 18 and 24 months, and at the last available visit. The medicines prescribed, together with the dose, duration of use, adverse effects and reasons for discontinuation, were documented. Results: The group consisted of 44 women (86%) and 7 men (14%), with a mean +/- SD age of 65.2 +/- 4.5 years, weight of 95.3 +/- 12.5 kg and BMI of 38.5 +/- 4.3 kg/m(2). The mean +/- SD time of follow-up was 39.3 +/- 26.4 months, and the mean weight loss was 6.65 kg (p < 0.01). After the first 6 months, the mean +/- SD weight loss was 5.7 +/- 3.8 kg (p < 0.0001). A smaller weight loss was seen between the 6th and 12th months, with no statistically significant change in weight thereafter. A weight loss of >= 5% was achieved by 64.71%, 63.64%, 62.16% and 69.70% in the 6th, 12th, 18th and 24th months, respectively, and a weight loss of >= 10% was achieved by 17.65%, 34.09%, 32.43% and 39.39% in the 6th, 12th, 18th and 24th months, respectively. The medicines prescribed were sibutramine, orlistat, fluoxetine, sertraline, topiramate, fenproporex, mazindol and amfepramone, alone or in combinations, concomitantly or sequentially. The reasons for discontinuation were lack of response (n = 13), loss of response (development of tolerance) [n= 11], lack of adherence (n = 14) and adverse effects (n= 14). One episode of atrial flutter occurred in a patient taking fenproporex. The weight-loss medications were generally well tolerated, and only transient adverse events were reported. Conclusions: Long-term pharmacotherapy for obesity was effective and well tolerated by this group of elderly patients.

Randomized Evaluation of Two Drug-Eluting Stents With Identical Metallic Platform and Biodegradable Polymer But Different Agents (Paclitaxel or Sirolimus) Compared Against Bare Stents: 1-Year Results of the PAINT Trial

Objectives: We tested two novel drug-eluting stents (DES), covered with a biodegradable-polymer carrier and releasing paclitaxel or sirolimus, which were compared against a bare metal stent (primary objective). The DES differed by the drug, but were identical otherwise, allowing to compare the anti-restenosis effects of sirolimus versus paclitaxel (secondary objective). Background: The efficacy of novel DES with biodegradable polymers should be tested in the context of randomized trials, even when using drugs known to be effective, such as sirolimus and paclitaxel. Methods: Overall, 274 patients with de novo coronary lesions in native vessels scheduled for stent implantation were randomly assigned (2:21 ratio) for the paclitaxel (n = 111), sirolimus (n = 106), or bare metal stent (n = 57) groups. Angiographic follow-up was obtained at 9 months and major cardiac adverse events up to 12 months. Results: Both paclitaxel and sirolimus stents reduced the 9-month in-stent late loss (0.54-0.44 mm, 0.32-0.43 mm, vs. 0.90-0.45 mm respectively), and 1-year risk of target vessel revascularization and combined major adverse cardiac events (P < 0.05 for both, in all comparisons), compared with controls. Sirolimus stents had lower late loss than paclitaxel stents (P < 0.01), but similar 1-year clinical outcomes. There were no differences in the risk of death, infarction, or stent thrombosis among the study groups. Conclusion: Both novel DES were effective in reducing neointimal hyperplasia and 1-year re-intervention, compared to bare metal stents. Our findings also suggest that sirolimus is more effective than paclitaxel in reducing angiographic neointima, although this effect was not associated with better clinical outcomes. (C) 2009 Wiley-Liss, Inc.