Safety and immunogenicity of single dose of tetanus–diphtheria (Td) vaccine among non/partially immune children against diphtheria and/or tetanus,Hyderabad, India, 2007

In Hyderabad, India, diphtheria is common among children aged 5–19 years. On account of low coverage of diphtheria vaccine boosters recommended under the universal immunization programme, a large proportion of children were susceptible/partially immune against diphtheria and/or tetanus. We evaluated immunogenicity and safety of single dose of indigenously developed tetanus–diphtheria (Td) vaccine (diphtheria–toxoid ≤5 Lf) among 483 school children from Hyderabad aged 7–17 years and susceptible/partially immune against diphtheria and/or tetanus. Serological testing 6 weeks after vaccination indicated that vaccine was highly immunogenic with >96% sero-protected against both antigens. The immune response observed indicated a booster response to previously acquired immunity. Administration of additional dose of Td vaccine to the older school children and replacing the tetanus toxoid vaccine with Td in the school health programme would considerably reduce diphtheria burden in Hyderabad.     

Enhanced Transdermal Peptide Delivery and Stability by Lipid Conjugation: Epidermal Permeation,Stereoselectivity and Mechanistic Insights

Purpose

Efficient delivery of therapeutic peptides to the skin will facilitate better outcomes in dermatology. The tetrapeptide AAPV, an elastase inhibitor with potential utility in the management of psoriasis was coupled to short chain lipoamino acids (Laa: C6-C10) to enhance the peptide permeation into and through human epidermis.

Methods

AAPV was conjugated to Laas by solid phase synthesis. Peptide stability, skin distribution and permeation, elastase activity and surface activity were determined.

Results

Laas increased peptide permeation into the skin. The permeation lag time and amount of peptide remaining in the skin increased with the carbon chain length of the Laa conjugate. We also demonstrated stereoselective permeation enhancement in favour of the D-diastereomer. Importantly, the elastase inhibition activity of the peptide was largely retained after coupling to the Laa conjugates, showing potential therapeutic utility. The Laa-peptide structures were shown to be surface active, suggesting that this surfactant-like activity coupled with enhanced lipophilicity may contribute to their interaction with and permeation through the lipid domains of the stratum corneum.

Conclusions

This study suggests that the Laa conjugation approach may be useful for enhancing the permeation of moderately sized peptide drugs with potential application in the treatment of skin disorders.     

MHB4 Comparison of Standard Gamble, Time Trade-Off, and Visual Analog Scale Scores for Hypothetical Stroke Health States Using a Computer-Based Program

The most frequently used techniques for conducting utility assessments are the Standard Gamble (SG), the Time Trade-Off (TTO), and the Visual Analog Scale (VAS).
OBJECTIVES: The objectives of this study were to compare scores obtained on the SG, TTO, and VAS for hypothetical stroke health states; to determine the effect of age and gender on utility scores; to identify any ceiling or floor effects, and to determine the presence of interviewer effects.
METHODS: Forty-nine PharmD students from the College of Pharmacy at the University of Iowa were selected as the sample, and utility assessments were conducted by two interviewers, for hypothetical stroke scenarios adapted from the Glasgow Outcomes Sale. The health states evaluated were Good Recovery, Moderate Disability, Severe Disability, and a Vegetative State. Two rounds of interviews were separated by a period of 4 months. Regresion analysis was used to identify the factors influencing utility scores.
RESULTS: Mean SG scores for the four health states were 82.2, 62.7, 26.3, and 3.3, respectively. TTO scores for the four health states were 79.9, 57.3, 24.6, and 2.9, respectively. However, VAS scores were found to be higher than both TTO and SG scores. Neither age nor gender were found to be statistically significant determinants of reported utility scores. Interviewer effects were found for one out of 12 assessments in round 1, while none were observed in round 2. Floor effects were observed for all three techniques for the vegetative state.
CONCLUSION: Further research using larger, more representative samples from the general population is required to establish the validity of computer-based programs for utility assessments.     

Quality of life assessment in patients with bipolar disorder treated with olanzapine added to lithium or valproic acid

BACKGROUND: The objective of this study was to determine the clinical and quality of life outcomes associated with adjunctive treatment of olanzapine added to either lithium or valproic acid/divalproex sodium in patients with bipolar disorder. METHODS: Patients with bipolar I disorder, were randomized to receive either olanzapine (5-20 mg) added to mood stabilizer therapy (n=224), or placebo added to mood stabilizer therapy (n=112) for 6 weeks. Changes in clinical outcomes over 6 weeks were measured by the Young Mania Rating Scale (Y-MRS) and the Hamilton Rating Scale for Depression (HAM-D). Quality of life was measured by the Lehman Brief Quality of Life Interview (QLI). RESULTS: Patients treated with olanzapine added to mood stabilizers, experienced significantly greater mean clinical improvements from baseline on both the Y-MRS and the HAM-D compared to those treated with placebo added to mood stabilizers. Over 6 weeks, patients treated with olanzapine added to mood stabilizers had significantly greater mean improvements from baseline on five of the nine subjective scales on the QLI, compared to patients treated with placebo added to mood stabilizers. Changes in scores on the subjective scales of the QLI were more strongly correlated to changes in depressive symptomatology measured by the HAM-D, than to changes in symptoms of mania measured by the Y-MRS. CONCLUSION: The results of this study demonstrate that patients receiving adjunctive treatment have significantly greater improvements in both clinical and quality of life outcomes compared to monotherapy with mood stabilizers.     

Cost-effectiveness of denosumab compared with zoledronic Acid in patients with breast cancer and bone metastases

BackgroundResults from a phase III clinical trial showed that denosumab significantly reduced the risk of first on-study and subsequent skeletal-related events (SREs) compared with zoledronic acid. This study aims to assess the cost-effectiveness of denosumab vs. zoledronic acid in the prevention of SREs in patients with advanced breast cancer and bone metastases.Materials and MethodsA Markov model was developed with 4-week model cycles and a 1-year time horizon. The health states were defined by SRE status (no SRE, first on-study SRE, subsequent SRE, no SRE but history of SRE) and SRE type (pathologic fracture, radiation to the bone, surgery to the bone, spinal cord compression). Costs (in 2011 US dollars) included drug, SRE treatment, and adverse event (AE) costs and were assessed from a third-party payer perspective. The primary outcome was incremental total cost per SRE avoided; the secondary outcome was incremental total cost per pathologic fracture avoided. One-way and probabilistic sensitivity analyses were used to assess the robustness of the model.ResultsDuring the 1-year treatment period, denosumab incurred $7522 higher costs ($30,033 for denosumab and $23,511 for zoledronic acid), 0.06 fewer SREs, and 0.02 fewer pathologic fractures per patient, which led to an incremental total cost per SRE and pathologic fracture avoided of $114,628 and $290,136, respectively, compared with zoledronic acid. Results were robust to 1-way and probabilistic sensitivity analyses.ConclusionAlthough denosumab demonstrated superiority in preventing SREs in the phase III trial, it may not be cost-effective compared with zoledronic acid because of its high cost.     

Brønsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the Strychnos alkaloids

The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Br?nsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C?-C?? bond of the akuammiline related alkaloids represented by strictamine (22), using metal-carbenoid chemistry, are also described.     

Effects of olanzapine alone and olanzapine/fluoxetine combination on health-related quality of life in patients with bipolar depression: secondary analyses of a double-blind, placebo-controlled, randomized clinical trial

BACKGROUND: Improving patients' health-related quality of life (HRQOL) could be a treatment goal for bipolar depression. OBJECTIVES: The objectives of these secondary analyses of a previous report were to determine the benefits of olanzapine alone and olanzapine-fluoxetine combination (OFC) for improving HRQOL in patients with bipolar depression using both a generic and a depression-specific HRQOL instrument, and to examine the association between the 2 HRQOL instruments and the construct validity of the depression-specific HRQOL instrument. METHODS: This was a double-blind, placebo-controlled, 83-site, international, randomized trial. Adults with bipolar I disorder, most recent episode depressed (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), were randomly assigned to receive olanzapine (6-20 mg/d), OFC (6/25, 12/25, or 12/50 mg/d), or placebo for 8 weeks. HRQOL improvement was calculated as last-observation-carried-forward changes in dimension and component summary scores on Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and total score on the Quality of Life in Depression Scale (QLDS). Results: Patients were assigned to receive olanzapine (n = 370), [corrected] OFC (n = 86), or placebo (n = 377) [corrected] for 8 weeks. Of 833 enrolled patients, 454 discontinued (olanzapine, 191/370 [51.6%] [corrected]OFC, 31/86 [36.0%]; and placebo, 232/377 [61.6%]) [corrected] Compared with placebo, olanzapine-treated patients exhibited greater improvements on SF-36 mental component summary (MCS) score ( P=0.002) and 3 of 8 SF-36 dimension scores (mental health [P=0.015], role-emotional [P=0.046], and social functioning [P=0.006). OFC-treated patients exhibited greater improvements on MCS score ( P<0.001) vs both placebo and olanzapine), 5 SF-36 dimension scores (general health perception (P<0.001) vs placebo; (P<0.001) vs olanzapinel, mental health [ P=0.001] vs both placebo and olanzapine], role-emotional [ P<0.001] vs placebo; [P=0.007] vs olanzapine], social functioning [ P=0.001] vs placebo; [P=0.032] vs olanzapine], and vitality [P=0.002] vs placebo; [P=0.011] vs olanzapine]), and QLDS total score ( P<0.001] vs both placebo and olanzapine). Changes in SF-36 scores of mental health, social functioning, role-emotional, and vitality were highly correlated to changes in the QLDS total score (all p < -0.5). CONCLUSIONS: Based on these analyses, patients with bipolar depression receiving olanzapine or OFC for 8 weeks had greater improvement in HRQOL than those receiving placebo. OFC treatment was associated with greater improvement in HRQOL than olanzapine alone. The correlation results support the construct validity of the QLDS.     

Dihydrofolate reductase as a target for chemotherapy in parasites

Opportunistic infections are known to cause morbidity and mortality in immunocompromised individuals. In addition, serious infections due to several parasites are also known to affect the quality and duration of life in normal individuals. The importance of dihydrofolate reductase (DHFR) in parasitic chemotherapy arises from its function in DNA biosynthesis and cell replication. DHFR catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), an essential cofactor in the biosynthesis of thymidylate monophosphate (dTMP). Inhibition of DHFR leads to a deficiency of dTMP since DHF cannot be recycled, and thus causes inhibition of cell growth. Methotrexate (MTX) and aminopterin (AMT) were among the first known classical inhibitors of DHFR. Trimethoprim (TMP) and pyrimethamine (PYR) are among the first known non classical inhibitors of DHFR. TMP and PYR are selective but weak inhibitors of DHFR from several parasitic organisms and coadministration of sulfonamides is required to provide synergistic effects for clinical utility. Unfortunately, the side effects associated with sulfa drugs in this combination often result in cessation of therapy. Trimetrexate (TMQ) and piritrexim (PTX) are two potent non classical inhibitors, neither of which exhibit selectivity for pathogen DHFR and must be used with host rescue. However, the current combination therapy suffers from high cost, in addition, several mutations have been reported in the active site of parasitic DHFR rendering the infections refractive to known DHFR inhibitors. The selectivity of TMP is a hallmark in the development of DHFR inhibitors and several efforts have been made to combine the potency of PTX and TMQ with the selectivity of TMP. Thus the structural requirements for DHFR inhibition are of critical importance in the design of antifolates for parasitic chemotherapy. Structural requirements for inhibition have been studied extensively and novel agents that exploit the differences in the active site of human and parasitic DHFR have been proposed. This review discusses the synthesis and structural requirements for selective DHFR inhibition and their relevance to parasitic chemotherapy, since 1995.     

Large bilateral star-shaped calculi in the seminal vesicles

Calculi in the seminal vesicles (SV) are extremely rare. A patient having large bilateral star-shaped calculi in the SV is reported. They were seen on plain x-ray and confirmed by computed tomography. On the reconstructed CT scans the large stone on the right side measured about 35 X 35 X 50 mm and the one on the left, 30 X 20 X 45 mm. They were not felt on rectal examination, as they were situated laterally.