Investigation of unknown impurities of paromomycin in a 15% topical cream by liquid chromatography combined with mass spectrometry.

RATIONALE: Characterization of unknown impurities in degraded paromomycin 15% topical cream samples by ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) gas-phase fragmentation is described. METHODS: A volatile reversed-phase high-performance liquid chromatography/charged aerosol detection (RP-HPLC/CAD) method was developed and validated for fast and consistent analysis of the paromomycin potency and impurity values in drug substance and drug product samples. A Veo charged aerosol detector was chosen for routine analysis. The method shows separation of two paromomycin isomers as well as twelve unknown impurity peaks. The identity of the unknown impurities was investigated by LC/MS/MS using a quadrupole time-of-flight (QTOF) mass spectrometer. RESULTS: Six of the HPLC/CAD impurity peaks met the ICH Q3B(R2) threshold for identification and were investigated by coupling the developed LC method with a QTOF instrument. Structures for the impurities were proposed based on gas-phase fragmentation patterns of the paromomycin reference standard. Impurity fragmentation pathways were proposed based on literature of other structurally related aminoglycoside compounds. CONCLUSIONS: Nine unknown paromomycin impurities were identified and the observed modifications included acetylation, carbamylation, gain of a hexose, and loss of glucosamine. The most abundant paromomycin modification was carbamylation by urea (a cream excipient) characterized by a 43 Da mass increase.

Beta-blockers for preventing aortic dissection in Marfan syndrome.

BACKGROUND: Marfan syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems. Aortic root dilatation is the most frequent cardiovascular manifestation and its complications, including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality. OBJECTIVES: To assess the long-term efficacy and safety of beta-blocker therapy as compared to placebo, no treatment or surveillance only in people with Marfan syndrome. SEARCH METHODS: We searched the following databases on 28 June 2017; CENTRAL, MEDLINE, Embase, Science Citation Index Expanded and the Conference Proceeding Citation Index - Science in the Web of Science Core Collection. We also searched the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 June 2017. We did not impose any restriction on language of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) of at least one year in duration assessing the effects of beta-blocker monotherapy compared with placebo, no treatment or surveillance only, in people of all ages with a confirmed diagnosis of Marfan syndrome were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for inclusion, extracted data and assessed trial quality. Trial authors were contacted to obtain missing data. Dichotomous outcomes will be reported as relative risk and continuous outcomes as mean differences with 95% confidence intervals. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (± standard error (SE)) optimal dose of propranolol was 212 ± 68 mg given in four divided doses daily.Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre-defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence).Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence.The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point.We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality. AUTHORS' CONCLUSIONS: Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.

Blood pressure lowering efficacy of renin inhibitors for primary hypertension.

BACKGROUND: Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II. OBJECTIVES: To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema). SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension. DATA COLLECTION AND ANALYSIS: This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs. MAIN RESULTS: 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. AUTHORS' CONCLUSIONS: Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

Field evaluations of topical arthropod repellents in North, Central, and South America.

Recently, vector-borne diseases have been resurging in endemic areas and expanding their geographic range into nonendemic areas. Such changes have refocused attention to the potential for major public health events, as naive populations are exposed to these pathogens. Personal topical repellents, recommended by the United States Centers for Disease Control and Prevention and World Health Organization, remain a first line of protection against infection. The current study evaluated the repellent efficacy of four new U.S. Environmental Protection Agency-registered topical repellent products, two with picaridin as the active ingredient and two with IR3535, against a standard DEET (N,N-diethyl-3-methylbenzamide)-based product. All products were evaluated against a wide range of vector species under field conditions across the Americas. Human volunteers were used to evaluate product efficacy as compared with a well-known DEET-based formulation and determine suitability for use by the U.S. military. Findings demonstrated the new formulations performed as well as the standard U.S. military repellent and could be recommended for use.

Field-user acceptability evaluation of a new stick camouflage face paint formulation with and without the insect repellent DEET.

Two newly designed formulations of stick camouflage face paint, one with 30% N,N-diethyl-3-methylbenzamide (DEET) and the other without DEET, were evaluated for acceptability among soldiers upon completion of normal military field training exercises. A total of 156 soldiers participated and completed a self-administered survey answering questions about product acceptability, packaging, and ease of use. Results of the study indicated that soldiers found stick formulations, with and without DEET, to be acceptable for use (62.9% and 83.7%, respectively). This data will be used by the Program Management Office at the U.S. Army Medical Materiel Development Activity to support a request to the Armed Forces Pest Management Board to assign a National Stock Number.

Quality of systematic reviews in HIV: The case of clinical outcomes associated with patient medication adherence.

AIM: Use of systematic reviews (SRs) as first-level evidence for guideline recommendations hinges on review quality. In particular, US guidelines for adherence-related recommendations in the treatment of human immunodeficiency virus (HIV) are not based on available SRs of adherence-outcome relationships; it is unclear why. No published studies report on the quality of SRs on HIV adherence and outcomes, which may be driving the lack of use. We describe the quality of this body of literature. METHODS: Literature searches were conducted in Ovid MEDLINE, EMBASE, CINAHL, PubMed Central, the Cochrane Library, Science Citation Index, Web of Science, ScIELO Citation Index, and Ovid Emcare. Screening and quality assessments were performed in duplicate using AMSTAR 2. Funding sources and impact factors of publishing journals were also extracted, and correlations between quality rankings and numbers of critical weaknesses versus impact factors were assessed using Spearman's rank correlation coefficient. RESULTS: Nine SRs of 1141 records met eligibility criteria. Overall confidence in the results was critically low for most (78%) SRs. Underperformance was found across all AMSTAR 2 domains. Impact factor (a surrogate or journal reputation) did not correlate with quality. CONCLUSIONS: SRs do not necessarily comprise top-level evidence despite the availability of quality appraisal tools and reporting guidance, which could explain the lack of SR evidence in US HIV medication adherence-related guideline recommendations. All parties to evidence synthesis publication should require quality assessment of studies.

A Comparative Study of Mosquito and Sand Fly (Diptera: Psychodidae: Phlebotominae) Sampling Using Dry Ice and Chemically Generated Carbon Dioxide From Three Different Prototype CO2 Generators.

A comparative study was conducted to test the efficiency of Centers for Disease Control and Prevention (CDC) light traps baited with either dry ice or carbon dioxide (CO2) produced from one of three different sources in collecting mosquitoes (Diptera: Culicidae) in Thailand. Treatments consisted of dry ice pellets, CO2 gas produced from one of three prototype CO2 generator systems (TDA, CUBE, Moustiq-Air Med-e-Cell - MEC), and a CDC light trap without a CO2 source. The best performing prototype from Thailand was then tested in collecting sand flies (Diptera: Psychodidae: Phlebotominae) in Greece. A total of 12,798 mosquitoes and 8,329 sand flies were sampled during the experimentation. The most prevalent mosquito species collected in Thailand were: Culex vishnui Theobald > Anopheles minimus Theobald > Culex tritaeniorhynchus Giles > Anopheles sawadwongporni Rattanarithikul & Green. By far the most prevalent sand fly species collected in Thessaloniki was Phlebotomus perfiliewi Parrot followed by Phlebotomus tobbi Adler and Theodor and Phlebotomus simici Nitzulescu. In general, the TDA treatment was the only treatment with no significant difference from the dry ice-treatment in mean trap catches. Although dry ice-baited traps caught higher numbers of mosquitoes and sand flies than the TDA-baited traps, there was no difference in the number of species collected. Results indicate that the traps baited with the TDA CO2 generator were as attractive as traps supplied with dry ice and, therefore, the TDA CO2 generator is a suitable alternative to dry ice as a source of carbon dioxide for use with adult mosquito and sand fly traps.

Topical paromomycin for New World cutaneous leishmaniasis.

BACKGROUND: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. METHODS: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. RESULTS: The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. CONCLUSIONS: Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.

Long-term resource addition to a detrital food web yields a pattern of responses more complex than pervasive bottom-up control.

BACKGROUND: Theory predicts strong bottom-up control in detritus-based food webs, yet field experiments with detritus-based terrestrial systems have uncovered contradictory evidence regarding the strength and pervasiveness of bottom-up control processes. Two factors likely leading to contradictory results are experiment duration, which influences exposure to temporal variation in abiotic factors such as rainfall and affects the likelihood of detecting approach to a new equilibrium; and openness of the experimental units to immigration and emigration. To investigate the contribution of these two factors, we conducted a long-term experiment with open and fenced plots in the forest that was the site of an earlier, short-term experiment (3.5 months) with open plots (Chen & Wise, 1999) that produced evidence of strong bottom-up control for 14 taxonomic groupings of primary consumers of fungi and detritus (microbi-detritivores) and their predators. METHODS: We added artificial high-quality detritus to ten 2 × 2-m forest-floor plots at bi-weekly intervals from April through September in three consecutive years (Supplemented treatment). Ten comparable Ambient plots were controls. Half of the Supplemented and Ambient plots were enclosed by metal fencing. RESULTS: Arthropod community structure (based upon 18 response variables) diverged over time between Supplemented and Ambient treatments, with no effect of Fencing on the multivariate response pattern. Fencing possibly influenced only ca. 30% of the subsequent univariate analyses. Multi- and univariate analyses revealed bottom-up control during Year 1 of some, but not all, microbi-detritivores and predators. During the following two years the pattern of responses became more complex than that observed by Chen & Wise (1999). Some taxa showed consistent bottom-up control whereas others did not. Variation across years could not be explained completely by differences in rainfall because some taxa exhibited negative, not positive, responses to detrital supplementation. DISCUSSION: Our 3-year experiment did not confirm the conclusion of strong, pervasive bottom-up control of both microbi-detritivores and predators reported by Chen & Wise (1999). Our longer-term experiment revealed a more complex pattern of responses, a pattern much closer to the range of outcomes reported in the literature for many short-term experiments. Much of the variation in responses across studies likely reflects variation in abiotic and biotic factors and the quality of added detritus. Nevertheless, it is also possible that long-term resource enhancement can drive a community towards a new equilibrium state that differs from what would have been predicted from the initial short-term responses exhibited by primary and secondary consumers.

Assessing the Dengue Diagnosis Capability Gap in the Military Health System.

Dengue, one of the most widespread infectious diseases, has affected U.S. military readiness throughout history. We explored the dengue diagnosis capability gap by circulating a questionnaire among military end users to determine in what capacity diagnostic test results are needed and how these results would be used at various roles of care in the Military Health System. Results were used to generate target product profiles for potential diagnostic tests. We determined that at far-forward locations, diagnostic tests need to be rugged and easy to use and are primarily needed to inform medical evacuation decisions. In mobile or fixed hospitals, diagnostics can be less portable but must be accurate enough to inform patient care decisions reliably. We then evaluated the suitability of using rapid diagnostic tests and enzyme-linked immunosorbent assays based on published performance characteristics, and we used a model to determine positive and negative predictive values in certain simulated deployments. In far-forward settings, a rapid diagnostic test comprising both antigen- and antibody-based detection can fulfill the capability gap with reasonable accuracy, whereas at higher roles of care immunoglobulin M-enzyme-linked immunosorbent assay was determined to be the most suitable option.

Evaluation of efficacy and duration of the stick camouflage face paint with 30% deet against mosquitoes in Belize.

A combination of insect repellent, N,N-diethyl-3-methylbenzamide (deet), with camouflage face paint in a newly designed stick formulation was evaluated on human volunteers under field conditions in Belize during February 2007. The formulation provided over 90% protection against mosquitoes for 8 hours and at least 80% protection for 12 hours, with 100% protection for 2 to 4 hours after application.

The role of the United States military in the development of vector control products, including insect repellents, insecticides, and bed nets.

Arthropod-borne diseases such as malaria, dengue, scrub typhus, and leishmaniasis continue to pose a significant threat to U.S. military forces deployed in support of operational and humanitarian missions. These diseases are transmitted by a variety of arthropods, including mosquitoes, ticks, chiggers, sand flies, and biting midges. In addition to disease threats, biting arthropods can cause dermatitis, allergic reactions, and sleep loss; therefore, monitoring of vector impact and integrated use of personal protective measures (PPM) and methods to reduce the vector populations are needed to protect service members. The U.S. military has played a vital role in vector identification tools and the development and testing of many of the most effective PPM and vector control products available today, including the topical repellent DEET and the repellent/insecticide permethrin, which is applied to clothing and bed nets. Efforts to develop superior products are ongoing. Although the U.S. military often needs vector control products with rather specific properties (e.g., undetectable, long-lasting in multiple climates) in order to protect its service members, many Department of Defense vector control products have had global impacts on endemic disease control.