A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities

Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.</jats:p

Dual partially harmonic tensors and Brauer-Schur-Weyl duality

Let $V$ be a $2m$-dimensional symplectic vector space over an algebraically closed field $K$. Let \mbb_n^{(f)} be the two-sided ideal of the Brauer algebra \mbb_n(-2m) over $K$ generated by $e_1e_3... e_{2f-1}$, where $0\leq f\leq [n/2]$. Let $\mathcal{HT}_{f}^{\otimes n}$ be the subspace of partially harmonic tensors of valence $f$ in $V^{\otimes n}$. In this paper, we prove that $\dim\mathcal{HT}_f^{\otimes n}$ and \dim\End_{KSp(V)}\Bigl(V^{\otimes n}/V^{\otimes n}\mbb_n^{(f)}\Bigr) are both independent of $K$, and the natural homomorphism from \mbb_n(-2m)/\mbb_n^{(f)} to \End_{KSp(V)}\Bigl(V^{\otimes n}/V^{\otimes n}\mbb_n^{(f)}\Bigr) is always surjective. We show that $\mathcal{HT}_{f}^{\otimes n}$ has a Weyl filtration and is isomorphic to the dual of V^{\otimes n}\mbb_n^{(f)}/V^{\otimes n}\mbb_n^{(f+1)} as a $Sp(V)$-(\mbb_n(-2m)/\mbb_n^{(f+1)})-bimodule. We obtain a $Sp(V)$-\mbb_n-bimodules filtration of $V^{\otimes n}$ such that each successive quotient is isomorphic to some \nabla(\lam)\otimes z_{g,\lam}\mbb_n with \lam\vdash n-2g, \ell(\lam)\leq m and $0\leq g\leq [n/2]$, where \nabla(\lam) is the co-Weyl module associated to \lam and z_{g,\lam} is an explicitly constructed maximal vector of weight \lam. As a byproduct, we show that each right \mbb_n-module z_{g,\lam}\mbb_n is integrally defined and stable under base change

Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice

BACKGROUND AND PURPOSE: Oxaliplatin is a platinum‐based chemotherapeutic drug used as a first‐line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side‐effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused by chronic oxaliplatin treatment, induces enteric neuronal damage and colonic dysmotility. EXPERIMENTAL APPROACH: Oxaliplatin (3 mg·kg(−1) per day) was administered in vivo to Balb/c mice intraperitoneally three times a week. The distal colon was collected at day 14 of treatment. Immunohistochemistry was performed in wholemount preparations of submucosal and myenteric ganglia. Neuromuscular transmission was studied by intracellular electrophysiology. Circular muscle tone was studied by force transducers. Colon propulsive activity studied in organ bath experiments and faeces were collected to measure water content. KEY RESULTS: Chronic in vivo oxaliplatin treatment resulted in increased formation of reactive oxygen species (O(2)ˉ), nitration of proteins, mitochondrial membrane depolarisation resulting in the release of cytochrome c, loss of neurons, increased inducible NOS expression and apoptosis in both the submucosal and myenteric plexuses of the colon. Oxaliplatin treatment enhanced NO‐mediated inhibitory junction potentials and altered the response of circular muscles to the NO donor, sodium nitroprusside. It also reduced the frequency of colonic migrating motor complexes and decreased circular muscle tone, effects reversed by the NO synthase inhibitor, Nω‐Nitro‐L‐arginine. CONCLUSION AND IMPLICATIONS: Our study is the first to provide evidence that oxidative stress is a key player in enteric neuropathy and colonic dysmotility leading to symptoms of chronic constipation observed in oxaliplatin‐treated mice

A review of the methodological features of systematic reviews in maternal medicine

Background In maternal medicine, research evidence is scattered making it difficult to access information for clinical decision making. Systematic reviews of good methodological quality are essential to provide valid inferences and to produce usable evidence summaries to guide management. This review assesses the methodological features of existing systematic reviews in maternal medicine, comparing Cochrane and non-Cochrane reviews in maternal medicine. Methods Medline, Embase, Database of Reviews of Effectiveness (DARE) and Cochrane Database of Systematic Reviews (CDSR) were searched for relevant reviews published between 2001 and 2006. We selected those reviews in which a minimum of two databases were searched and the primary outcome was related to the maternal condition. The selected reviews were assessed for information on framing of question, literature search and methods of review. Results Out of 2846 citations, 68 reviews were selected. Among these, 39 (57%) were Cochrane reviews. Most of the reviews (50/68, 74%) evaluated therapeutic interventions. Overall, 54/68 (79%) addressed a focussed question. Although 64/68 (94%) reviews had a detailed search description, only 17/68 (25%) searched without language restriction. 32/68 (47%) attempted to include unpublished data and 11/68 (16%) assessed for the risk of missing studies quantitatively. The reviews had deficiencies in the assessment of validity of studies and exploration for heterogeneity. When compared to Cochrane reviews, other reviews were significantly inferior in specifying questions (OR 20.3, 95% CI 1.1–381.3, p = 0.04), framing focussed questions (OR 30.9, 95% CI 3.7- 256.2, p = 0.001), use of unpublished data (OR 5.6, 95% CI 1.9–16.4, p = 0.002), assessment for heterogeneity (OR 38.1, 95%CI 2.1, 688.2, p = 0.01) and use of meta-analyses (OR 3.7, 95% CI 1.3–10.8, p = 0.02). Conclusion This study identifies areas which have a strong influence on maternal morbidity and mortality but lack good quality systematic reviews. Overall quality of the existing systematic reviews was variable. Cochrane reviews were of better quality as compared to other reviews. There is a need for good quality systematic reviews to inform practice in maternal medicine

Focusing and Compression of Ultrashort Pulses through Scattering Media

Light scattering in inhomogeneous media induces wavefront distortions which pose an inherent limitation in many optical applications. Examples range from microscopy and nanosurgery to astronomy. In recent years, ongoing efforts have made the correction of spatial distortions possible by wavefront shaping techniques. However, when ultrashort pulses are employed scattering induces temporal distortions which hinder their use in nonlinear processes such as in multiphoton microscopy and quantum control experiments. Here we show that correction of both spatial and temporal distortions can be attained by manipulating only the spatial degrees of freedom of the incident wavefront. Moreover, by optimizing a nonlinear signal the refocused pulse can be shorter than the input pulse. We demonstrate focusing of 100fs pulses through a 1mm thick brain tissue, and 1000-fold enhancement of a localized two-photon fluorescence signal. Our results open up new possibilities for optical manipulation and nonlinear imaging in scattering media

High prevalence of Trichomonas gallinae in wild columbids across western and southern Europe

Avian trichomonosis is known as a widespread disease in columbids and passerines, and recent findings have highlighted the pathogenic character of some lineages found in wild birds. Trichomonosis can affect wild bird populations including endangered species, as has been shown for Mauritian pink pigeons Nesoenas mayeri in Mauritius and suggested for European turtle doves Streptopelia turtur in the UK. However, the disease trichomonosis is caused only by pathogenic lineages of the parasite Trichomonas gallinae. Therefore, understanding the prevalence and distribution of both potentially pathogenic and non-pathogenic T. gallinae lineages in turtle doves and other columbids across Europe is relevant to estimate the potential impact of the disease on a continental scale

Solving the mu problem with a heavy Higgs boson

We discuss the generation of the mu-term in a class of supersymmetric models characterized by a low energy effective superpotential containing a term lambda S H_1 H_2 with a large coupling lambda~2. These models generically predict a lightest Higgs boson well above the LEP limit of 114 GeV and have been shown to be compatible with the unification of gauge couplings. Here we discuss a specific example where the superpotential has no dimensionful parameters and we point out the relation between the generated mu-term and the mass of the lightest Higgs boson. We discuss the fine-tuning of the model and we find that the generation of a phenomenologically viable mu-term fits very well with a heavy lightest Higgs boson and a low degree of fine-tuning. We discuss experimental constraints from collider direct searches, precision data, thermal relic dark matter abundance, and WIMP searches finding that the most natural region of the parameter space is still allowed by current experiments. We analyse bounds on the masses of the superpartners coming from Naturalness arguments and discuss the main signatures of the model for the LHC and future WIMP searches.Comment: Extended discussion of the LHC phenomenology, as published on JHEP plus an addendum on the existence of further extremal points of the potential. 47 pages, 16 figure

An assessment of the malaria-related knowledge and practices of Tanzania's drug retailers: exploring the impact of drug store accreditation.

BACKGROUND: Since 2003 Tanzania has upgraded its approximately 7000 drug stores to Accredited Drug Dispensing Outlets (ADDOs), involving dispenser training, introduction of record keeping and enhanced regulation. Prior to accreditation, drug stores could officially stock over-the-counter medicines only, though many stocked prescription-only antimalarials. ADDOs are permitted to stock 49 prescription-only medicines, including artemisinin combination therapies and one form of quinine injectable. Oral artemisinin monotherapies and other injectables were not permitted at any time. By late 2011 conversion was complete in 14 of 21 regions. We explored variation in malaria-related knowledge and practices of drug retailers in ADDO and non-ADDO regions. METHODS: Data were collected as part of the Independent Evaluation of the Affordable Medicines Facility - malaria (AMFm), involving a nationally representative survey of antimalarial retailers in October-December 2011. We randomly selected 49 wards and interviewed all drug stores stocking antimalarials. We compare ADDO and non-ADDO regions, excluding the largest city, Dar es Salaam, due to the unique characteristics of its market. RESULTS: Interviews were conducted in 133 drug stores in ADDO regions and 119 in non-ADDO regions. Staff qualifications were very similar in both areas. There was no significant difference in the availability of the first line antimalarial (68.9% in ADDO regions and 65.2% in non-ADDO regions); both areas had over 98% availability of non-artemisinin therapies and below 3.0% of artemisinin monotherapies. Staff in ADDO regions had better knowledge of the first line antimalarial than non-ADDO regions (99.5% and 91.5%, p = 0.001). There was weak evidence of a lower price and higher market share of the first line antimalarial in ADDO regions. Drug stores in ADDO regions were more likely to stock ADDO-certified injectables than those in non-ADDO regions (23.0% and 3.9%, p = 0.005). CONCLUSIONS: ADDO conversion is frequently cited as a model for improving retail sector drug provision. Drug stores in ADDO regions performed better on some indicators, possibly indicating some small benefits from ADDO conversion, but also weaknesses in ADDO regulation and high staff turnover. More evidence is needed on the value-added and value for money of the ADDO roll out to inform retail policy in Tanzania and elsewhere

Study of cosolvent-induced α-chymotrypsin fibrillogenesis: Does protein surface hydrophobicity trigger early stages of aggregation reaction?

The misfolding of specific proteins is often associated with their assembly into fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterize amyloid formation in vitro, there is no deep knowledge about the environment (in which aggregation occurs) as well as mechanism of this type of protein aggregation. Alpha-chymotrypsin was recently driven toward amyloid aggregation by the addition of intermediate concentrations of trifluoroethanol. In the present study, approaches such as turbidimetric, thermodynamic, intrinsic fluorescence and quenching studies as well as chemical modification have been successfully used to elucidate the underlying role of hydrophobic interactions (involved in early stages of amyloid formation) in α-chymotrypsin-based experimental system. © 2009 Springer Science+Business Media, LLC

Composite GUTs: models and expectations at the LHC

We investigate grand unified theories (GUTs) in scenarios where electroweak (EW) symmetry breaking is triggered by a light composite Higgs, arising as a Nambu-Goldstone boson from a strongly interacting sector. The evolution of the standard model (SM) gauge couplings can be predicted at leading order, if the global symmetry of the composite sector is a simple group G that contains the SM gauge group. It was noticed that, if the right-handed top quark is also composite, precision gauge unification can be achieved. We build minimal consistent models for a composite sector with these properties, thus demonstrating how composite GUTs may represent an alternative to supersymmetric GUTs. Taking into account the new contributions to the EW precision parameters, we compute the Higgs effective potential and prove that it realizes consistently EW symmetry breaking with little fine-tuning. The G group structure and the requirement of proton stability determine the nature of the light composite states accompanying the Higgs and the top quark: a coloured triplet scalar and several vector-like fermions with exotic quantum numbers. We analyse the signatures of these composite partners at hadron colliders: distinctive final states contain multiple top and bottom quarks, either alone or accompanied by a heavy stable charged particle, or by missing transverse energy.Comment: 55 pages, 13 figures, final version to be published in JHE