Predicting crystal form stability under real-world conditions.

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2-4. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid-solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1-2 kJ mol-1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control5.

Templated Nucleation of Clotrimazole and Ketoprofen on Polymer Substrates.

The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API-polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API-polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API-polymer interaction energies are correlated with heterogeneous crystallization outcomes.

Transforming Computed Energy Landscapes into Experimental Realities: The Role of Structural Rugosity.

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures.

The importance of configurational disorder in crystal structure prediction: the case of loratadine.

Loratadine, an over-the-counter antihistamine medication, has two known monotropically related polymorphs, both of which feature disorder. A combined experimental and computational approach using variable temperature single crystal X-ray diffraction (VT-SCXRD) analysis and dispersion corrected density functional theory (DFT-D) reveals that the nature of the disorder in each form is markedly different and cannot be described by a simple isolated-site model with thermally populated conformations in either of the two cases. In Form I, the ethyl carbamate functionality adopts two different configurations, with adjacent moieties interacting along one-dimensional chains. The most stable arrangement features alternating configurations, but because of the low energetic cost of stacking faults, the domain sizes are short and an average crystal structure is observed experimentally. The configurational free energy of the disordered structure is lower than the energy of the two corresponding ordered crystal structures, but the energy decrease is dominated by the lower lattice energy of the alternating arrangement with a small entropic contribution. In Form II, the flexible cycloheptane bridge adopts two different configurations. The disorder is not an equilibrium property but is instead frozen-in during the crystallisation process. The configurational free energy of the disordered structure falls in between the lattice energies of the two corresponding ordered structures. The two ordered components of each disordered structure are all found in a crystal structure prediction (CSP) study with the GRACE programme. However, the experimentally observed stability relationship is only reproduced when the energy contribution of disorder is taken into account. The disordered model of Form I is found to be lower in energy than all the other predicted structures and there is no indication of a missing, thermodynamically more stable, form. The case of loratadine demonstrates that experimentally observed disorder close to 50/50 does not necessarily correspond to a free energy decrease by kT ln 2.

Prolapse and sexual function in women with benign joint hypermobility syndrome.

OBJECTIVE: To determine whether pelvic organ prolapse (POP) and sexual dysfunction are more severe in women with benign joint hypermobility syndrome (BJHS) than in the normal population. DESIGN: Case-control study. SETTING: King's College Hospital NHS Foundation Trust, London, UK and University College Hospital, London, UK. POPULATION: Women diagnosed with BJHS (n = 60) at University College Hospital. Control participants (n = 60) recruited from King's College Hospital NHS Foundation Trust. METHODS: Objective assessment of POP was undertaken using the Pelvic Organ Prolapse Quantification System (POP-Q). Both groups were asked to complete the Prolapse quality of life (P-QOL) and pelvic organ prolapse/urinary incontinence sexual (PISQ-12) questionnaires. MAIN OUTCOME MEASURES: Comparison of vaginal anatomy using POP-Q between the two groups. Comparison of P-QOL and PISQ-12 quality of life scores between the two groups. RESULTS: In all, 120 women (60 in Study group, 60 in Control group) were recruited. All women in the study group were matched with healthy control women according to age, parity and ethnicity. There was a statistically significant difference between points Aa, Ba, Ap, Bp and C in study and control groups showing that prolapse is objectively more severe in those with BJHS. Significantly more women with BJHS felt that POP interfered with sex and defecation compared with the control group. The impact of prolapse symptoms on quality of life was statistically different in almost all nine P-QOL domains. CONCLUSIONS: A large number of women with BJHS have prolapse symptoms, which significantly affect their quality of life. POP is more severe in women with BJHS.

Lower urinary tract symptoms in women with benign joint hypermobility syndrome: a case-control study.

INTRODUCTION AND HYPOTHESIS: Benign joint hypermobility syndrome (BJHS) is a connective tissue disorder associated with joint hypermobility. BJHS is under-recognised by medical professionals and is poorly managed. The aim of our study was to determine whether lower urinary tract symptoms (LUTS), including urinary incontinence (UI) and anterior compartment prolapse, are more common in women with BJHS than in the normal population. METHODS: This was a prospective case-control study. Women diagnosed with BJHS according to the Brighton criteria were recruited from a tertiary referral clinic. Controls were recruited from hospital personnel. Both groups completed the King's Health Questionnaire (KHQ) and the Prolapse Quality of Life Questionnaire (P-QoL). Objective assessment of pelvic organ prolapse (POP) was undertaken using the Pelvic Organ Prolapse Quantification (POP-Q) system. Analyses were performed using SPSS version 17.0. The statistical difference was analysed using McNemar's test. Comparison of QoL scores was performed with the Wilcoxon signed-rank test. RESULTS: Sixty individuals were recruited and matched with 60 healthy women. The prevalence of UI in those with BJHS was significantly higher than in controls(73.3 % vs. 48.3 %). The impact of UI on QoL was statistically significant in all domains of the KHQ. There was a significant difference between groups in most urinary-specific symptoms of the KHQ. A significant number of women with BJHS suffer from voiding difficulties. Prolapse of the anterior vaginal wall was objectively more severe in those with BJHS. CONCLUSIONS: Women with BJHS have LUTS and anterior compartment prolapse, which significantly impair their QoL. It is important to identify women who are symptomatic. The addition of a systematic active case-finding approach may be more effective in identifying these cases.

The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study.

BACKGROUND: Patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS-HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS-HT in a 'non-patient' population and the effect of the above-mentioned factors has never been studied. METHODS: In a cross sectional study, a hypermobility questionnaire was used to screen university students; further clinical examination established the diagnosis of EDS-HT. Validated questionnaires assessed for GI, somatic, pain and autonomic symptoms, psychopathology and quality of life (QOL). These were compared in students with and without EDS-HT; logistic regression analysis examined associations between EDS-HT, GI symptoms and other variables. KEY RESULTS: Of 1998 students screened, 162 were included: 74 EDS-HT (21.0 years, 53% female) vs 88 Non-EDS-HT (21.5 years, 65% female). Compared to non-EDS-HT students, EDS-HT students were more likely to have multiple GI symptoms (41.9% vs 27.3% P=.05), particularly postprandial fullness (34.4% vs 15.9%, P=.01) and early satiety (32% vs 17%, P=.03), greater autonomic (P<.001) and somatic symptoms (P=.04) but not psychopathology (P>.8). The association between EDS-HT and postprandial symptoms was dependent on autonomic factors but independent of pain and psychopathology. Pain-related QOL scores were reduced in the EDS-HT group (80 vs 90, P=.03). CONCLUSIONS AND INFERENCES: The previously described association between EDS-HT, dyspepsia, pain and autonomic symptoms in patients is also present in non-patient groups. Future studies are necessary to explore the etiological role of connective tissue in GI and extra intestinal symptoms.

Ehlers-Danlos syndrome.

The Ehlers-Danlos syndromes (EDSs) were originally described by Ehlers in Denmark and Danlos in Paris in 1898 and 1908, respectively. They had both published individual case studies in which the common factor was laxity of ligaments leading to joint hypermobility and hyperextensibility of the skin. The choice of the name of this eponymous disease had been made by Dr Parkes Weber, an eminent London physician in the 1930s, who had a penchant for eponymous diseases, having had no less than seven attributed to himself, at least in part. Unfortunately, this was before the age of a computerised literature search, and Parkes Weber had inadvertently overlooked the very first description of EDS which had been made by Tchernabogov, a Russian dermatologist, whose description was published in 1891 and remains one of the best descriptions of EDS in the literature.

Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study.

BACKGROUND: The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL). METHODS: Prospective case-control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS. KEY RESULTS: JHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07-2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25-3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06-3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p < 0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004). CONCLUSIONS & INFERENCES: JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association.

Subclass distribution of IgG and IgA responses to rubella virus in man.

Monoclonal anti-subclass antibodies were used in a micro-ELISA method to determine rubella-specific IgG subclass antibodies in serum from 22 subjects who had acute rubella or had been vaccinated, from 10 infants with congenital rubella, and in serum and synovial fluid samples from 21 patients with chronic arthritis. In nearly all samples IgG1 was the only type of IgG antibody detected. In acute infections it was present within 10 days of the onset of the rash. IgG4 antibody was detected in sera from two immune individuals. Rubella-specific IgA1 subclass antibody was detected by the same technique in sera from 6 of 12 subjects with acute rubella as early as 3 days but not later than 28 days after the appearance of the rash.

Preliminary experience with diacetylrhein in the treatment of osteoarthritis.

A single-blind, placebo controlled study was carried out over a 12-week period in 12 patients with osteoarthritis of the hip or knee to assess the effectiveness of 50 mg diacetylrhein per day. The 4 weeks of active treatment were preceded and followed by periods on placebo. Response to treatment as assessed by pain score, walking time and the number of 'rescue' analgesic tablets (paracetamol) consumed showed that 6 patients improved, 4 were unchanged and 2 deteriorated. Improvement was not apparent for several weeks after starting active treatment and remission lasted for 2 weeks to 3 or more months after the drug was withdrawn. The action of diacetylrhein is not yet established, but it does not appear to be related to analgesia or inhibition of prostaglandin synthetase activity. It is considered that further studies of this interesting drug are warranted to determine the most effective dose and duration of treatment.

A comparison of two formulations of indomethacin ('Flexin Continus' tablets and 'Indocid' capsules) in the treatment of rheumatoid arthritis.

A multi-centre, double-blind, crossover study was carried out in 80 patients with rheumatoid arthritis to compare the efficacy and side-effect profiles of two formulations of indomethacin. Patients were allocated at random to receive 75 mg indomethacin per day either as 1 controlled-release tablet at night or as 1 immediate-release capsule given 3-times a day for a period of 4 weeks before being crossed over to receive the alternative treatment for a further 4 weeks. Pain scores, daily symptomatology and the requirement for escape analgesia recorded by both investigator and patient indicated that controlled-release indomethacin tablets, 75 mg given at night, was as efficacous as immediate-release indomethacin capsules given 3-times daily. However, the controlled-release formulation had a superior side-effect profile with a reduced incidence of abdominal/epigastric pain compared to the immediate-release preparation.

A comparison of two formulations of indomethacin ('Flexin Continus' tablets and 'Indocid' capsules) in the treatment of osteoarthritis.

The efficacy and side-effect profiles of two formulations of indomethacin were compared in a multi-centre, double-blind, crossover study in 77 patients with osteoarthritis. Patients were allocated at random to receive 75 mg indomethacin per day either as 1 controlled-release tablet at night or as 1 immediate-release capsule given 3-times daily for a period of 4 weeks, after which patients were crossed over to receive the alternative treatment for a further 4 weeks. Pain scores, daily symptomatology and the requirement for escape analgesia recorded by the investigator and patient indicate that controlled-release indomethacin tablets, 75 mg given at night, were as efficacious as immediate-release indomethacin capsules, 25 mg given 3-times daily, in the treatment of osteoarthritis. The side-effect profiles of the two formulations were similar.

Ventricular septal aneurysm in a case of Ehlers-Danlos syndrome.

Cardiac abnormalities are a recognised feature of connective tissue disorders. We report a case of Ehlers-Danlos syndrome associated with an aneurysm of the membranous ventricular septum and mitral valve prolapse. To our knowledge this is the first reported association of Ehlers-Danlos syndrome and ventricular septal aneurysm.

An electrogoniometer for the measurement of thoracolumbar rotation.

A simple, noninvasive method of measuring thoracolumbar rotation was developed using an electrogoniometer mounted on thermoplastic girdles. The instrument is designed to adjust to trunk movement that might occur in the sagittal and coronal planes while transmitting the torque that results from rotation in the horizontal plane directly to the active potentiometer of the electrogoniometer. Experiments were carried out to determine the accuracy, validity and reliability of the device and it was concluded that this method of measurement of horizontal trunk movement could be used in kinematic investigations.

Toward a rational therapeutic strategy for arachnoiditis. A possible role for d-penicillamine.

Twenty-six patients (13 men and 13 women), ranging in age from 38 to 75 years, with surgical and/or radiculographic evidence of chronic adhesive spinal arachnoiditis (CASA) were admitted to a randomly allocated, double-blind, 6-month crossover trial of d-penicillamine (500 mg/day) versus matching placebo. Assessments using subjective and objective criteria at 3-month intervals demonstrated no statistically significant effect with either d-penicillamine or placebo or between them. Thirteen of the 17 patients completing the trial expressed no clear preference. One patient preferred placebo. The remaining three patients who expressed strong preference for d-penicillamine (supported by objective data) subsequently maintained improvement on long-term therapy for up to 5 years. It is concluded that there may be a small subgroup of patients with CASA who might benefit from d-penicillamine therapy.

Outcome assessment after epidural corticosteroid injection for low back pain and sciatica.

Epidural corticosteroid injection is a relatively effective treatment for low back pain and sciatica with a low incidence of side effects, although the patient's perspective in terms of outcome and satisfaction has not been studied well. The assessment of outcome in low back pain patients is complex. Three types of measure were compared: 1) a clinical score, 2) patient ratings of pain and disability, and 3) patient satisfaction ratings. There were significant discrepancies among the results. Consequently, clinical trials using different outcome measures may reach different conclusions. It therefore is vital to have planned the study carefully in advance, considering the questions to be asked, especially in this area, where patient-derived measures (e.g., "patient satisfaction") are so important. This study of 35 patients showed a fall in clinical signs/symptoms, disability, and pain 1 week after the injection, with maintenance of the reduction in disability at 3 months. Eighty-five percent reported at least some improvement at 1 week and 43% had improvement lasting 3 months. Patients with a more depressed mood had higher levels of disability both before and after the procedure. Anxiety before the procedure did not adversely affect outcome, and it was well tolerated by most patients. At 3 months 83% were satisfied with the treatment they had received and a patient satisfaction questionnaire gave similar results. We continue to recommend this treatment as a well-tolerated procedure, with which most patients are satisfied.

Pain, distress and joint hyperlaxity.

Pain dominates the lives of many patients with hyperlaxity syndromes, most commonly the Benign Joint Hypermobility Syndrome (BJHS/EDS). As a result they may experience psychosocial problems, which in many cases severely affects their healthy functioning. Above all is the overriding chronic pain in joints, muscles and ligaments, which arises from an inherent predisposition to the effects of everyday trauma, but other factors such as associated osteoarthritis or fibromyalgia are also important. There may also be neurophysiological factors at play producing nociceptive enhancement. Pain and distress of visceral origin can result from laxity of connective tissue within or providing support for the abdominal, thoracic or pelvic viscera leading to hernia, uterine and/or rectal prolapse, mitral valve prolapse or spontaneous pneumothorax. In children joint hyperlaxity is an important (and often unrecognised) source of rheumatic symptoms, which may be ignored or erroneously ascribed to juvenile idiopathic arthritis. The management of pain and distress in the hyperlaxity syndromes requires skill, patience, compassion and understanding. Often the results of conventional anti-rheumatic therapy (including anti-rheumatic drugs and surgery) as applied to other rheumatic diseases are disappointing and innovative approaches are required. Amongst these, for which evidence of efficacy is available, are physiotherapeutic and orthotic stabilisation of hyperlax joints, proprioceptive enhancement and the newer pain management techniques including cognitive behavioural therapy.

Thiopurinol: dose-related effect on urinary oxypurine excretion.

1. The important fact which emerges from these studies both without and with dietary purine supplementation is that thiopurinol dose possess apparent in vivo xanthine oxidase inhibitory activity but the dose must be increased well above therapeutic levels for this effect to manifest. 2. The considerable reduction in total endogenous urinary purine excretion at these high doses substantiates an additional inhibitory effect of thiopurinol on de novo purine synthesis. 3. Thiopurinol, like its analogue allopurinol, is also capable of reducing the absorption of dietary purine administered in the form of guanine in the pig.

How should we treat tophaceous gout in patients with allopurinol hypersensitivity?

We studied purine metabolism in gouty patients from three categories: primary gout, familial juvenile hyperuricaemic nephropathy (FJHN) and partial HPRT deficiency.