Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: a global phase 3, randomised, placebo-controlled superiority study (VANISH 306).

OBJECTIVE: To evaluate the efficacy and safety of ibrexafungerp versus placebo for acute vulvovaginal candidiasis (VVC) treatment. DESIGN: Global phase 3, randomised, placebo-controlled superiority study. SETTING: Study sites in the USA (n = 19) and Bulgaria (n = 18). POPULATION: Female patients aged ≥12 years with acute VVC and a vulvovaginal signs and symptoms (VSS) score ≥4 at baseline. METHODS: Patients were randomly assigned 2:1 to ibrexafungerp (300 mg twice for 1 day) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was the percentage of patients with a clinical cure (VSS = 0) at the test-of-cure visit (day 11 ± 3). Secondary endpoints included percentages of patients with mycological eradication, clinical cure and mycological eradication (overall success), clinical improvement (VSS ≤1) at test-of-cure visit, and complete resolution of symptoms at follow-up visit (day 25 ± 4). RESULTS: At the test-of-cure visit, patients receiving ibrexafungerp had significantly higher rates of clinical cure (63.3% [119/188] versus 44.0% [37/84]; P = 0.007), mycological eradication (58.5% [110/188] versus 29.8% [25/84]; P < 0.001), overall success (46.1% [82/188] versus 28.4% [23/84]; P = 0.022) and clinical improvement (72.3% [136/188] versus 54.8% [46/84]; P = 0.01) versus those receiving placebo. Symptom resolution was sustained and further increased with ibrexafungerp (73.9%) versus placebo (52.4%) at follow-up (P = 0.001). Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mild to moderate in severity. CONCLUSIONS: Ibrexafungerp demonstrated statistical superiority over placebo for the primary and secondary endpoints. Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute VVC. TWEETABLE ABSTRACT: Ibrexafungerp is statistically superior to placebo for the treatment of vulvovaginal candidiasis.

Pregabalin prescriptions in the United Kingdom: a drug utilisation study of The Health Improvement Network (THIN) primary care database.

AIM: In Europe, pregabalin is approved for treatment of neuropathic pain, general anxiety disorder (GAD) and as adjunctive therapy for epilepsy. The purpose of this study was to assess utilisation of pregabalin in the UK, including patients with a recorded history of substance abuse, from a large general practice database. METHODS: This observational drug utilisation study (DUS) analysed pregabalin prescription data from the UK Health Improvement Network primary care database between September 2004 and July 2009. Patient demographics, diagnoses (by READ codes) and pregabalin dosing data were collected. Diagnosis codes were used as proxy for approved indication for pregabalin. RESULT: A cohort of 18,951 patients was prescribed pregabalin; dosing information was available for 13,480 (71.1%). Median age of patients was 58 years, and majority were female (60.1%). Median (interquartile range) prescribed average daily dose (ADD) of pregabalin for all patients was 150.0 (162.5) mg/day; this was highest in patients with epilepsy (191.9 mg/day), followed by neuropathic pain (158.0 mg/day) and GAD (150.0 mg/day). Only 1.0% (136/13,480) of patients were prescribed an ADD of pregabalin over the maximum approved dose of 600 mg/day. Of these, 18.4% (25/136) of patients had a history of substance abuse compared with 14.0% (1884/13,480) in the full population. CONCLUSION: Data from this DUS indicated that the majority of pregabalin prescribing in the UK was consistent with product labelling. The proportion of patients with prescribed ADD > 600 mg/day was small and with a similar proportion with a history of substance abuse as in the full population.

Acamprosate modulates experimental autoimmune encephalomyelitis.

OBJECTIVE: This pilot study aimed to determine the efficacy of acamprosate (N-acetyl homotaurine) in reducing the pathological features of experimental autoimmune encephalomyelitis (EAE) which is an animal model for multiple sclerosis (MS). BACKGROUND: The amino acid taurine has multiple biological activities including immunomodulation and neuromodulation. The synthetic acetylated taurine derivative, acamprosate, which crosses the blood-brain barrier more readily compared to taurine, is currently being used for the prevention of alcohol withdrawal symptoms associated with enhanced glutamatergic receptor function and GABA receptor hypofunction. METHODS: EAE was induced in C57BL/6 female mice with myelin oligodendrocyte glyocoprotein, amino acid 35-55. Mice were treated with 20, 100 and 500 mg/kg acamprosate for 21 days. RESULTS: Neurological scores at disease peak were reduced by 21, 64 and 9% in the 20, 100 and 500 mg/kg groups, respectively. Neurological improvement in the 100 mg/kg group correlated with a reduction in numbers of inflammatory lesions and the extent of CNS demyelination. Blood TNF-α levels were significantly reduced in the 500 mg/kg group. DISCUSSION: Acamprosate and other taurine analogs have a potential for future MS therapy.

Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis.

The importance of B7 costimulation in regulating T cell expansion and peripheral tolerance suggests that it may also play a significant regulatory role in the development of autoimmune disease. It is unclear whether B7 costimulation is involved only in the expansion of autoreactive T cells in the periphery, or if it is also required for effector activation of autoreactive T cells in the target organ for mediating tissue injury and propagating autoimmune disease. In this study, the role of B7-CD28 costimulation and the relative importance of B7 costimulators for the induction and effector phases of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide were examined. Wild-type, B7-1/B7-2-deficient mice, or CD28-deficient C57BL/6 mice were immunized with MOG 35-55 peptide. Mice lacking both B7-1 and B7-2 or CD28 showed no or minimal clinical signs of EAE and markedly reduced inflammatory infiltrates in the brain and spinal cord. However, mice lacking either B7-1 or B7-2 alone developed clinical and pathologic EAE that was comparable to EAE in wild-type mice, indicating overlapping functions for B7-1 and B7-2. Resistance to EAE was not due to a lack of induction of T helper type 1 (Th1) cytokines, since T cells from B7-1/B7-2(-/-) mice show reduced proliferative responses, but greater interferon gamma production compared with T cells from wild-type mice. To study the role of B7 molecules in the effector phase of the disease, MOG 35-55-specific T lines were adoptively transferred into the B7-1/B7-2(-/-) and wild-type mice. Clinical and histologic EAE were markedly reduced in B7-1/B7-2(-/-) compared with wild-type recipient mice. These results demonstrate that B7 costimulation has critical roles not only in the initial activation and expansion of MOG-reactive T cells, but also in the effector phase of encephalitogenic T cell activation within the central nervous system.

T cell receptor (TCR) usage determines disease susceptibility in experimental autoimmune encephalomyelitis: studies with TCR V beta 8.2 transgenic mice.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced in laboratory animals by immunization with the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the role of the T cell receptor (TCR) repertoire in susceptibility to EAE induced by these two autoantigens. Autoreactive T cells induced after immunization with MBP use a limited set of TCR. In contrast, we demonstrate that T cell clones that recognize the encephalitogenic PLP epitope (PLP 139-151) use diverse TCR genes. When the TCR repertoire is limited by introduction of a novel rearranged TCR V beta 8.2 chain in transgenic SJL mice, EAE could be induced in the transgenic mice by immunization with the encephalitogenic epitopes of PLP, but not with the encephalitogenic epitope of MBP. Thus, skewing the TCR repertoire affects the susceptibility to EAE by immunization with MBP but not with PLP. These data demonstrate the biological consequences of the usage of a more diverse T cell repertoire in the development of an autoimmune disease.

The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease.

Multiple sclerosis is a demyelinating disease, characterized by inflammation in the brain and spinal cord, possibly due to autoimmunity. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated an abundance of transcripts for osteopontin (OPN). Microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of MS, also revealed increased OPN transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in OPN-/- mice produced more interleukin 10 and less interferon-gamma than in OPN+/+ mice. Osteopontin thus appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and it may offer a potential target in blocking development of progressive MS.

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

INTRODUCTION: Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription and unnecessary drug exposure and for which there are few therapeutic alternatives. Regrettably, although the azole class of drugs has expanded, new classes of antifungal drugs have not been forthcoming, limiting effective treatment options in patients with azole resistant Candida vaginitis. AREAS COVERED: This review covers published data on epidemiology, pathophysiology and treatment options for women with azole-resistant refractory VVC. EXPERT OPINION: Fluconazole resistant C.albicans adds to the challenge of azole resistant non-albicans Candida spp. Both issues follow years of indiscriminate drug prescription and unnecessary fluconazole exposure. Although an understanding of azole resistance in yeast has been established, this knowledge has not translated into useful therapeutic advantage. Treatment options for such women with refractory symptoms are extremely limited. New therapeutic options and strategies are urgently needed to meet this challenge of azole drug resistance.

The peripheral metabolism of triiodothyronine in normal subjects and in patients with hyperthyroidism.

In order to assess the contribution of 3.3',5-triiodo-L-thyronine (T(3)) to overall thyroid hormone economy, conjoint measurements of the kinetics of peripheral T(3) metabolism and the total concentration of T(3) in serum were made in a group of normal subjects and in a group of patients with hyperthyroid Graves' disease. As judged from the disappearance of trichloroacetic acid-precipitable (131)I from serum after a single intravenous dose of labeled T(3), the following mean values were obtained in the normal subjects: volume of distribution, 43 liters or 0.62 liter/kg; fractional turnover rate. 52% per 24 hr: clearance rate, 22.3 liters/24 hr: and absolute disposal rate, 60 mug/24 hr. In the patients with untreated hyperthyroidism, values for all these functions were greatly increased. After treatment, the volume of T(3) distribution returned to normal but the fractional turnover rate remained abnormally rapid.

Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern.

Heterochromatin in metazoans induces transcriptional silencing, as exemplified by position effect variegation in Drosophila melanogaster and X-chromosome inactivation in mammals. Heterochromatic DNA is packaged in nucleosomes that are distinct in their acetylation pattern from those present in euchromatin, although the role these differences play in the structure of heterochromatin or in the effects of heterochromatin on transcriptional activity is unclear. Here we report that, as observed in the facultative heterochromatin of the inactive X chromosome in female mammalian cells, histones H3 and H4 in chromatin spanning the transcriptionally silenced mating-type cassettes of the yeast Saccharomyces cerevisiae are hypoacetylated relative to histones H3 and H4 of transcriptionally active regions of the genome. By immunoprecipitation of chromatin fragments with antibodies specific for H4 acetylated at particular lysine residues, we found that only three of the four lysine residues in the amino-terminal domain of histone H4 spanning the silent cassettes are hypoacetylated. Lysine 12 shows significant acetylation levels. This is identical to the pattern of histone H4 acetylation observed in centric heterochromatin of D. melanogaster. These two observations provide additional evidence that the silent cassettes are encompassed in the yeast equivalent of metazoan heterochromatin. Further, mutational analysis of the amino-terminal domain of histone H4 in S. cerevisiae demonstrated that this observed pattern of histone H4 acetylation is required for transcriptional silencing. This result, in conjunction with prior mutational analyses of yeast histones H3 and H4, indicates that the particular pattern of nucleosome acetylation found in heterochromatin is required for its effects on transcription and is not simply a side effect of heterochromatin formation.

Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation.

For many years it has been noted that there is a correlation between acetylation of histones and an increase in transcriptional activity. One prediction, based on this correlation, is that hypomorphic or null mutations in histone deacetylase genes should lead to increased levels of histone acetylation and result in increased levels of transcription. It was therefore surprising when it was reported, in both yeast and fruit flies, that mutations that reduced or eliminated a histone deacetylase resulted in transcriptional silencing of genes subject to telomeric and heterochromatic position effect variegation (PEV). Here we report the first mutational analysis of a histone deacetylase in a multicellular eukaryote by examining six new mutations in HDAC1 of Drosophila melanogaster. We observed a suite of phenotypes accompanying the mutations consistent with the notion that HDAC1 acts as a global transcriptional regulator. However, in contrast to recent findings, here we report that specific missense mutations in the structural gene of HDAC1 suppress the silencing of genes subject to PEV. We propose that the missense mutations reported here are acting as antimorphic mutations that "poison" the deacetylase complex and propose a model that accounts for the various phenotypes associated with lesions in the deacetylase locus.

Thyroid ophthalmopathy.

Thyroid associated ophthalmopathy (TAO) is an inflammatory orbital disease of autoimmune origin with the potential to cause severe functional and psychosocial effects. It presents one of the most difficult challenges in the clinical practice of ophthalmology. Pathogenesis of the disease is not yet fully understood. It is usually associated with thyroid dysfunction. TAO has a variable clinical presentation; it may cause severe damage to vision and orbital architecture. TAO is the most frequent cause of unilateral or bilateral proptosis in adults. Potential sight-threatening complications include optic neuropathy and severe corneal exposure keratopathy. Most patients do not require specific therapy. Those with moderately severe or severe disease are treated with steroids and/or orbital radiation during the inflammatory phase and surgical therapy during the inactive phase. Decompression may be needed in either phase. Although appropriate treatment can restore near normal function and appearance in most cases, the management of TAO is difficult, controversial, and far from optimal. Disease severity is the key determinant of the indication for therapy, while therapeutic choice depends on inflammatory activity. Clinical management is difficult because no immediate or dramatic cure exists. With appropriate medical and surgical treatment, patients can be restored to normal function and appearance in most cases, but the process to reach this goal will usually be lengthy.

Leiomyoblastoma associated with intractable hypercalcemia and elevated 1,25-dihydroxycholecalciferol levels. Treatment by hepatic enzyme induction.

A 42-year-old woman, with a previously resected jejunal leiomyoblastoma, was first seen with liver metastases 31/2 years after the tumor resection. Intractable malignant hypercalcemia appeared eight months later, together with renal insufficiency. No osteolytic lesions were detected. Levels of parathyroid hormone, cyclic adenosine monophosphate, and 1,25-dihydroxycholecalciferol (1,25[OH]2D) were not useful in distinguishing between the hypercalcemia of malignancy and concurrent hyperparathyroidism. Despite renal insufficiency, hypercalcemia, and subtotal parathyroidectomy, the 1,25(OH)2D levels remained elevated, consistent with the speculation that a tumor product stimulated 1-alpha-hydroxylation of 25-hydroxycholecalciferol. Phenytoin and phenobarbital (enzyme induction therapy), in combination with phosphorus and glucocorticoids, appeared to be useful in controlling the hypercalcemia.

Transitory hypocalcemia complicating measles.

During an epidemic of measles, 12 young adults developed hypocalcemia associated with a decrease in parathyroid hormone level. Calcium and parathyroid hormone levels returned to normal in five of the 12 patients for whom convalescent data were available.

Chronic renal insufficiency from cortical necrosis induced by arsenic poisoning.

A 39-year-old man had anuria and azotemia and was found to be suffering from acute arsenic poisoning. After two peritoneal dialyses, partial renal function returned, and the patient has survived for five years without dialysis. Renal cortical necrosis was demonstrated by renal biopsy and renal calcification. We suggest that arsenic be added to the list of substances capable of causing renal cortical necrosis and recommend consideration of this complication in cases of arsenical poisoning.

The extracellular matrix in multiple sclerosis lesions.

Receptor-mediated recognition of extracellular matrix (ECM) molecules transduces intracellular signals that determine many cellular behaviors under normal and pathological conditions. This review briefly describes the major central nervous system (CNS) white matter ECM molecules and their receptors, the mechanisms by which the ECM may be altered in multiple sclerosis (MS) lesions, and potential roles for inflammatory and CNS resident cell interactions with specific ECM molecules in these lesions. In acute lesions, ECM recognition and cell signaling contribute to leukocyte migration through blood vessel walls, and within the CNS, through leukocyte and CNS resident cell immune activation and demyelination. An abnormal ECM in chronic MS lesions may preclude ECM-dependent developmental processes that lead to remyelination and axon regeneration. Thus, the composition of the ECM and the cellular recognition of its individual components may be critical to the pathogenesis of all stages of MS. An understanding of these complex interactions may lead to additional strategies for intervention and the promotion of reparative processes in MS patients.

Vestibular (acoustic) schwannomas: histologic features in neurofibromatosis 2 and in unilateral cases.

Unilateral vestibular schwannomas (VS) differ from those in patients with neurofibromatosis 2 (NF-2) clinically and by in situ appearance. To determine whether there are histopathologic differences, the presence of each of 16 histologic features was compared in first surgical resection specimens of 48 VS from 39 NF-2 patients and 293 unilateral VS. Antoni A and B areas, nuclear atypia, whorls, scarring, chronic inflammation, and sheets of macrophages were found equally in both groups. Vestibular schwannomas in NF-2 had more Verocay bodies, foci of high cellularity, and lobular growth patterns, the latter possibly correlating with in situ appearance. Ten NF-2 VS specimens had either meningiomas or microscopic meningeal cell proliferations removed with the VS from the same area, whereas none of the patients with a unilateral VS had these findings. Unilateral VS had more hyalinized and malformed vessels, recent and old thromboses and hemosiderin deposits. The differences could not be attributed to patient ages because there were similar differences between the VS in NF-2 and the unilateral VS of 40 patients age-matched to the NF-2 patients. There were more female patients in both groups, but gender did not influence the occurrence of any histologic features. There were nine additional patients with apparently unilateral VS but in whom the diagnosis of NF-2 was suggested by additional findings; six of the VS from these patients had lobular patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Major histocompatibility complex molecule expression in the human central nervous system: immunohistochemical analysis of 40 patients.

To determine factors affecting major histocompatibility complex (MHC) molecule expression in situ in the human central nervous system (CNS) cryostat tissue sections from 36 autopsies and four biopsies were stained by immunoperoxidase with antibodies to class I (HLA-alpha chain, beta-2 microglobulin), class II (HLA-DR, HLA-DQ) MHC, lymphocyte, and macrophage antigens and Factor VIII-related antigen (VIII-RA). Stained cells and vessels/mm2 were counted in gray and white matter of four CNS anatomic levels. Class I molecules were found on parenchymal and endothelial cells (approximately 50% of VIII-RA + vessels) but not neurons, and were more abundant in gray than white matter (p less than 0.02). Class I molecules were absent in infants, but in adults expression was unaffected by age, sex, postmortem interval, presence of CNS lesions, or systemic illnesses. Expression of HLA-alpha chain and beta-2 microglobulin were the same. Class II molecules were usually absent but were found on parenchymal and endothelial cells in older adults, most frequently in association with macrophage infiltrates and spinal cord tract degenerations, but not with systemic illnesses. Expression of HLA-DR was greater than that of HLA-DQ. In the human CNS, regulation regulation of expression of MHC molecules is complex, can be affected by age, regional anatomy, and by local or remote CNS lesions, and may influence patterns and degrees of T cell immune responses.

White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis.

Extracellular matrix (ECM) alterations in the central nervous system (CNS) of multiple sclerosis (MS) patients result from blood-brain barrier breakdown, release and activation of proteases, and synthesis of ECM components. To elucidate their potential pathophysiologic roles, we analyzed expression of major CNS ECM proteoglycans (PGs) in MS and control CNS tissues. In active MS plaque edges, 3 CNS lecticans (versican, aggrecan, and neurocan) and dermatan sulfate PG were increased in association with astrocytosis; in active plaque centers they were decreased in the ECM and accumulated in foamy macrophages, suggesting that these ECM PGs are injured and phagocytosed along with myelin. In inactive lesions they were diminished and in normal-appearing white matter they showed heretofore-unappreciated abnormal heterogeneous aggregation. Phosphacan, an ECM PG abundant in both gray and white matter, was less markedly altered. Since in development the spaciotemporal expression of ECM PGs influences neurite outgrowth, cell migration, axon guidance, and myelination, these data suggest that 1) enhanced white matter lectican and dermatan sulfate PG expression in the pro-inflammatory milieu of expanding lesion edges contributes to their sharp boundaries and the failure of neuronal ingrowth; 2) decreases in plaque centers may preclude regeneration and repair; and 3) diffuse ECM PG damage relates to axon degeneration outside of overt lesions. Thus, ECM PG alterations are specific, temporally dynamic, and widespread in MS patients and may play critical roles in lesion pathogenesis and CNS dysfunction.