Interventions for hyperhidrosis in secondary care : a systematic review and value-of-information analysis

Background: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. Objective: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. Methods: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost-effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. Results and conclusions: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost-effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of £9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost-effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. Limitations: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. Future work: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses

Potential Cancer- and Alzheimer’s Disease-Targeting Phosphodiesterase Inhibitors from Uvaria alba: Insights from In Vitro and Consensus Virtual Screening

Inhibition of the major cyclic adenosine monophosphate- metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50- ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (16), and of an AChE and KEAP-1 BTB domain for 3- (3,4-dihydroxybenzyl)-3',4',6-trihydroxy-2,4-dimethoxychalcone (8) and grandifloracin (15), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin (15) with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties

Antitubercular and Cytotoxic Chlorinated seco-Cyclohexenes from Uvaria alba

Two new chlorine-containing polyoxygenated seco-cyclohexenes, albanols A (1) and B (2), along with the oxepinone metabolite grandiuvarone (3) were isolated from the endemic Philippine Annonaceae plant Uvaria alba. Both new compounds exhibited modest antitubercular activity. Compound 1 showed cytostatic activity (ranging from 1-50 mu M) against HeLa cells and weak antiproliferative activity against HUVEC and K-562 cells with GI50 values of 106 and 81 mu M, respectively

Antiproliferative, cholinesterase and phosphodiesterase inhibitory activity of the DCM sub-extract of Uvaria alba: In vitro and in silico perspectives

Aims: To evaluate the in vitro antiproliferative, anticholinesterase and anti-phosphodiesterase activities of the sub-extracts of Uvaria alba (family Annonaceae) and explore putative binding mechanisms of its chemical constituents in silico. Main methods: U. alba sub-extracts, obtained by solvent-solvent partition, were subjected to antiproliferative and cytotoxicity screening against chronic myelogenous leukemia (K-562) and human cervical cancer (HeLa) cells, respectively. Inhibitory assays against acetylcholinesterase (AChE) and phosphodiesterase (PDE4 B2) enzymes were also performed. The dichloromethane sub-extract (UaD) was chemically profiled using LC-HR-ESIMS-QToF to identify secondary metabolites 1–18. Molecular docking and molecular dynamics simulations were performed to determine the affinity of the putatively annotated metabolites against PDE4 B2B, AChE, ubiquitin specific peptidase 14 (USP14), and Kelch-like ECH-associated protein 1 (Keap1). In addition, DFT calculations were also performed to demonstrate Michael addition reaction between electrophilic cytotoxic metabolites and Cys151 of the Keap1-BTB domain. Key findings: UaD showed antiproliferative and cytostatic activities against K-562 and HeLa, respectively, and inhibitory activities against AChE and PDE4 B2. Meanwhile, its polyphenolic constituents 3-(3,4-dihydroxybenzyl)-3’,4’,6-trihydroxy-2,4-dimethoxychalcone (8) and grandifloracin (15) showed favorable binding to AChE and Keap1-BTB domain, respectively. The most electrophilic and kinetically stable grandifloracin (15), favorably formed a beta-addition adduct with the Cys151 of Keap1 via Michael addition. The top-ranked ligand-protein complexes attained dynamic stability at 50-ns simulations with high free energy of binding. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties. Significance: The study highlights the role of U. alba secondary metabolites as potential inhibitors against the aforementioned target proteins in an effort to discover new drug leads for cancer and Alzheimer’s.</div