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排序方式: 共有7703条查询结果,搜索用时 15 毫秒
1.
Jae Eun Choi Tyler Werbel Zhenping Wang Chia Chi Wu Tony L. Yaksh Anna Di Nardo 《Journal of dermatological science》2019,93(1):58-64
Background
Rosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown.Objectives
To investigate the molecular mechanism by which botulinum toxin improves rosacea lesions.Methods
Primary human and murine mast cells were pretreated with onabotulinum toxin A or B or control. Mast cell degranulation was evaluated by β-hexosaminidase activity. Expression of botulinum toxin receptor Sv2 was measured by qPCR. The presence of SNAP-25 and VAMP2 was established by immunofluorescence. In vivo rosacea model was established by intradermally injecting LL-37 with or without onabotulinum toxin A pretreatment. Mast cell degranulation was assessed in vivo by histologic counts. Rosacea biomarkers were analyzed by qPCR of mouse skin sections.Results
Onabotulinum toxin A and B inhibited compound 48/80-induced degranulation of both human and murine mast cells. Expression of Sv2 was established in mouse mast cells. Onabotulinum toxin A and B increased cleaved SNAP-25 and decreased VAMP2 staining in mast cells respectively. In mice, injection of onabotulinum toxin A significantly reduced LL-37-induced skin erythema, mast cell degranulation, and mRNA expression of rosacea biomarkers.Conclusions
These findings suggest that onabotulinum toxin reduces rosacea-associated skin inflammation by directly inhibiting mast cell degranulation. Periodic applications of onabotulinum toxin may be an effective therapy for refractory rosacea and deserves further study. 相似文献2.
Hyperhidrosis can seriously impair patients’ quality of life. Medical history, including heredity and hyperhidrosis during youth, as well as current age and time elapsed since menopause, is important to consider when distinguishing between postmenopausal hyperhidrosis and vasomotor symptoms to enable adequate treatment. This report concerns a subgroup of eight postmenopausal patients participating in a randomized controlled trial regarding botulinum toxin (Btx) type B treatment in craniofacial hyperhidrosis. Even though the sample size is small and the enrolment is not yet completed, the promising data collected hitherto are interesting to present in advance because this subtype of craniofacial hyperhidrosis is often underrecognized and challenging to treat. Patients were randomized to receive Btx type B or placebo. Measurements were performed before treatment and 3 ± 1 weeks after. The Dermatology Life Quality Index (DLQI) score was improved for all patients after Btx type B treatment (n = 3) with a median decrease of 9 points (90% median improvement). The placebo group (n = 5) had a median increase of 2 points (–18% median decline). When the same group (n = 5) received Btx type B (open) the DLQI score decreased with a median of 7 points compared with baseline (91% median improvement). Treatment‐related adverse events were temporary and did not prevent improvement of life quality. Furthermore, background data evaluation uncovered interesting findings regarding vasomotor symptoms in relation to postmenopausal hyperhidrosis. In conclusion, the results indicated that Btx type B seems to be a safe and effective treatment in postmenopausal craniofacial hyperhidrosis. Further research is encouraged. 相似文献
3.
《Drug metabolism and pharmacokinetics》2019,34(1):87-94
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
4.
A. Esquenazi 《European journal of neurology》2006,13(S4):27-34
Spasticity is a widespread, disabling form of muscle overactivity affecting patients with central nervous system damage resulting in upper motor neurone syndrome. There is a range of effective therapies for the treatment of spasticity (e.g. physical, anaesthetic, chemodenervation and neurolytic injections, systemic medication and surgery), but all therapies must be based on an individualized, multidisciplinary programme targeted to achieve patient goals. Appropriate therapy should be based on the extent and severity of spasticity, but spasticity and its consequences, regardless of presentation or cause, are commonly treated with systemic agents. This may be ill-advised as systemic treatment is associated with many undesirable effects. In particular, elderly patients with post-stroke spasticity are at risk from the central adverse effects of systemic medication (e.g. sedation and gait disturbance), which make them more susceptible to falling, with an associated increased risk of fracture. The rising costs of fracture care and its sequelae are fast becoming an international problem contributing to high healthcare expenditure. Botulinum toxin type-A (BoNT-A) treatment is highly effective for some of the more common forms of spasticity and muscle overactivity, and has a favourable profile when compared with systemic agents and other focal treatments. Therefore, the clinical benefits of BoNT-A treatment outweigh the apparent high costs of this intervention, showing it to be a cost-effective treatment. 相似文献
5.
M. Naumann A. Albanese F. Heinen G. Molenaers M. Relja 《European journal of neurology》2006,13(S4):35-40
Botulinum toxin serotype A (BoNT-A) has long heritage of use leading to confidence in its safety and efficacy. The application of BoNT-A does not lead to persistent histological changes in the nerve terminal or the target muscle. Clinical trials defined the safety and tolerability profile of BoNT-A across common therapeutic indications and showed an incidence of adverse events of approximately 25% in the BoNT-A-treated group compared with 15% in the control group. Focal weakness was the only adverse event to occur more often following BoNT-A treatment. Long-term BoNT-A administration has been assessed in various treatment settings, with the level and duration of BoNT-A efficacy response being maintained over repeated rounds of injection with no major safety concerns. The treatment of children with cerebral palsy often require long-term, repeated, multimuscle BoNT-A injections that lead to the administration of comparably higher toxin doses. Despite the high total body doses used, their distribution over multiple muscles and injection sites means that systemic side effects are rare. Recent formulation changes have reduced the incidence of antibody development following treatment with BOTOX® . These findings show long-term BoNT-A treatment to be both safe and efficacious for a wide variety of indications. 相似文献
6.
Despite the widespread use of botulinum toxin to treat muscle dystonias, no method exists to quantify muscle paralysis in either human or nonhuman models. In this study we examined how the location, dose, and volume of botulinum injection affects paralysis in the rat tibialis anterior muscle. Paralysis was quantified by electrically stimulating the nerve to the tibialis anterior and then staining sections of the muscle for glycogen. The areas of glycogen-containing fibers represented regions of botulinum action. The results showed that the most important injection technique is to inject botulinum directly into the motor endplate region of a muscle. Injections only 0.5 cm from the motor endplate resulted in a 50% decrease in paralysis. Increases in dose increased paralysis, however, some of that increase was simply due to the increased volume of injection. Thus, delivering toxin in small volumes near the MEP band of a muscle should produce the most effectiveparalysis. © 1993 John Wiley & Sons, Inc. 相似文献
7.
Birger Ragnarson Göran Örnung Ole P Ottersen Gunnar Grant Brun Ulfhake 《Journal of neuroscience methods》1998,80(2):42-136
Choleragenoid (cholera toxin B-fragment; CTB) is an anterograde, retrograde and transganglionic neuronal tracer. We describe a method for detecting CTB-labeled neuronal cell bodies, neurites and boutons at the ultrastructural level, using postembedding immunogold techniques on freeze-substituted Lowicryl HM20™ embedded nervous tissue. Primary afferents and motoneurons were labeled by injection of CTB in the dorsal ramus of the C2 spinal nerve of the rat. Following fixation with paraformaldehyde (4%) and glutaraldehyde (0.25%), tissue sections from the spinal cord C2 segment were freeze-substituted and embedded in Lowicryl HM20™ and subsequently processed with postembedding immunocytochemistry for CTB and glutamate. Immunogold particles indicating CTB immunoreactivity were found over primary afferents and motoneurons. In primary afferents in the central cervical nucleus (CCN) and motor nuclei, immunogold labeling was seen in boutons over vesicle-containing axoplasm and to a lesser extent over axoplasm devoid of vesicles, but not over mitochondria or axolemma. In motoneurons, immunogold particles were seen over the Golgi apparatus in the soma and over lysosomes in both soma and dendrites. Quantification of glutamate-like immunoreactivity in 20 CTB-labeled and 20 CTB-negative boutons in the neuropil was found similar, indicating that CTB does not interfere with the immunocytochemical detection of neuronal epitopes such as the transmitter substance glutamate. 相似文献
8.
9.
Birgit T Priest Kenneth M Blumenthal Jaime J Smith Vivien A Warren McHardy M Smith 《Toxicon》2007,49(2):194-201
The tarantula venom peptides ProTx-I and ProTx-II inhibit voltage-gated sodium channels by shifting their voltage dependence of activation to a more positive potential, thus acting by a mechanism similar to that of potassium channel gating modifiers such as hanatoxin and VSTX1. ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency and represent the first potent peptidyl inhibitors of TTX-resistant sodium channels. Like gating modifiers of potassium channels, ProTx-I and ProTx-II conform to the inhibitory cystine knot motif, and ProTx-II was demonstrated to bind to sodium channels in the closed state. Both toxins have been synthesized chemically, and ProTx-II, produced by recombinant means, has been used to map the interaction surface of the peptide with the Nav1.5 channel. In comparison, beta-scorpion toxins activate sodium channels by shifting the voltage dependence of activation to more negative potentials, and together these peptides represent valuable tools for exploring the gating mechanism of sodium channels. 相似文献
10.
Graham M Nicholson 《Toxicon》2007,49(4):413-422
Arthropod pests are responsible for major crop devastation and are vectors for the transmission of new and re-emerging diseases in humans and livestock. Despite many years of effective control by conventional agrochemical insecticides, a number of factors are threatening the effectiveness and continued use of these agents. These include the development of insecticide resistance and use-cancellation or de-registration of some insecticides due to human health and environmental concerns. Several approaches are being investigated for the design of new (bio)pesticides. These include the development of transgenic plants and recombinant baculoviruses as delivery systems for a variety of insect-selective toxins. Additional approaches for the development of foliar sprays include the rational design of peptidomimetics based on the key residues of these toxins that interact with the insect target. This special issue provides an overview of these phyletically selective animal, plant and microbial toxins and their diverse mechanisms of action to paralyze or kill arthropods. In addition, it reviews their potential for biopesticide discovery and validation of novel insecticide targets and provides an overview of the strengths and weaknesses of biopesticides in the global control of arthropod pests. 相似文献