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Background: This is an updated version of the Cochrane Review published in 2015. Epilepsy is a chronic neurological disorder, characterised by recurring, unprovoked seizures. Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with drug-resistant epilepsy. VNS consists of chronic, intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator., Objectives: To evaluate the efficacy and tolerability of VNS when used as add-on treatment for people with drug-resistant focal epilepsy., Search Methods: For this update, we searched the Cochrane Register of Studies (CRS), and MEDLINE Ovid on 3 March 2022. We imposed no language restrictions. CRS Web includes randomised or quasi-randomised controlled trials from the Specialised Registers of Cochrane Review Groups, including Epilepsy, CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform., Selection Criteria: We considered parallel or cross-over, randomised, double-blind, controlled trials of VNS as add-on treatment, which compared high- and low-level stimulation (including three different stimulation paradigms: rapid, mild, and slow duty-cycle), and VNS stimulation versus no stimulation, or a different intervention. We considered adults or children with drug-resistant focal seizures who were either not eligible for surgery, or who had failed surgery., Data Collection and Analysis: We followed standard Cochrane methods, assessing the following outcomes: 1. 50% or greater reduction in seizure frequency 2. Treatment withdrawal (any reason) 3. Adverse effects 4. Quality of life (QoL) 5. Cognition 6. Mood, Main Results: We did not identify any new studies for this update, therefore, the conclusions are unchanged. We included the five randomised controlled trials (RCT) from the last update, with a total of 439 participants. The baseline phase ranged from 4 to 12 weeks, and double-blind treatment phases from 12 to 20 weeks. We rated two studies at an overall low risk of bias, and three at an overall unclear risk of bias, due to lack of reported information about study design. Effective blinding of studies of VNS is difficult, due to the frequency of stimulation-related side effects, such as voice alteration. The risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.73 (95% confidence interval (CI) 1.13 to 2.64; 4 RCTs, 373 participants; moderate-certainty evidence), showing that high frequency VNS was over one and a half times more effective than low frequency VNS. The RR for treatment withdrawal was 2.56 (95% CI 0.51 to 12.71; 4 RCTs, 375 participants; low-certainty evidence). Results for the top five reported adverse events were: hoarseness RR 2.17 (99% CI 1.49 to 3.17; 3 RCTs, 330 participants; moderate-certainty evidence); cough RR 1.09 (99% CI 0.74 to 1.62; 3 RCTs, 334 participants; moderate-certainty evidence); dyspnoea RR 2.45 (99% CI 1.07 to 5.60; 3 RCTs, 312 participants; low-certainty evidence); pain RR 1.01 (99% CI 0.60 to 1.68; 2 RCTs; 312 participants; moderate-certainty evidence); paraesthesia 0.78 (99% CI 0.39 to 1.53; 2 RCTs, 312 participants; moderate-certainty evidence). Results from two studies (312 participants) showed that a small number of favourable QOL effects were associated with VNS stimulation, but results were inconclusive between high- and low-level stimulation groups. One study (198 participants) found inconclusive results between high- and low-level stimulation for cognition on all measures used. One study (114 participants) found the majority of participants showed an improvement in mood on the Montgomery-Åsberg Depression Rating Scale compared to baseline, but results between high- and low-level stimulation were inconclusive. We found no important heterogeneity between studies for any of the outcomes., Authors' Conclusions: VNS for focal seizures appears to be an effective and well-tolerated treatment. Results of the overall efficacy analysis show that high-level stimulation reduced the frequency of seizures better than low-level stimulation. There were very few withdrawals, which suggests that VNS is well tolerated. Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnoea, pain, paraesthesia, nausea, and headache, with hoarseness and dyspnoea more likely to occur with high-level stimulation than low-level stimulation. However, the evidence for these outcomes is limited, and of moderate to low certainty. Further high-quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug-resistant focal seizures., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT)., Material and Methods: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17)., Results: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy., Conclusions: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas., Methods: In 28 healthy volunteers, capsaicin (100 μg/0.1 mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10 mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10 cm). Contralateral injection of 0.1 mL isotonic saline served as a control., Results: Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p < 0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0 ± 2.6 cm 10 min in normal skin to 10.3 ± 1.8 cm 10 min in allodynic skin (p < 0.01) for cowhage and -56% from 20.0 ± 3.5 cm 10 min in normal skin to 8.8 ± 2.3 cm 10 min allodynic skin (p < 0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli., Conclusions: Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain., Significance: This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients., (© 2017 European Pain Federation - EFIC®.)

Background: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions., Objectives: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search., Selection Criteria: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI., Data Collection and Analysis: We used standard methodological procedures as expected by Cochrane., Main Results: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I 2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I 2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I 2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality., Authors' Conclusions: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy., (© 2015, The American College of Clinical Pharmacology.)

Background: The objective of the current prospective, multicenter, international study was to trace the incidence and severity of acute oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical pattern. The authors also specifically tested whether patients who had more symptoms of acute OXLIPN eventually would develop a more severe chronic, cumulative form of OXLIPN., Methods: One hundred seventy patients (mean ± standard deviation age, 63.7 ± 8.7 years) who were scheduled to receive either combined leucovorin, 5-fluoruracil, and oxaliplatin (FOLFOX) or combined capecitabine and oxaliplatin (XELOX) for metastatic colorectal cancer were monitored prospectively at baseline and were followed in 4 European sites. The incidence of hyperexcitability symptoms secondary to acute OXLIPN was assessed by using a descriptive questionnaire (yes/no question) at each clinical evaluation. Motor and neurosensory criteria according to version 3 of the National Cancer Institute's Common Toxicity Criteria were applied to clinically grade the severity of OXLIPN., Results: Acute OXLIPN was present in 146 of 170 patients (85.9%). The vast majority of these patients manifested cold-induced perioral (95.2%) or pharyngolaryngeal (91.8%) dysesthesias. Severe acute OXLIPN that required prolongation of oxaliplatin infusion from 2 hours to 4 to 6 hours occurred in 32 of 146 patients (21.9%). The increased number of acute OXLIPN symptoms was correlated significantly (Spearman rho correlation coefficient [r]) with both the development (r = 0.602; P < .001) and the degree of the chronic, cumulative form (r = 0.702; P < .001)., Conclusions: The current results indicated that the vast majority of patients with colorectal cancer who receive oxaliplatin-based chemotherapy will manifest symptoms of a transient acute syndrome soon after oxaliplatin administration. Patients who have a more complex combination of acute phenomena related to axonal hyperexcitability are those who eventually develop more severe OXLIPN. Therefore, it may be advisable to test agents against acute OXLIPN to verify their effects on the chronic form., (Copyright © 2012 American Cancer Society.)

Background: Zonisamide, a sulfonamide analog, is an antiepileptic drug with mechanisms of action similar to topiramate. Because of its pharmacodynamic and pharmacokinetics profiles, zonisamide is also potentially suitable for migraine prevention., Methods: Tolerability and effectiveness of zonisamide for migraine prophylaxis in patients with a good response to topiramate, but interrupting it for intolerable side effects, were evaluated in 34 patients. After a 1-month period of wash-out, patients were treated with zonisamide (up to a 100 mg/day dosage) for 6 consecutive months., Results: Zonisamide was well tolerated, only 4 (12%) patients reported transient and tolerable side effects. Mean number of days with headache per month was reduced from 14.9 ± 5.3 during the wash-out period to 2.5 ± 0.6 after 6 months of zonisamide (P < .001). We observed a significant reduction in headache severity and disability, as assessed by visual analog scale and migraine disability assessment scale. Finally, when compared with the 1-month period prior to starting zonisamide, a reduced use of analgesics was recorded at the end of the follow-up., Conclusion: Our findings support the use of zonisamide as an alternative therapy for migraine prevention in patients with good response, but poor tolerance to topiramate., (© 2011 American Headache Society.)

Objectives: A minority of HIV-infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d-drugs) such as stavudine (d4T) and didanosine (DDI) experiences dose-limiting neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d-drugs are among the few affordable options available in developing countries, continuing d-drug therapy would be a desirable strategy for many HIV-infected individuals. Therefore, we evaluated the safety of continuing d-drug therapy., Methods: In a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIV-infected individuals on stable ARV regimens that did (n=252) or did not (n=250) include d-drugs. Rates of worsening were compared using proportional hazards model and the log-rank test., Results: The risk ratios (RR) were not significantly larger for worsening neuropathy signs [0.94; 95% confidence interval (CI) 0.84-1.07] or symptoms (0.99; 95% CI 0.88-1.14) in patients taking d-drugs continuously compared to those not taking d-drugs., Conclusions: Continued d-drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non-d-drug-containing regimens. If applicable in developing countries, these findings suggest that in most patients d-drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.

The efficacy, safety and tolerability of topiramate has been demonstrated in three large multicenter, randomized, double-blind, placebo-controlled trials. To characterize the time course of adverse events (AEs) that led to treatment discontinuation in >/=2% of patients who received topiramate 100 mg/day during three pivotal, multicenter, randomized, double-blind, placebo-controlled, and 26-week trials. The pooled population comprised all randomized patients who reported safety data during the double-blind phase (topiramate 100 mg/day, n = 386; placebo n = 372), which consisted of a 4-week titration period and a 22-week maintenance period. Incidence, time to onset, and cumulative mean rate of AEs were assessed. Overall, AEs led to treatment discontinuation in 24.9% of patients receiving topiramate 100 mg/day and 11.0% receiving placebo (P < 0.001). AEs leading to discontinuation during the double-blind phase in > or =2% of patients included paresthesia (8.0% discontinued), any cognitive symptoms (7.3% discontinued), fatigue (4.7% discontinued), insomnia (3.4% discontinued), nausea (2.3% discontinued), loss of appetite, anxiety, and dizziness (2.1% discontinued because each AE). Most AEs began during the titration period. Paresthesia, any cognitive symptoms, nausea, and loss of appetite occurred at a higher rate in the topiramate group than in the placebo group (P < 0.01). AEs leading to discontinuation of topiramate are probably to occur during dose titration. If a patient has not experienced one of these AEs within the first 6 weeks of initiating topiramate 100 mg/day, these AEs are unlikely to occur.

We report the case of a patient with acute lymphoblastic leukaemia who, after the initiation of treatment with vincristine (VCR), developed a fulminant motor polyradiculoneuropathy resembling an axonal variant of Guillain-Barré syndrome (GBS). This report shows that differentiating between axonal GBS and VCR-induced acute neurotoxicity may be a challenge for clinicians.

Migraineurs treated with topiramate often experience adverse effects, such as paresthesia, fatigue, memory difficulty, or taste perversion. To investigate correlations between side effects and drug efficacy, we analyzed for these in 133 migraineurs treated with topiramate (100 mg/day). A 4-week baseline screening phase preceded a 4-week titration period and a 20-week maintenance phase. A total of 118 patients were evaluated at 3 months and 89 patients at 6 months. Patients who developed paresthesia (n = 73) showed lower headache days than those who did not (n = 60) (P = 0.026 at 3 months, P = 0.002 at 6 months), and had a higher responder rate (3 months, 57.5% and 6 months, 65.8%) than those who did not develop paresthesia (3 months, 38.3% and 6 months, 41.7%). Moreover, retrospective analysis of patients that dropped out showed no survival bias between paresthesia and headache improvement. Other adverse effects were not found to correlate with drug efficacy. This study suggests that the development of paresthesia predicts a favorable response to topiramate in migraine prophylaxis.

Allergic reactions to acrylates in sculptured nails are common. However, there are few reports of paresthesia as a consequence of acrylic exposure, and such paresthesia does not necessarily accompany the evolution of the dermatitis.

Background: Regimens combining oxaliplatin with fluorouracil and folinic acid are standard therapeutic options for patients with metastatic colorectal carcinoma. Oxaliplatin has a good safety profile, although it is responsible for dose-limiting neurotoxicity typically consisting of two distinct clusters of symptoms. Cold-induced distal paresthesiae occur during or shortly after infusion in most patients and are usually transient and mild. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment., Methods: The authors report four cases of atypical neurotoxicity induced by oxaliplatin in patients treated for metastatic colorectal carcinoma. Two patients were male and two were female, with an age range of 52-59 years., Results: Three patients experienced Lhermitte sign and two experienced urinary retention. In all cases, the cumulative dose of oxaliplatin was higher than 1000 mg (range, 1248-2040 mg). Brain and spinal magnetic resonance imaging was performed in two patients and was normal. Somatosensory evoked potentials were recorded in two patients and suggested cervical dorsal column dysfunction. Symptoms resolved a few weeks after discontinuation of oxaliplatin., Conclusions: Lhermitte sign may be induced via a neurotoxic effect on the ascending axons of these T-shaped neurons. An atonic bladder may be the result of damage to the sensory portion of the sacral reflex arc, either in the dorsal roots, as for example in diabetic neuropathy, or in the posterior columns, as in tabes dorsalis. Alternatively, it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. It is unclear at present whether the micturition difficulties observed in patients in the current series are due to sensory neuropathy or to autonomic neuropathy, event if the former hypothesis seems more likely, as autonomic neuropathy has not been previously observed with oxaliplatin, and its association with cisplatin is exceedingly rare and controversial., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10500)

Objective: To evaluate the tolerability and safety of frovatriptan 2.5 mg in patients with migraine., Background: Frovatriptan is a new, selective serotonin agonist (triptan) developed for the acute treatment of migraine. Dose range-finding studies identified 2.5 mg as the dose that conferred the optimal combination of efficacy and tolerability., Methods: The tolerability and safety of frovatriptan 2.5 mg were assessed during controlled, acute migraine treatment studies, including a study that compared frovatriptan 2.5 mg with sumatriptan 100 mg, as well as a 12-month open-label study during which patients could take up to three doses of frovatriptan 2.5 mg within a 24-hour period. Safety and tolerability were assessed through the collection of adverse events, monitoring of heart rate and blood pressure performance of 12-lead electrocardiogram, hematology screen, and blood chemistry studies., Results: In the short-term studies, 1554 patients took frovatriptan 2.5 mg and 838 took placebo. In the 12-month study, 496 patients treated 13 878 migraine attacks. Frovatriptan was well tolerated in the short- and long-term studies with 1% of patients in the short-term studies and 5% of patients in the long-term study withdrawing due to lack of tolerability. The incidence of adverse events was higher in the frovatriptan-treated patients than in the patients who took placebo (47% versus 34%) and the spectrum of adverse events was similar. When compared to sumatriptan 100 mg, significantly fewer patients taking frovatriptan experienced adverse events (43% versus 36%; P=.03) and the number of adverse events was lower (0.62 versus 0.91), there were also fewer adverse events suggestive of cardiovascular symptoms in the frovatriptan group. Analysis of the entire clinical database (n=2392) demonstrated that frovatriptan was well tolerated by the patients regardless of their age, gender, race, concomitant medication, or the presence of cardiovascular risk factors. No effects of frovatriptan on heart rate, blood pressure, 12-lead electrocardiogram, hematology screen, or blood chemistry were observed. No patient suffered any treatment-related serious adverse event., Conclusions: Short- and long-term use of frovatriptan 2.5 mg was well tolerated by a wide variety of patients. Frovatriptan treatment produced an adverse events profile similar to that of placebo, and in a direct comparison study was better tolerated than sumatriptan 100 mg.

Objective: To evaluate the efficacy of topiramate in the preventative treatment of episodic migraine., Background: Topiramate is a broad-spectrum antiepileptic drug effective for treatment of multiple seizure types in adults and children. Antiepileptic agents have demonstrated efficacy in migraine prevention, and open-label experience from our clinic has suggested that topiramate might be effective for this use. We consequently conducted a single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate for the preventative treatment of migraine., Methods: Forty patients, aged 19 to 62 years (mean, 38.2 years), were randomly assigned in a 1:1 ratio to receive topiramate (n = 19; all women) or placebo (n = 21; 20 women, 1 man). Following a prospective baseline phase of 4 weeks, the study drug dose was titrated weekly in 25-mg increments over 8 weeks to 200 mg per day or to the maximum tolerated dose. The titration phase was followed by an 8-week maintenance phase., Results: During the entire double-blind phase, topiramate-treated patients experienced a significantly lower 28-day migraine frequency (3.31 +/- 1.7 versus 3.83 +/- 2.1; P =.002) compared to placebo, irrespective of use of concomitant migraine prevention medications. The mean 28-day migraine frequency was reduced by 36% in patients receiving topiramate as compared with 14% in patients receiving placebo (P =.004). Twenty-six percent of the patients on topiramate and 9.5% of the patients on placebo achieved a 50% reduction in migraine frequency (P >.05). The mean dose of topiramate was 125 mg per day (range, 25 to 200 mg per day). Topiramate was well tolerated; 2 of 19 topiramate-treated patients discontinued treatment due to adverse events. Adverse effects that occurred more frequently in topiramate-treated patients included paresthesia, weight loss, altered taste, anorexia, and memory impairment., Conclusions: Preventative therapy with topiramate significantly reduced migraine frequency. Larger multicenter clinical studies may further delineate the role of topiramate in migraine prevention.

Skin care products are complex formulations that may cause sensory irritation symptoms, characterized by stinging, burning, and itching. Substances capable of counteracting sensory irritation are of great practical interest. Strontium salts have been demonstrated to inhibit sensory irritation and inflammation when applied topically. In this double-blind study, we evaluated the efficacy of strontium nitrate in reducing chemically-induced skin sensory irritation in 8 subjects. In a random order, 20% strontium nitrate in 70% glycolic acid (pH=0.6) (mixture) was applied to the volar aspect of the forearm and a positive control (70% glycolic acid, pH=0.6) to the contralateral forearm. The irritation sensation was evaluated each min for the first 20 min after topical application using a scale from 0-4. The duration of the irritation sensation in min was also recorded. Strontium nitrate mixed with glycolic acid, in comparison with glycolic acid alone, markedly (p<0.01) shortened the duration of the irritation sensation from 24.4+/-4.1 (mean+/-SEM) min to 8.9+/-3.7 (mean+/-SEM) min, and significantly (p<0.05) reduced the mean magnitude of the irritation sensation at all time points (overall). The study demonstrated that strontium nitrate potently suppresses the sensation of chemically-induced irritation.

Background: The aim of the current trial was to assess the efficacy and toxicity of weekly intravenous vinorelbine tartrate with daily oral tamoxifen in the treatment of patients with advanced or metastatic malignant melanoma., Methods: Thirty-one patients were treated with vinorelbine tartrate, 30 mg/m(2) intravenously, weekly every 13 weeks and then every 2 weeks thereafter until progression of disease or severity of toxicity warranted discontinuation. Tamoxifen, 10 mg orally, twice a day was administered daily starting on Day 1 of chemotherapy with vinorelbine tartrate. Thirty patients had cutaneous melanoma with metastases and 1 patient had ocular melanoma with metastases. Eight patients had received prior chemotherapy., Results: Of the 30 evaluable patients with cutaneous melanoma, 6 achieved a partial response, for an overall response rate of 20% (95% confidence interval, 7-38%). There was no response in the patient with ocular melanoma. Major sites of response include the adrenal gland, lung, tonsil, and cutaneous/subcutaneous tissues. Three patients had a prolonged duration of response lasting > or = 12 months. Side effects generally were mild and tolerable. Grade 3 or 4 hematologic toxicity occurred in 26% and 13% of patients, respectively. Nonhematologic toxicity included mild fatigue, paresthesia, and local arm discomfort from infusion., Conclusions: Weekly intravenous vinorelbine tartrate plus daily oral tamoxifen appears to be active in the treatment of patients with malignant melanoma. Further clinical trials in malignant melanoma patients treated with vinorelbine tartrate and tamoxifen appear warranted., (Copyright 2000 American Cancer Society.)

Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compound for the treatment of migraine headaches with a prolonged duration of response. A double-blind, placebo-controlled, parallel-group, ascending-dose study in 24 healthy subjects was designed to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant-rate IV infusions at three dose levels (12.7, 25.3, and 38.0 mg), which were targeted to produce plasma concentrations in and above the therapeutic range. The best fitting of the plasma concentration-time data was obtained by using a triexponential function yielding a terminal t1/2 of 8 hours. The areas under the plasma concentration versus time curves were proportional to dose, indicating linear pharmacokinetics. Moreover, the clearance and steady-state volume of distribution values were independent of the dose. The change in pulse rate and supine systolic and diastolic blood pressure was determined as pharmacodynamic effects of avitriptan. A "threshold log-linear" model, which accounts for the linear increase in pharmacodynamic effect with the log of plasma concentrations when the latter was higher than a certain threshold value, adequately described the pharmacodynamic data. The threshold plasma drug concentrations for the pulse rate and the diastolic and systolic blood pressure were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent, linear pharmacokinetics and increases systolic and diastolic blood pressure in a predictable manner at a higher plasma concentration. However, this drug does not produce a significant change in pulse rate at the dose levels (12.7-38 mg) evaluated in this study.

Atypical sensations following the use of subcutaneous sumatriptan are common, but of uncertain origin. They are almost always benign, but can be mistaken for a serious adverse event by the patient. Two patients are presented with tingling or burning sensations limited to areas of heat exposure or sunburn. In these individuals, side effects are most likely generated superficially in the skin.

4 cases with differing presentations of contact allergy to acrylates in sculptured acrylic nails are presented. These reactions include nail fold, fingertip and hand dermatitis, face and neck dermatitis, dystrophic nail changes and paraesthesia. We discuss acrylic nails and review the previously published reactions to acrylates in acrylic nails.

In an evaluation of the safety of new chemicals, of products containing them, or of novel formulations of existing chemicals which may come into contact with the skin, it is important to incorporate an assessment of specially susceptible sub-populations. Such a group is represented by those who are more likely to experience sensory effects such as stinging. Since these individuals are easily and rapidly identifiable, we investigated whether they represented a group who were also more susceptible to the effects of an irritant. The primary purpose was to discover whether 'stingers' might represent an easily and rapidly identifiable sub-population with a more generally increased tendency to give skin responses. The response to a 0.3% sodium dodecyl sulphate patch test was assessed in a group of 25 'stingers' and compared to the response in 25 'non-stingers'. There was no difference in either the pattern or strength of the irritant response assessed by subjective erythema and dryness scores. Thus the data suggest that there is no correlation between the susceptibility of an individual to a skin stinging response and an irritation reaction.

The combination of rapid, diffuse alopecia, and neurologic and gastrointestinal disturbance is pathognomonic for thallium toxicity. The hair mount, showing a tapered or bayonet anagen hair with black pigmentation at the base, may be highly diagnostic before the onset of alopecia. We saw a 10-year-old boy who suffered from thallium poisoning.

Within DSM Chemicals BV, a producer of acrylonitrile, skin complaints are frequent. The majority of these are of an irritant nature, while a smaller portion is based on acquired allergies. Allergological examination revealed 5 employees with an allergy to acrylonitrile. 1 of these subjects also developed paraesthesiae in the skin sites affected, a finding not previously described for acrylonitrile. In the guinea pig maximization test (GPMT), acrylonitrile showed strong allergenic potential. For prevention and treatment of contact allergologic disorders, close cooperation between occupational health officer, dermatologist and toxicologist in chemical companies is recommended.

Ten of 11 patients with ovarian cancer receiving cisplatin developed a distal sensory neuropathy, manifested early by decreased vibratory sensibility in toes and depressed ankle jerks and later by uncomfortable paresthesias. Eleven patients receiving cisplatin, 50 mg/m2 monthly (mean total, 580 mg/m2) were studied prospectively with monthly neurologic examinations and conduction velocity determinations of median, peroneal, and sural nerves. Early signs were decreased vibratory sensibility in toes (mean dose, 417 +/- 132 mg/m2 [SD]) and loss of ankle jerks (mean dose, 455 +/- 86 mg/m2). With continued therapy, four developed paresthesias. Strength was unaffected. Sural nerve responses abruptly disappeared in six of peripheral nerves from four patients showed axonal degeneration and secondary myelin breakdown. Platinum concentrations in three patients were similar in tumor (3.3 micrograms/g), sural nerves (3.5 micrograms/g), and spinal ganglia (3.8 micrograms/g), but lower in brain (0.17 microgram/g). This may explain the cisplatin toxicity of peripheral nerves with relative sparing of the central nervous system.

Twenty-five patients with a variety of histologic types of advanced non-Hodgkin's lymphoma refractory to previous chemotherapy were entered into a trial of vincristine infusion. Patients received 5-day courses of vincristine 0.25 mg/m2/day by continuous intravenous infusion after an initial 0.5 mg intravenous bolus injection. Courses were repeated every 3 weeks. Objective responses were observed in nine patients (36%), all of whom had previously received vincristine given by conventional bolus injection. A complete response occurred in a patient with diffuse mixed histiocytic lymphocytic lymphoma, and partial responses were observed in eight patients with the following histologic types: diffuse poorly differentiated lymphocytic (4); nodular poorly differentiated lymphocytic (2); diffuse mixed histiocytic lymphocytic (1); and diffuse histiocytic (1). Duration of response lasted from 1.2 to 16.2 months (mean, 4.4 months). The principal complication of therapy was mild-to-moderate neurotoxicity; this occurred in 12 patients (48%) who received a total of 54 courses of vincristine infusion. Hematologic toxicity was minimal and nausea/vomiting did not occur. Vincristine infusion may afford palliation for patients with advanced non-Hodgkin's lymphomas who have become refractory to standard chemotherapeutic regimens even if they have received prior vincristine by conventional bolus injection. These data suggest the possibility of enhancing the therapeutic efficacy of vincristine in the treatment of non-Hodgkin's lymphoma by use of an infusion technique.

Synthetic pyrethroids are potent insecticides, utilized for food protection and general pest control. Numerous investigations have indicated that ultra-low volume applications are effective and may eliminate the developing problem of resistance to the currently utilized insecticides. The most prominent health symptom that accompanies topical contact with these agents appears to be a cutaneous sensation, paresthesia. In this investigation, a substantial difference in the degree of paresthesia was noted between the formulated grade of 4 synthetic pyrethroids. Also, dl-alpha tocopheryl acetate was statistically validated as an efficacious therapeutic agent for cutaneous exposure to these insecticides.

Cisplatin is a recognized neurotoxic agent that commonly causes ototoxicity and peripheral neuropathy. In conjunction with characteristic peripheral neuropathy, two patients treated with high-dose cisplatin developed Lhermitte's sign, a manifestation of posterior column spinal cord pathology. After cisplatin therapy was stopped, this symptom gradually resolved. This suggests that at high doses cisplatin may also cause demyelinating central nervous system lesions involving the spinal cord.