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Topiramate is an approved and effective drug in migraine prophylaxis. Paresthesia is the most commonly reported side effect. The primary objective of this study was to compare the frequency of topiramate-induced paresthesia in migraine headache to epileptic patients. Patients with migraine without aura and epilepsy were enrolled in this observational study. All cases were interviewed by telephone about their history of paresthesia. Confounding factors were controlled through logistic regression. The odds ratio of developing topiramate-induced paresthesia in migraine compared to epilepsy patients was 3.4. Three factors were independent contributors to developing topiramate-induced paresthesia: female sex (odds ratio 2.1), topiramate dosage (odds ratio 0.3) and duration of therapy. Our findings indicate an independent association between migraine and development of paresthesia. Migraineurs were more likely than epileptic patients to report paresthesia as topiramate adverse effects. Female sex, treatment duration and topiramate dosage contribute significantly to subsequent development of paresthesia.

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.)

Purpose: Paclitaxel can cause an acute pain syndrome (P-APS), considered to be an acute form of neuropathy and chronic chemotherapy-induced peripheral neuropathy (CIPN). Anecdotal reports suggested that gabapentin may be helpful in the prevention of these toxicities. The purpose of this pilot study was to obtain data to support or refute the utility of pregabalin for the prevention of P-APS and CIPN., Methods: Patients scheduled to receive weekly paclitaxel (80 mg/m(2)/dose) were randomized 1:1 to receive pregabalin 75 mg or a placebo, twice daily, during the 12 weeks of chemotherapy. Patients completed the European Organization of Research and Treatment of Cancer Quality of Life (EORTC QLQ) CIPN20 questionnaire at baseline, prior to each dose of paclitaxel and monthly for 6 months post-treatment. Patients completed a post-paclitaxel questionnaire for 6 days after each dose of paclitaxel and an acute pain syndrome symptom questionnaire on day 8. The primary end point was to determine the effect of pregabalin on the maximum of the worst acute pain scores for the week following paclitaxel administration for cycle 1., Results: Forty-six patients were randomly assigned to the treatment or placebo arm. There was no suggestion of a difference between the two study arms with regard to P-APS measures. While there was a suggestion that pregabalin decreased numbness, there was no suggestion that it decreased tingling, pain, or the EORTC QLQ-CIPN20 subscale scores. There were no evident toxicity differences between the two study arms., Conclusions: The results of this pilot trial do not support that pregabalin is helpful for preventing P-APS or paclitaxel-associated CIPN.

Objective: We examined the emergence of chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting toxicity of oxaliplatin, over the course of oxaliplatin-based chemotherapy for colorectal cancer (CRC). Predicting which patients will likely develop CIPN is an ongoing clinical challenge., Methods: Oxaliplatin-naïve patients with CRC underwent quantitative sensory testing (QST) before beginning oxaliplatin-based chemotherapy and then rated CIPN-related symptoms via the MD Anderson Symptom Inventory (MDASI) weekly for 26 weeks. Mixed modeling examined the value of QST for predicting higher CIPN (MDASI numbness/tingling) during treatment. Trajectory analysis identified a patient subgroup with consistently higher CIPN symptoms., Results: Numbness/tingling was the most frequent, most severe symptom, with 51% of patients clustering into a high CIPN subgroup. Touch sensation deficits (Bumps Detection test) significantly predicted the development of more severe numbness/tingling [estimate (est) = 0.106, p = 0.0003]. The high CIPN subgroup reported increased pain (est = 0.472, p < 0.0001) and interference with walking (est = 0.840, p < 0.0001). In the high CIPN subgroup, patient-reported numbness/tingling worsened rapidly in weeks 0-5 (est = 0.57, p < 0.0001) and then more gradually in weeks 6-26 (est = 0.07, p < 0.0001)., Conclusion: Prechemotherapy screening with a simple, easily administered objective measure of touch sensation deficits (Bumps Detection test) and monitoring of patient-reported numbness/tingling during the first 2-3 chemotherapy cycles may support improved personalized care of CRC patients with oxaliplatin-induced CIPN., (© 2016 S. Karger AG, Basel.)

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important neurologic complications experienced by patients receiving chemotherapy. The neuropathy often interferes with daily activities and exercise leading to severe impairment of the patient's quality of life (QoL). The evolution of most CIPNs is characterized by a gradual onset of signs/symptoms, beginning in the lower limbs and advancing proximally into a bilateral stocking and glove distribution. Patients often complain of numbness, tingling and pain in the affected areas. The symptoms become aggravated with repeated cycles of chemotherapy. When the offending agent is withheld, the symptoms generally abate, but relief is not guaranteed. The consequences of delay or discontinuation of treatment may affect overall patient survival.

β-alanine is a common ingredient in supplements consumed by athletes. Indeed, athletes may believe that the β-alanine induced paresthesia, experienced shortly after ingestion, is associated with its ergogenic effect despite no scientific mechanism supporting this notion. The present study examined changes in cycling performance under conditions of β-alanine induced paresthesia. Eight competitive cyclists (VO2max = 61.8 ± 4.2 mL·kg·min(-1)) performed three practices, one baseline and four experimental trials. The experimental trials comprised a 1-km cycling time trial under four conditions with varying information (i.e., athlete informed β-alanine or placebo) and supplement content (athlete received β-alanine or placebo) delivered to the cyclist: informed β-alanine/received β-alanine, informed placebo/received β-alanine, informed β-alanine/received placebo and informed placebo/received placebo. Questionnaires were undertaken exploring the cyclists' experience of the effects of the experimental conditions. A possibly likely increase in mean power was associated with conditions in which β-alanine was administered (±95% CL: 2.2% ± 4.0%), but these results were inconclusive for performance enhancement (p = 0.32, effect size = 0.18, smallest worthwhile change = 56% beneficial). A possibly harmful effect was observed when cyclists were correctly informed that they had ingested a placebo (-1.0% ± 1.9%). Questionnaire data suggested that β-alanine ingestion resulted in evident sensory side effects and six cyclists reported placebo effects. Acute ingestion of β-alanine is not associated with improved 1-km TT performance in competitive cyclists. These findings are in contrast to the athlete's "belief" as cyclists reported improved energy and the ability to sustain a higher power output under conditions of β-alanine induced paresthesia.

Purpose: Magnesium is an important electrolyte for very many cell functions and its deficiency may lead to a wide spectrum of diseases. We report a clinical case of hypomagnesemia resulting from the chronic use of a proton pump inhibitor (PPI). PPIs are drugs widely used in medical practice, and a growing number of cases of PPIs causing hypomagnesemia have been described. Our aim was to monitor the clinical and electrolyte findings during recovery from hypomagnesemia caused by long-term PPI use., Results: A 65-year old female who had been using omeprazole for 10 years, presented with arrhythmia and paresthesia of the lower and upper limbs that had been attributed to severe hypomagnesemia, hypocalcemia, and hypoparathyroidism. Her laboratory tests revealed the following results: magnesium 0.6 mg/dL (NR: 1.5 to 2.5 mg/dL), calcium 7.3 mg/dL (NR: 8.5 to 10.2 mg/dL), parathyroid hormone (PTH) 13.3 pg/mL (NR: 15 to 65 pg/mL), and low urinary calcium and magnesium excretion. Her electrocardiogram disclosed typical, prolonged QT interval, ST depression, and U waves. We discuss the differential diagnoses, pathophysiology, and reversibility of symptoms after effective treatment of the hypomagnesemia., Conclusion: this report emphasizes that even if long-term PPI users appear largely asymptomatic, life-threatening arrhythmias can present very suddenly. Long-term PPI users should be monitored for otherwise unexplained hypomagnesemia, hypocalcemia, functional hypoparathyroidism and associated symptoms.

Objectives: This study characterized the incidence and clinical features of oral adverse events among cancer patients who received VEGFR-directed multitargeted tyrosine kinase inhibitor (VR-TKI) therapies., Methods: Electronic medical records of adult cancer patients treated with sunitinib, sorafenib, regorafenib, pazopanib, cabozantinib, imatinib, and bevacizumab therapy at Dana-Farber Cancer Institute from 2009 to 2012 were reviewed. Data collected included patient characteristics, oral and non-oral adverse events, and time to onset. Time oral adverse event-free was the primary outcome., Results: A total of 747 patients with 806 individual courses of therapy were treated for a median of 3.9months with sunitinib (n=161), sorafenib (n=172), regorafenib (n=15), pazopanib (n=132), cabozantinib (n=23), imatinib (n=144), or bevacizumab (n=159) for lung cancer (21%), gastrointestinal stromal tumor (15%), and metastatic renal cell carcinoma (13%). An oral adverse event was reported in 23.7% of patients at a median of 1.9months after starting therapy. The most commonly reported oral adverse event was oral mucosal sensitivity (dysesthesia), occurring in 12% of patients, typically without clinical findings. Multivariate models showed patients who received VR-TKI therapy were at greater risk of any oral adverse event compared with patients treated with imatinib or bevacizumab. Patients receiving VR-TKI therapy who developed an oral adverse event were also at increased risk for hand-foot skin reaction (15.9%)., Conclusions: VR-TKI associated oral adverse events are characterized primarily by dysesthesia with lack of clinical signs. Oral dysesthesia is more commonly associated with VR-TKIs than with bevacizumab or imatinib. Management is largely empirical and requires further investigation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chemotherapy-induced peripheral neuropathy is a debilitating side effect of chemotherapy, which manifests as paresthesias, dysesthesias, and numbness in the hands and feet. Numerous chemoprotective agents and treatments have been used with limited success to treat chemotherapy-induced peripheral neuropathy. We report a case in which a patient presenting with chemotherapy-induced peripheral neuropathy received an IV lidocaine infusion over the course of 60 minutes with complete symptomatic pain relief for a prolonged period of 2 weeks.

Background: Previous data have indicated the efficacy of dexmedetomidine as an additive to peripheral regional anaesthesia. There are no pharmacodynamic data regarding the addition of dexmedetomidine to local anaesthetics for perineural administration., Objective: The objective of this study is to assess the dose-dependency of dexmedetomidine when injected with ropivacaine for peripheral nerve blockade., Design: A randomised, triple-blind, controlled study in volunteers., Setting: Department of Clinical Pharmacology, Medical University of Vienna., Participants: Twenty-four volunteers., Interventions: All volunteers received an ulnar nerve block with 22.5 mg ropivacaine alone (R), or mixed with 50 (RD50), 100 (RD100) or 150 μg (RD150) dexmedetomidine., Main Outcome Measures: The primary outcome was the duration of complete sensory block to pinprick and time to complete recovery of pinprick. Secondary outcomes included block success and onset time, motor block, haemodynamic parameters and sedation level., Results: There was a significant dose-dependent (P < 0.0001) increase in the mean duration (SD) of sensory block with dexmedetomidine: R: 8.7 (1.5) h, RD50: 16.4 (4.0) h, RD100: 20.4 (2.8) h and group RD150: 21.2 (1.7) h. Sedation was also enhanced in a dose-dependent (P < 0.001) manner. Two volunteers each receiving 150 μg dexmedetomidine had postblock paraesthesia for 72 h., Conclusion: Dexmedetomidine mixed with ropivacaine produces a dose-dependent prolongation of sensory block and clinically relevant dose-dependent sedation. Dexmedetomidine 100 μg may represent a balance between efficacy and sedation.

Saxitoxins (STX) and tetrodotoxins (TTX) are a group of chemical compounds produced by certain species of marine algae and fish. Lethal dose for a human is about 0.5-2.0 mg when the toxin enters the body via food, and 0.05 mg of poisoning at the time of injection. In the case of aerosol the lethal dose for human being is 5 mg/min/m(3). STX and TTX poisoning cause mostly symptoms from the nervous system in the form of: paresthesia around the lips, tongue, gums, distal segments of the limbs, headache, dysphonia, astigmatism, floating feeling, muscle weakness, paralysis of cranial and peripheral nerves. There is no specific antidote for STX and TTX. It is recommended supportive treatment., (© 2015 MEDPRESS.)

Background: Paresthesia was the third-most-common adverse event following immunization (AEFI) with 2009 monovalent AS03-adjuvanted A(H1N1)pdm09 vaccine in Quebec, Canada and was also frequently reported in Europe. This study assessed clinical features and risk factors associated with this unexpected AEFI., Methods: Reports to the passive surveillance system were summarized. A case-control study was conducted to assess risk factors and additional investigations were undertaken among cases with symptoms persisting ≥12 months., Results: There were 328 reports of paresthesia affecting the vaccinated arm (58%), but also face (45%), lower limbs (40%) and back/thorax (23%) with numbness but also muscle weakness (61%), motor impairment (61%), generalized myalgia (37%), visual (14%) and/or speech effects (15%). Reporting rate was highest in women of reproductive age, peaking at 30-39 years-old (28/100,000 doses administered) and exceeding that of men of the same age (7/100,000 doses) by 4-fold. Median time to onset was 2h. Symptoms subsided within one week in 37% but lasted ≥6 months in 26%. No consistent or objective neurological findings were identified. Risk was increased with allergy history, respiratory illness the day of vaccination, depressive symptoms and family history of pulmonary disease, but decreased with physical activity the day of vaccination, and regular weekly alcohol consumption., Conclusion: Paresthesia following 2009 pandemic vaccine receipt lasted several weeks and included other motor-sensory disturbances in an important subset of patients. Although it does not correspond with known neurological disease, and causality remains uncertain, further investigation is warranted to understand the nature and frequency of paresthesia as a possible AEFI with influenza vaccines., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Case description The use of i.v. colistin reappeared recently for the treatment of multidrug-resistant Gram negative organisms in the intensive care and cystic fibrosis (CF) setting. According to the latest pharmacokinetic data, a loading dose and high antibiotic doses are given. Two cases of adverse events (paraesthesias, bad taste) were observed immediately after the start of infusion of a high dose of i.v. colistin in adult CF patients at the Ghent University Hospital. Conclusion Recommendations for optimal administration of i.v. colistin in adult CF patients are scarce. This article highlights the importance of mode of administration to avoid toxicity and relates it to recent pharmacokinetic/-dynamic literature.

This study was aimed to evaluate the possible alert signals of paraesthesia by local anaesthetics, focusing on those used in dentistry. A case/non-case study of spontaneous adverse events recorded in FAERS (FDA Adverse Event Reporting System) between 2004 and 2011 was performed. Cases were represented by the reports of reactions grouped under the term 'Paraesthesias and dysaesthesias' involving local anaesthetics (ATC: N01B*); non-cases were all other reports of the same drugs. Reporting odds ratios (ROR) with the relevant 95% confidence intervals (95CI) were calculated. Alert signal was considered when number of cases >3 and lower limit of ROR 95CI > 1. To estimate the specificity of signals for dentistry, the analysis was restricted to the specific term "Oral Paraesthesia" and to reports concerning dental practice. Overall, 528 reports of 'Paraesthesias and dysaesthesias' were retrieved, corresponding to 573 drug-reaction pairs (247 lidocaine, 99 bupivacaine, 85 articaine, 30 prilocaine, 112 others). The signal was significant only for articaine (ROR=18.38; 95CI = 13.95-24.21) and prilocaine (2.66; 1.82-3.90). The analysis of the specific term "Oral Paraesthesia" retrieved 82 reports corresponding to 90 drug-reaction pairs (37 articaine, 19 lidocaine, 14 prilocaine, 7 bupivacaine, 13 others) and confirmed the signal for articaine (58.77; 37.82-91.31) and prilocaine (8.73; 4.89-15.57). The analysis of reports concerning dental procedures retrieved a signal for articaine, both for any procedures (8.84; 2.79-27.97) and for non-surgical ones (15.79; 1.87-133.46). In conclusion, among local anaesthetics, only articaine and prilocaine generated a signal of paraesthesia, especially when used in dentistry., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

This functional magnetic resonance imaging (fMRI) study explored the central nervous processing of itch induced by histamine and capsaicin, delivered via inactivated cowhage spicules, and the influence of low-dose naltrexone. Scratch bouts were delivered at regular intervals after spicule insertion in order temporarily to suppress the itch. At the end of each trial the subjects rated their itch and scratch-related sensations. Stepwise multiple regression analyses were employed for identifying cerebral networks contributing to the intensities of "itching", "burning", "stinging", "pricking" and "itch relief by scratching". In the capsaicin experiments a network for "burning" was identified, which included the posterior insula, caudate and putamen. In the histamine experiments networks for "itching" and "itch relief" were found, which included operculum, hippocampus and amygdala. Naltrexone generally reduced fMRI activation and the correlations between fMRI signal and ratings. Furthermore, scratching was significantly less pleasant under naltrexone.

Objective: To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs., Methods: Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co-primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs., Results: Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy., Conclusions: Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes., Trial Registration Number: NCT00809354., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of oxaliplatin which can negatively influence quality of life. We aimed to study the influence of cumulative dose, dose schedule and dose reductions of adjuvant oxaliplatin on long-term severity and prevalence of CIPN among colorectal cancer (CRC) survivors., Material and Methods: In total 207 patients, diagnosed with CRC between 2000 and 2009 who underwent adjuvant treatment with oxaliplatin, were included. They completed the EORTC QLQ-CIPN20 2-11 years after diagnosis. Data on oxaliplatin administration and acute neuropathy during treatment were extracted from the medical files. Subscales were analyzed with analysis of covariance and neuropathy symptoms with logistic regression analysis., Results: Patients who received cumulative oxaliplatin dose of ≥ 842 mg/m(2) had a significantly worse EORTC QLQ-CIPN20 sensory score compared to those who received a low cumulative dose of < 421 mg/m(2) (mean 19 vs. 8; p = 0.02). They more often reported tingling toes/feet (13% vs. 2%, respectively; p = 0.01). Dose intensity and time delay did not influence the occurrence of CIPN. Patients receiving a dose reduction because of neuropathy (N = 50) reported a significantly worse sensory score at very similar cumulative doses, than those who did not receive a dose reduction because of neuropathy (N = 96) (mean 21 vs. 15; p = 0.01)., Conclusion: Cumulative dose of oxaliplatin is associated with long-term CIPN. The risk of developing long-term CIPN could only be reduced by decreasing the cumulative dose, whereas delay probably is not beneficial. Patients receiving a dose reduction because of acute neuropathy are still at risk of developing long-term CIPN. Future studies should focus on identifying patients who are at risk of developing CIPN.

In recent times there has been raised interest regarding the use of articaine hydrochloride as a dental local anaesthetic solution. The use of articaine hydrochloride as a dental local anaesthetic agent has been reported to be safe and effective. Paraesthesia is a rare but unwanted adverse effect attributed to the use of this local anaesthetic in dentistry, particularly following the administration of a nerve block injection. There is no evidence to support the opinion that the use of articaine carries a greater associated risk of paraesthesia than with the use of any other local anaesthetic. Clinical Relevance: The aim of this article is to review the relative merits of articaine hydrochloride against its documented potential drawbacks. The article will also aim to update readers on the use of articaine hydrochloride for local analgesia in dentistry, including the pharmacology, efficacy and safety concerns (including the risks of nerve paraesthesia) commonly associated with the administration of this agent.

Background: Modern anticancer chemotherapy can cause numerous adverse effects in the organism, whose functioning has already been disrupted by the neoplastic process itself., Objectives: The aim of the study was to evaluate and compare the frequency and severity of the toxicity of FOLFOX-4 and CLF-1 anticancer therapy in patients with colon cancer, and to analyze certain factors that might have increased the toxicity of the chemotherapy., Material and Methods: The study involved 64 patients suffering from generalized colon cancer, including 48 patients treated according to the FOLFOX-4 regimen and 16 patients treated according to the CLF-1 regimen. The toxicity of each regimen was analyzed on the basis of a confidential questionnaire formulated by the authors and laboratory research according to the extended WHO toxicity criteria., Results: The analysis of the symptoms of toxicity symptoms associated with the use of the FOLFOX-4 and CLF-1 therapeutic regimens revealed that the most common side effects included nausea and vomiting, despite ondansetron premedication, and neurotoxicity. Disruption of the functioning of the nervous system under the FOLFOX-4 regimen statistically significant exacerbation that increased with the number of chemotherapy cycles administered; this was more common and more severe in women. Paresthesia was also revealed to be a neurotoxic effect of the FOLFOX-4 regimen after termination of therapy. A statistically significant relationship was observed between the use of vitamin supplements and the incidence and severity of the toxicity of the FOLFOX-4 regimen., Conclusions: The findings of the current study regarding the toxicity of the FOLFOX-4 and CLF-1 therapy regimens should be taken into consideration when monitoring chemotherapy safety in colon cancer. The patients' tolerance of the administered medication and the side effects reported by patients should be constantly evaluated, which will help prevent these side effects, apply appropriate therapy and contribute to the improvement of the patients' quality of life. The functioning of the central nervous system should be carefully evaluated when planning the anticancer therapy, especially if repeated administration of neurotoxic drugs is necessary in cases of a recurrence of the disease. Chemotherapy should be thoroughly monitored for safety, especially in women over 65 years of age suffering from coexisting diseases. Colon cancer patients and their families should be informed of the risks of nutritional supplements before the start of the anticancer chemotherapy, and may need to dispense with their use.

Purpose: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two)., Patients and Methods: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR)., Results: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively., Conclusion: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib., (© 2014 by American Society of Clinical Oncology.)

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess β-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) μU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) μU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of β-cell function.

Carnosine, dipeptide formed by amino acids ß-alanine and L-histidine, has important physiological functions among which its antioxidant and related memory and learning. However, in connection with the exercise, the most important functions would be associated with muscle contractility, improving calcium sensitivity in muscle fibers, and the regulatory function of pH. Thus, it is proposed that carnosine is the major intracellular buffer, but could contribute to 7-10% in buffer or buffer capacity. Since carnosine synthesis seems to be limited by the availability of ß-alanine supplementation with this compound has been gaining increasing popularity among the athlete population. Therefore, the objective of this study literature review was to examine all those research works have shown the effect of ß-alanine supplementation on athletic performance. Moreover, it also has attempted to establish a specific dosage that maximizing the potential benefits, minimize paresthesia, the main side effect presented in response to supplementation., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

The increasing number of longer-living patients with diffuse large B-cell lymphoma (DLBCL) and serious side effects of treatment urged us to study the health-related quality of life (HRQoL) and persistent (treatment-related) symptoms in unselected patients after different treatment modalities and compare HRQoL of patients with a normative population. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with DLBCL from 2004 to 2010. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was completed twice, with a 1-year interval. Detailed data on treatment were extracted from the Population-based HAematological Registry for Observational Studies. Two hundred fifty-six patients responded (84 %, T1). Compared to patients treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days ((R-)CHOP21), those who underwent (R-)CHOP14 more often reported tingling in the hands and feet (27 vs 42 %, p = 0.02) and fatigue (35 vs 46 %, p = 0.03) and reported a lower global health status/HRQoL. Mean HRQoL was statistically and clinically relevantly lower among DLBCL patients compared to a normative population (p < 0.01). Persistent tingling in hands/feet was reported more often by older patients and patients treated with (R-)CHOP14 independently of the other characteristics. Furthermore, patients who reported symptoms exhibited significantly lower HRQoL compared to patients without symptoms/worries. Patients treated with (R-)CHOP14 reported more neuropathic symptoms, more fatigue, and a lower HRQoL than patients treated with (R-)CHOP21. Alertness for persistent symptoms that occur during and after treatment of DLBCL patients is needed and may help to avoid lasting negative influence on their HRQoL.

A 55-year-old woman on treatment with capecitabine and paclitaxel for breast carcinoma presented with history of a tingling sensation in her hands and feet with a progressive burning sensation. She also noted discomfort, minimal pain and stiffness while holding objects. On examination, there was patchy hyperpigmentation of both the palms and soles, and the dorsa of hands and feet. This was accompanied by a thickening of the skin more over the knuckles and toes. In addition there was a moist desquamation around the toes and over the palmar creases and a bluish discoloration of the lunulae of both thumbnails. She was diagnosed with hand and foot syndrome and started on pyridoxine and emollients. The finding of keratoderma noted in our patient is not seen commonly in hand and foot syndrome.

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.

Background and Purpose: Failed closed treatment of carpal tunnel syndrome (CTS) is often followed by surgery. We investigated whether preoperative steroid injections could have a negative effect on the long-term outcome of the operation., Patients and Methods: 174 hands (164 patients) were operated on by a single surgeon at Tartu University Hospital in 2005. The patients were interviewed by telephone 5-6 years after the operation. Self-reported data were gathered retrospectively concerning the number of steroid injections received before the surgery and the perceived regression of symptoms (on a 100-point numeric rating scale) at the time of interview. The patients were also asked about the presence of specific symptoms of CTS if regression of their symptoms had not been complete., Results: 93 of the 174 hands had complete regression of symptoms. Each additional injection was associated with an increased risk of occurrence of pain (RR = 1.1, 95% CI: 1.02-1-2), paresthesiae (RR = 1.1, CI: 1.1-1.2), and nocturnal awakenings (RR = 1.2, CI: 1.1-1.3). There was a weak association between the number of injections and the score given to regression of symptoms., Interpretation: This is the first study to indicate that patients who received a greater number of local steroid injections preoperatively were more likely to have postoperative complaints associated with CTS.

Background: Lhermitte's sign (LS) is characterized by electric shock-like sensations, spreading along the spine in a cervico-caudal direction and into the arms and legs. It is felt upon flexion of the neck and reflects a myelopathy resulting from damage to sensory axons at the dorsal columns of the cervical spinal cord. In patients with cancer, LS can occur due to direct tumour involvement of the spine or in relation to radiotherapy. Chemotherapy-related LS has only rarely been reported., Case Report: We present the case of a 44-year-old patient treated with platinum- and etoposide-based chemotherapy for metastatic seminoma, who subsequently developed severe disabling LS. The severity and duration of LS in this case exceeds prior reports. We review the literature on chemotherapy-related LS and discuss the practice implications., Conclusion: Neuropathy and LS related to cisplatin-based chemotherapy can result in significant adverse effects. Raised awareness of this complication could aid sub-phenotyping of the population most at risk and assist strategies to avert discomfort and disability post chemotherapy., (© 2014 S. Karger GmbH, Freiburg.)

This study investigated another type of carbonic anhydrase inhibitor and antiepileptic drug, zonisamide, in order to evaluate its potential effectiveness for migraine prophylaxis refractory to topiramate, and to assess intolerability to adverse events, paresthesia in particular. This is an open-labeled retrospective single center study. We included headache patients who met the requirement of migraine without aura and were refractory to topiramate. Patients were treated only with zonisamide 100 mg/day, directly switching from topiramate. Patients were monitored every month for three months. A positive response to treatment (responders) was defined as a 50% or greater reduction in headache days at three months after study commencement, compared with baseline. One hundred and twenty migraineurs who were refractory to topiramate were recruited. Compared with baseline, headache days with zonisamide showed a decrease, compared with baseline (P < 0.01). Two patients complained of adverse effects, such as paresthesia. These results suggest that zonisamide is effective for migraine prophylaxis refractory to topiramate, or intolerable patients due to topiramate-induced paresthesia.

Introduction: Intraoral anesthesia is probably the most commonly used procedure in dentistry., Methods: Although inferior alveolar nerve block (IANB) anesthesia is one of the safest procedures to anesthetize the mandibular teeth, side effects of IANB anesthesia can still give rise to potential risks for patients. Fortunately, most observed alterations are transient and self-limited., Results: The complications of IANB anesthesia are varied in nature and could be specifically categorized into systemic, localized, and distant complications. When the complications occur around the orofacial structures including the temporomandibular joint, middle ear, facial skin, and the eye, which are away from the oral cavity, it can be defined as distant complications. However, to our best knowledge, the concomitant occurrence of neurologic phenomena such as Horner syndrome combined with cutaneous complications in a patient receiving IANB anesthesia has never been discussed., Conclusions: In this exceptional case, the unusual Horner syndrome manifestations related to unilateral ptosis, miosis, and anisocoria were simultaneously developed with skin ischemia, paresthesia, and asymmetric flushing after the administration of IANB anesthesia., (Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Venlafaxine is a serotonin norepinephrine reuptake inhibitor that is used for mood, anxiety, and pain disorders. We report a case of dose-related paresthesias in association with venlafaxine use in a patient with major depressive disorder., Case Report: A young male patient with major depression started treatment with venlafaxine XR at 37.5 mg/d, and the dose was titrated to 75 mg/d with no significant adverse effects. Upon increasing the dose to 150 mg/d, the patient reported tingling, numbness, and itching in his upper extremities. The dose was reduced to 75 mg/d, at which time, the symptoms disappeared. Since the patient still had target symptoms of depression, the patient was willing to try increasing the dose back to 150 mg/d. Upon rechallenge, the tingling, numbness, and itching reappeared. The dose of venlafaxine was decreased back to 75 mg/d. Per the Naranjo scale, the probability score for the above adverse drug reaction is 5 (probable). We discuss the published evidence of paresthesias associated with antidepressants and clinical implications for recognizing paresthesias during venlafaxine treatment that may be useful for clinicians., Conclusion: Clinicians need to be aware of the possible emergence of paresthesias with venlafaxine treatment, especially at doses of ≥ 150 mg/day. Patients who receive venlafaxine for pain disorders should be closely monitored for worsening of pain symptoms and may require adjustment of their doses.

Severe peripheral neuropathy and myelopathy are rare complications after stem cell transplantation (SCT). In our institution, seven patients of precursor T lymphoblastic leukemia/lymphoma without the central nervous involvement who had been treated by nelarabine to control their diseases received SCT from HLA-haploidentical familial donor (HLA-haploidentical SCT) with the conditioning regimen including high-dose cytarabine (HDAC). Three of evaluable six patients developed irreversible paresthesia and muscle weakness in both lower extremities after neutrophil engraftment. The results of nerve conduction studies and short latency somatosensory evoked potentials suggested axonal neuropathy of both lower extremities in all three patients and myelopathy in two patients. Negative findings of PET-CT, and analyses of repeated cerebrospinal fluid samples and the bone marrow also indicated that tumor involvement was improbable. In all three patients, the symptoms worsened or persisted despite administration of corticosteroid and intravenous immunoglobulin. The high frequency of the neurological symptoms in our patients previously treated by nelarabine strongly suggested the association of the nelarabine use. Furthermore, the HLA-haploidentical SCT setting and the use of a potentially neurotoxic agent, HDAC might augment the neurotoxicity of nelarabine. It may be desirable that HLA-haploidentical SCT candidates avoid receiving nelarabine., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Progestogens are widely used to treat a large number of common conditions. We aimed to investigate a potential signal concerning progestogens and paraesthesia., Methods: Data were obtained from the VigiBase, the WHO Global Individual Case Safety Reports (ICSR) database, which is maintained by the Uppsala Monitoring Centre. We collected all suspected reports of paraesthesia associated with oral progestogens, reported between January 1972 and June 2012 and classified in VigiBase according to WHO-Adverse Reaction Terminology critical term 'paraesthesia'. A disproportionality analysis was conducted using the Information Component (IC) and the standard deviation (IC025) as a measure., Results: Out of the total number of reports collected in the VigiBase (7,332,991), paraesthesia was associated with progestogen therapy in 920 reports, coming from 22 countries. Progestogens had the highest number of suspected reports (n = 864) than the other Anatomical Therapeutic Chemical (ATC) considered. Only norethisterone was associated with paraesthesia with positive IC (0.47) and IC025 (0.02)., Conclusions: Norethisterone-associated paraesthesia appears to be a rare outcome. However, the widespread use of progestogens in medical practice suggests that it is a complaint that can affect a large number of women. Since paraesthesia can be caused by several drugs, clinicians should consider that it may be also caused by norethisterone.

Background: Articaine and chloroprocaine have recently gained interest as short-acting spinal anaesthetics. Based on previous work comparing articaine 60 mg with chloroprocaine 40 mg, we hypothesised that articaine 40 mg and chloroprocaine 40 mg would produce similar spinal anaesthesa regarding block onset, maximal spread, and recovery., Methods: In this randomised, double-blind study, adult patients (18-70 years, American Society of Anaesthesiologists physical status I-III, BMI < 36 kg/m(2) ) scheduled for day-case knee arthroscopy received either articaine 40 mg (20 mg/ml) (group A40, n = 16) or chloroprocaine 40 mg (20 mg/ml) (group C40, n = 18) intrathecally. Telephone interviews were performed on the first and seventh postoperative day to disclose possible side effects, e.g. transient neurological symptoms (TNS)., Results: The groups were comparable regarding demographic data, onset and maximal spread of spinal anaesthesia, and duration of surgery. Surgery could be performed successfully under spinal anaesthesia except once in A40 (insufficient block) and once in C40 (prolonged surgery). Complete recovery was significantly slower in A40 vs. C40 for both motor block (105 (94/120) vs. 75 (71/90) min) [P < 0.001, Mann-Whitney U-test (MW-U)] and sensory block [135 (109/176) vs. 105 min (90/124)] (P < 0.02, MW-U), respectively [data are median (25th/75th percentiles)]. One patient from A40 showed mild TNS., Conclusion: Both A40 and C40 provided mainly adequate spinal anaesthesia for day-case knee arthroscopy. While onset and maximal spread were comparable, the recovery from motor block was clearly faster with chloroprocaine after equivalent doses of spinal articaine and chloroprocaine., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aim: to assess the safety and effectiveness of candesartan and candesartan/HCT fixed-dose combination (FDC) in patients with hypertension in daily clinical practice., Methods: an open observational study with a 12-week period of treatment. Candesartan tablets of 4 mg, 8 mg, or 16 mg, or candesartan/HCT FDC tablets (16/12.5 mg) were prescribed to adult hypertensive subjects, both treatment-naive patients and previously treated but uncontrolled patients, depending on the physicians' discretion based on his/her judgment on the clinical condition., Results: from a total of 112 treatment-naive patients and 381 previously treated patients eligible for safety analysis, there were only 3 patients with adverse events, and 2 of which were considered possibly related to candesartan (0.41%) and there were no serious adverse events. Both patients were previously treated patients, one patient experienced nausea and the other patient experienced paresthesia. Candesartan and candesartan/HCT were effective in lowering systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline at weeks 4, 8, and 12, in both groups, with 26-27 mm Hg decreases in SBP at week 12 and a trend toward a larger reduction in treatment-naive patients than in previously treated patients, although not statistically significant. However, in terms of patients achieving a BP of <140/90 mm Hg between groups were significantly superior in treatment-naive patients than in previously treated patients at week 8 (56% vs 40%; p=0.003) and week 12 (69% vs 53%; p=0.004). Candesartan and candesartan/HCT were also effective for patients with long-standing (>4 years) uncontrolled hypertension with previous antihypertensive therapy, which was most commonly calcium channel blockers (became controlled in >50% of all uncontrolled patients)., Conclusion: results of this open observational study showed that candesartan and candesartan/HCT were well tolerated and effective in both treatment-naive patients and uncontrolled hypertensive patients with previous antihypertensive treatment.

Nerve injury after peripheral regional anesthesia is rare and is not usually permanent. Some authors believe that inducing peripheral nerve blocks in patients during general anesthesia or analgosedation adds an additional risk factor for neuronal damage. This is based on published case reports showing that there is a positive correlation between paresthesia experienced during regional anesthesia and subsequent nerve injury. Therefore, many sources recommend that regional nerve blocks should only be performed in awake or lightly sedated patients, at least in adults. However, there is no scientific basis for this recommendation. Furthermore, there is no proof that regional anesthesia performed in patients under general anesthesia or deep sedation bears a greater risk than in awake or lightly sedated patients. Currently anesthesiologists are free to follow personal preferences in this matter as there is no good evidence favoring one approach over the other. The risk of systemic toxicity of local anesthetic agents is not higher in patients who receive regional anesthesia under general anesthesia or deep sedation. Finally, in children and uncooperative adults the administration of peripheral nerve blocks under general anesthesia or deep sedation is widely accepted.

The drug with perhaps the greatest impact on the practice of Psychiatry is Methamphetamine. By increasing the extracellular concentrations of dopamine while slowly damaging the dopaminergic neurotransmission, Meth is a powerfully addictive drug whose chronic use preferentially causes psychiatric complications. Chronic Meth users have deficits in memory and executive functioning as well as higher rates of anxiety, depression, and most notably psychosis. It is because of addiction and chronic psychosis from Meth abuse that the Meth user is most likely to come to the attention of the practicing Psychiatrist/Psychologist. Understanding the chronic neurologic manifestations of Meth abuse will better arm practitioners with the diagnostic and therapeutic tools needed to make the Meth epidemic one of historical interest only., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Although oral topiramate (TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration (FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation., Methods: This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2., Key Findings: All subjects completed the study. The mean (±standard deviation) absolute oral bioavailability was 109% (±10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (±0.29) and 0.94 L/kg (±0.24). Clearances were 1.33 L/h (±0.26) and 1.22 L/h (±0.26). The half-life values were 42.3 h (±6.2) and 41.2 h (±7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion., Significance: In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

We describe the case of a woman, aged 41 years, who received a combination chemotherapy including vincristine, doxorubicine, ifosfamide and etoposide due to Ewings sarcoma. She was treated prophylactic with fluconazole to prevent oral candidosis. Unexpectedly, she developed severe neurotoxic side effects. Treatment with multiple substrates of cytochrome P450 3A4 combined with inhibition of the enzyme by fluconazole impairs metabolism and thereby increase plasma concentrations of vincristine, which is considered to be the main reason for the neurotoxic side effects.