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Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD 50 dose of paraoxon., (© 2022. The Author(s).)

Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal condition marked by chronic bowel pain or discomfort, as well as changes in abdominal motility. Despite its worldwide prevalence and clinical impact, the cause of IBS is unknown. Inflammation could play a fundamental role in the development of IBS. The aim of this study was to examine whether pentoxifylline, a competitive nonselective phosphodiesterase inhibitor, is useful in alleviating abdominal pain in IBS patients treated with mebeverine., Methods: A randomized, controlled, and prospective clinical study that included 50 outpatients who met the inclusion criteria for IBS. Patients are allocated randomly into two groups (n = 25). Group 1 (mebeverine group) received mebeverine 135 mg three times daily (t.i.d) for three months. Group 2 (pentoxifylline group) received mebeverine 135 mg t.i.d and pentoxifylline 400 mg two times daily for three months. Patients were assessed by a gastroenterologist at baseline and three months after the medication had been started. The serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-alpha, fecal Neutrophil Gelatinase Associated Lipocalin (NGAL), and fecal myeloperoxidase were measured at the start and after three months of therapy. The Numeric Pain Rating scale (NRS) was assessed at baseline and after therapy., Results: the pentoxifylline group showed a significant decrease in the level of measured biomarkers and a significant decrease in NRS., Conclusion: Pentoxifylline could be a promising adjuvant anti-inflammatory drug in the treatment of abdominal pain in IBS patients treated with mebeverine., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Many studies are performed with the aerial parts of Cannabis sativa L. (Cannabaceae). However, roots remain poorly studied, despite citations in the scientific literature. The C. sativa roots are indicated for the treatment of pain, inflammation, fever, among other health problems., Aim of the Study: This study aimed to evaluate the antinociceptive, antipyretic, antiasthmatic, and spasmolytic activities of C. sativa roots in experimental models using mice and rats., Material and Methods: The chemical composition of the aqueous extract of C. sativa roots (AECsR) was evaluated by LC-MS. The antinociceptive activity was assessed in mice by the induction of writhing with acetic acid, paw licking with formalin, and reactivity in the hot plate test. Fever was induced by the administration of a suspension of Saccharomyces cerevisiae in young rats. The asthmatic activity was performed with ovalbumin (OVA)-immunized mice with cellular and histological analysis. Finally, the spasmolytic activity was performed using mice isolated trachea. For in vivo studies, the doses were 12.5, 25, or 50 mg/kg whereas for in vitro, the concentration of AECsR was 729 μg/mL., Results: From the LC-MS data, we identified p-coumaroyltyramine, feruloyltyramine canabissativine in AECsR. The extract promoted a reduction of writhing in all tested doses (12.5, 25, or 50 mg/kg). Similarly, it reduced the pain in the formalin test at doses of 12.5 and 50 mg/kg (first phase) and 12.5 and 25 mg/kg (second phase). In the hot plate test, the doses of 12.5, 25, and 50 mg/kg promoted antinociceptive effect at different times, and the lowest dose maintained its action in the analyzes performed at 60, 90, and 120 min after administration. The anti-inflammatory activity of AECsR was observed in the mouse model of asthma, reducing the total leukocyte count in the bronchoalveolar fluid (BALF) at a dose of 25 mg/kg, as well as reducing eosinophilia in all tested doses (12.5, 25, and 50 mg/kg). Histological analysis of lungs stained with H&E and PAS showed a reduction in the number of inflammatory cells in the perivascular and peribronchial region, as well as reduced mucus production., Conclusion: The results suggest that AECsR promotes pain control, either by a central or inflammatory mechanism, and has antiasthmatic activity. However, there was no antipyretic or spasmolytic effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abstract: Acute dystonic reactions are a worrying reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. It must be diagnosed and treated quickly. The aim of this study was to examine the clinical presentations, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute dystonic reactions in children.Nine pediatric patients who were treated for acute dystonic reactions between May, 2018 and May, 2020 and had adequate follow-up were included in the study. Medical record data were reviewed age, gender, etiology, features of family, treatment, and results.Three of the patients were female and 6 were male. Their average age was 11 years (4-17). All patients were evaluated as a drug-induced acute dystonic reaction. Of the 9 patients, 5 were due to metoclopramide, 3 were due to risperidone, and 1 was due to aripiprazole. It was learned that a similar situation against other drugs developed in the family history of 3 patients. As a treatment, all of them were intramuscularly applied biperiden suitable for their weight and 30 minutes dramatic improvement was observed. Additional dose had to be administered in only 1 case. All cases were discharged for 24 hours. No problem was observed in their follow-up.Drug-induced acute dystonic reaction can be diagnosed and has a clinical picture that completely resolves when effective treatment is applied. However, it should not be forgotten that it can reach life-threatening dimensions clinically., Competing Interests: The author has no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: There are many studies and therapeutic properties attributed to the flowers and leaves of the Cannabis species, but even with few pharmacological studies, Cannabis sativa L. (Cannabaceae) roots presents several therapeutic indications in folk medicine., Aim of the Study: This study aimed to evaluate the anti-inflammatory and spasmolytic effects as well as the toxicological profile of the aqueous extract of Cannabis sativa roots (CsAqEx) in mice., Materials and Methods: We assessed the anti-inflammatory effect with carrageenan-induced leukocyte migration assay, and carrageenan and histamine-induced paw edema methods; The spasmolytic effect was assessed through in vitro assays with isolated mice trachea. To assess motor coordination and mobility, mice went through the rotarod and open field tests, respectively. For the single-dose toxicity study, we administered CsAqEx at the dose of 1000 mg/kg by gavage. In a repeated dose toxicity study, animals received CsAqEx at doses of 25 mg or 100 mg/kg for 28 days., Results: The CsAqEx inhibited the migration of leukocytes at the doses of 25, 50, and 100 mg/kg. The CsAqEx showed anti-inflammatory activity after the intraplantar injection of carrageenan, presenting a reduction in edema formation at all tested doses (12.5, 25, 50 and 100 mg/kg). The dose of 12.5 mg/kg of CsAqEx prevented edema formation after intraplantar injection of histamine. In an organ bath, 729 μg/mL of CsAqEx did not promote spasmolytic effect on isolated mice tracheal rings contracted by carbachol (CCh) or potassium chloride (KCl). We did not observe clinical signs of toxicity in the animals after acute treatment with CsAqEx, which suggested that the median lethal dose (LD 50 ) is greater than 1000 mg/kg. Repeated dose exposure to the CsAqEx did not produce significant changes in hematological, biochemical, or organ histology parameters., Conclusions: The results suggest that the anti-inflammatory effect of CsAqEx is related to the reduction of vascular extravasation and migration of inflammatory cells, without effects on the central nervous system. Moreover, there was no spasmolytic effect on airway smooth muscle and no toxicity was observed on mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Peppermint oil is well known to inhibit smooth muscle contractions, and its topical administration during colonoscopy is reported to reduce colonic spasms., Aims: We aimed to assess whether oral administration of IBGard™, a sustained-release peppermint oil formulation, before colonoscopy reduces spasms and improves adenoma detection rate (ADR).  METHODS: We performed a single-center randomized, double-blinded, placebo-controlled trial. Patients undergoing screening or surveillance colonoscopies were randomized to receive IBGard™ or placebo. The endoscopist graded spasms during insertion, inspection, and polypectomy. Bowel preparation, procedure time, and time of drug administration were documented. Statistical analysis was performed using the Student's t test and Wilcoxon rank-sum test., Results: There was no significant difference in baseline characteristics or dose-timing distribution between IBGard™ and placebo groups. Similarly, there was no difference in ADR (IBGard™ = 47.8%, placebo = 43.1%, p = 0.51), intubation spasm score (1.23 vs 1.2, p = 0.9), withdrawal spasm score (1.3 vs 1.23, p = 0.72), or polypectomy spasm score (0.52 vs 0.46, p = 0.69). Limiting the analysis to patients who received the drug more than 60 min prior to the start of the procedure did not produce any significant differences in these endpoints., Conclusions: This randomized controlled trial failed to show benefit of orally administered IBGard™ prior to colonoscopy on the presence of colonic spasms or ADR. Because of its low barrier to widespread adoption, the use of appropriately formulated and timed oral peppermint oil warrants further study to determine its efficacy in reducing colonic spasms and improving colonoscopy quality.

Objective: To assess the effectiveness of hyoscine-N-butylbromide on the duration of the first stage of labor among nulliparous women., Methods: A randomized double-blind placebo-controlled study among 126 nulliparous women admitted in the active phase of labor to a teaching hospital in Sagamu, Nigeria, from January to August 2018. Based on the inclusion criteria, women were recruited and randomized to the study or control group, and given intravenous hyoscine-N-butylbromide 20 mg (1 mL) or sterile water (1 mL), respectively, during the active phase. Labor progress and outcomes were compared between the groups., Results: The mean ± SD duration of active phase of first stage of labor was significantly shorter in the hyoscine-N-butylbromide group (324.9 ± 134.6 min) than in the control group (392.7 ± 119.6 min) (P = 0.004). The rate of cervical dilatation was 1.4 ± 0.8 cm/h in the hyoscine-N-butylbromide group and 1.0 ± 0.5 cm/h in the control group (P = 0.004). There were no significant differences in fetal heart rate, maternal vital signs, or Apgar scores between the two groups., Conclusion: Hyoscine-N-butylbromide was found to be effective in shortening the duration of the first stage of labor without adverse outcomes for mother or neonate. The trial was registered with the Pan African Clinical trials Registry (PACTR), protocol number: PACTR201808146688942 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=3532)., (© 2020 International Federation of Gynecology and Obstetrics.)

Background: Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment., Results: Atropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 μg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols., Conclusions: Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 μg/kg/24 h offers a safe alternative.

Objective: Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety., Patients and Methods: An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS)., Results: Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001)., Conclusions: These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The aim of our prospective randomized study was to assess diagnostic quality and stability of bowel distension in patients with Crohn's disease (CD) and healthy volunteers subjected to synchronous magnetic resonance enterography and colonography (MREC), as well as to test the role of water enema and intravenous spasmolytics. The influence of gastric content, age, gender, and body mass on bowel distension was also evaluated., Method: Study groups included 164 CD patients and 53 healthy volunteers. After bowel preparation, randomized subgroups started ingestion ≥1000 mL of hyperosmolar solution within 30, 45, 60, 75, and 90 min before admission to MRI, respectively. Patients were examined in prone position and water enema was applied. Spasmolytics were administered prior to I.V. gadolinium. Distension of five bowel segments was independently assessed by two experienced radiologists., Results: MREC yields diagnostic distension of the jejunum in 81.1 % and 79.2 % patients in the CD group and controls, respectively. For the terminal ileum it was >94 % in both groups. Good and excellent distension was achieved in other bowel segments. Distension was maintained up to 75 min from the start of oral ingestion. Water enema and spasmolytics significantly and independently improved distension of the small bowel. Distension of the cecum after spasmolytics was decreased. Gastric content, age, gender and body mass had no significant influence of bowel distension., Conclusions: MREC enables diagnostic distension of the colon and ileum (including terminal segment) in CD patients and healthy volunteers and diagnostically acceptable distension of the jejunum., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAF V600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (C max ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for C max , AUC inf , and AUC last of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates., (© 2020, The American College of Clinical Pharmacology.)

Background and Aims: We examined the efficacy of the combined use of L-menthol spraying (L-mentholS) as an antispasmodic agent and carbon dioxide insufflation (CO2I) on the adenoma detection rate (ADR) in a prospective, single-center trial with a 2 × 2 factorial design., Methods: We randomly assigned 611 patients scheduled to undergo colonoscopy to 4 groups: (1) the L-mentholS + CO2I (n = 153), (2) L-mentholS + air insufflation (AI; n = 156), (3) CO2I (n = 153), and (4) AI (n = 149) groups. We used 20 mL of 0.8%-L-menthol solution for the L-mentholS. The primary outcome was the difference in the ADR, and the secondary outcomes were the differences in colonic peristalsis and abdominal pain. -Results: The ADRs were not different among the groups: 1/2/3/4; 39.9%/43.6%/41.2%/51.0%. CO2I was associated with a significant decrease in the ADR (OR 0.57; 95% CI 0.35- 0.93) with a multiple logistic regression. The interaction between L-mentholS and CO2I was associated with a suppression of the decrease in the ADR. Both L-mentholS and CO2I were associated with a significant decrease in abdominal pain, and L-mentholS was associated with a significant improvement of peristalsis., Conclusions: The fact that CO2I was associated with significant decreases in the ADR was a problem. The combined use of L-mentholS and CO2I could help to suppress the decrease in the ADR., (© 2019 S. Karger AG, Basel.)

Multiparametric magnetic resonance imaging (MRI) now plays an essential role in prostate cancer diagnosis and management. The increasing use of MRI before biopsy makes obtaining images of the highest quality vital. The European Society of Urogenital Radiology (ESUR) 2012 guidelines and subsequent Prostate Imaging -Reporting Data System (PI-RADS) version 2 recommendations in 2015 address the technical considerations for optimising MRI acquisition; however, the quality of the multiparametric sequences employed depends not only on the hardware and software utilised and scanning parameters selected, but also on patient-related factors, for which current guidance is lacking. Patient preparation factors include bowel peristalsis, rectal distension, the presence of total hip replacement (THR), post-biopsy haemorrhage, and abstinence from ejaculation. New evidence has been accrued since the release of PI-RADS v2, and this review aims to explore the key issues of patient preparation and their potential to further optimise the image quality of mpMRI., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: The effect of sugammadex on consciousness is not yet fully understood. This prospective, randomized, double-blind, multicenter study was performed to compare the effects of intravenous (IV) sugammadex and neostigmine + atropine reversals on time-to-consciousness during intraoperative wake-up tests in patients undergoing spinal surgery., Subjects and Methods: A total of 66 American Society of Anesthesiologists I-II patients aged 10-25 years undergoing spinal surgery were recruited. In all patients, bispectral index (BIS), motor-evoked potential (MEP), somatosensory-evoked potentials (SSEP), and train-of-four (TOF) scores were monitored. Patients received the same total IV anesthesia protocol with a propofol-remifentanil mixture. Patients were randomly allocated into two groups. During wake-up test, when the TOF count reached 2 (T 2 ), either sugammadex 2 mg.kg -1 in group S or neostigmine 0.04 mg.kg -1 + atropine 0.01 mg.kg -1 in group N were administered. BIS 90 , SSEP 90 , MEP 90 was recorded when TOF ratio reached 90, whereas time-to-consciousness (Time cons ) was recorded when the patient responded to verbal commands., Results: BIS 90 (77.4 ± 4.7, 74.8 ± 3.7), SSEP 90 (36 ± 9.9, 29.7 ± 8.5), and MEP 90 (465.3 ± 34.8, 431.3 ± 28.2) values were significantly greater in group S than in group N (P < 0.05 for each variables). Time cons was significantly shorter with sugammadex than with the neostigmine + atropine combination (P < 0.05)., Conclusion: Using IV sugammadex 2 mg.kg -1 reversal provides faster responses to verbal commands than neostigmine-atropine combination during the intraoperative wake-up test in patients undergoing spinal surgery because the time to consciousness was significantly shorter. This difference was thought to be related with faster return of neuromuscular transmission because the TOF ratio was >0.9 well before return of consciousness in both groups., Competing Interests: None

Purpose: Post-operative pain after breast cancer surgery is a major problem and women undergoing mastectomy and breast reconstruction experience post-operative pain syndromes in approximately one-half of all cases. Patients who have undergone breast reconstruction after mastectomy can suffer from acute postoperative pain with moderate or strong tension. In some cases, chronic neuropathic pain syndromes may occur after surgery. Opioids are used to treat pain, with serious side effects. The systemic postoperative analgesic regimen as thiocochlicoside P.O. along with paracetamol and NSAIDs I.V., which may limit the administration of opioids without reducing pain relief, seems to be necessary. Materials and Methods: This study was a clinical trial randomizing 70 patients undergoing breast reconstruction. Two main protocols of systematic post-operative analgesia, one using thiocochlicoside (group A) and the other without them (group B), were used. Both groups received paracetamol X3 and lornoxicam X2 I.V. systematically. The pain measurement scale (NPS) used to measure post-operative pain. Likert scales were used to evaluate patient’s satisfaction and the difficulty from the side effects . An anonymous questionnaire was used for the data collection. Results: Statistically significant difference was found between pain on the day of surgery (p = 0.017) as well as the three subsequent days (p = 0.000). In group A , pain was reduced directly to half (Χ2 surgery pain = 93.888, p = 0.000) especially on the first post-operative day. In group A the satisfaction with analgesic treatment was higher than in group B (p = 0.002). Conclusion: The use of thiocochlicoside in post-operative analgesia in breast reconstruction after mastectomy contributes to reduce the pain intensity experienced by patients and to reduce the side effects of opioid analgesics as a result of reduced demand for opioid analgesics. Patients who received the analgesia using muscle relaxants-spasmolytic reported greater satisfaction., (Creative Commons Attribution License)

Verbena officinalis L. has a folkloric repute for the management of digestive disorders, including diarrhea. However, the safety and efficacy of the plant material has not been scientifically validated yet. This study was, therefore, aimed to evaluate the overall antidiarrheal activity of the 80% methanol extracts of V officinalis in mice. The antidiarrheal activity of the 80% methanol extracts of the roots (R-80ME) and the leaves (L-80ME) of V officinalis was tested in castor oil-induced diarrhea in mice. R-80ME was further evaluated using charcoal meal and entero-pooling. In each test, group I and group II (controls) received 10 mL/kg distilled water and standard drug (5 mg/kg loperamide), respectively, whereas groups III, IV, and V (test groups) received 100, 200, and 400 mg/kg of the 80ME, respectively. The R-80ME at 200 mg/kg ( P < .01) and 400 mg/kg ( P < .001) significantly delayed the onset of diarrhea compared with negative control. Both R-80ME and L-80ME at 200 and 400 mg/kg significantly decreased the frequency of wet fecal outputs ( P < .01). Generally, 70.24% inhibition of the number of wet fecal output was recorded at R-80ME 400 mg/kg. Results from the charcoal meal test revealed that the R-80ME at 200 ( P < .01) and 400 mg/kg ( P < .001) produced a significant antimotility effect. In entero-pooling test, the R-80ME, at 200 and 400 mg/kg doses ( P < .01), showed a significant decline in both the volume and weight of intestinal contents. The maximum in vivo antidiarrheal index was determined to be 95.25 at dose of 400 mg/kg R-80ME. This study demonstrated that the 80ME, mainly the root extract, produced promising antidiarrheal activity and hence provides a scientific support for acclaimed traditional use of the plant material for treatment of diarrheal diseases.

Context: Death rattle (DR) is a dramatic sign in the dying patient. Existing studies with anticholinergic agents are controversial, as this class of drugs has been commonly administered without considering the rationale of the mechanism of action. A meaningful use of these drugs may provide a better outcome., Objectives: The aim of this study was to assess the efficacy of hyoscine butylbromide (HB), given prophylactically in comparison with HB administered once DR occurs., Methods: Dying patients having a score of ≥3 in the Richmond Agitation-Sedation Scale-palliative version were included in the study. HB (60 mg/day) was given when DR occurred (Group 1) or as pre-emptive treatment (Group 2). The onset of DR (death rattle free time) and intensity of DR were recorded at intervals until death., Results: Eighty-one and 51 patients were randomized to Group 1 and 2, respectively. Patients in Group 2 survived longer than those in Group 1 (P < 0.05). DR occurred in 49 (60.5%) and three patients (5.9%) in Group 1 and 2, respectively (P = 0.001). A significant difference in the number of patients reporting DR was found at intervals examined (30 minutes, one hour, and then every six hours until death [P = 0.001]). In Group 1 and 2, DR free time was 20.4 (20.5) and 27.3 hours (25.2), respectively (P = 0.001). In Group 1, the treatment was considered effective in 10 patients (20.4%) only, after a mean of 14.4 hours (SD 8.57)., Conclusion: The prophylactic use of HB is an efficient method to prevent DR, whereas the late administration produces a limited response, confirming data from traditional studies performed with anticholinergics. This could be considered a new paradigm to manage a difficult and dramatic sign, such as DR., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Peppermint oil (PO) has been shown to reduce abdominal pain in patients with irritable bowel syndrome (IBS). PO is assumed to induce intestinal smooth muscle relaxation and desensitization of nociceptive nerve afferents. To increase colonic PO concentration, an ileocolonic release peppermint oil (IC-PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of the currently available small intestinal release PO (SI-PO) and the novel IC-PO., Methods: In this randomized, double-blind, crossover study, subjects received 182 mg of either SI-PO or IC-PO in a crossover design with a washout period of more than 14 days. Blood samples were collected to determine menthol glucuronide concentrations., Results: Eight healthy volunteers (50% female, median age 22) were included. The time to reach the maximum concentration (T max ) of IC-PO was significantly longer compared to SI-PO with a median (IQR) of 360 (360-405) versus 180 (120-180) min. The lag time (T lag ) was significantly longer with a median (IQR) of 225 (204-284) for IC-PO compared to 37 (6-65) min for SI-PO. The areas under the menthol glucuronide plasma concentration-time curves were significantly smaller with a median (IQR) of 2331 μg h/L (2006-2510) for IC-PO compared to 2623 μg h/L (2471-2920) for SI-PO. No significant differences were found in peak concentrations and elimination half-lives., Conclusion: IC-PO has a significantly delayed peak menthol glucuronide concentration and T lag , both pointing to the release of PO in the more distal part of the intestine. This may enhance therapeutic efficacy as it results in increased exposure of colonic mucosal afferents to the PO. A randomized controlled trial investigating the efficacy of SI and IC-PO in IBS is currently ongoing., Trial Registration: ClinicalTrials.gov identifier, NCT02291445, EudraCT database 2014-004195-32.

Abdominal pain is a common health problem that requires efficacious and safe therapy. Broccoli is a rich source of health-promoting bioactive compounds with potential for pain therapy. However, there is a lack of scientific pharmacological evidence to support this. Our aim was to investigate the antinociceptive and spasmolytic activities of broccoli aqueous extracts from seeds, sprouts, and inflorescence, as well as some metabolites. Experiments were done using enteral and parenteral administration in an in vivo model of pain accompanied with an in vitro assay. Data established that sprouts (100 mg/kg, i.p. and 1000 mg/kg, p.o.) produced significant and major antinociceptive effect at similar or even lower doses in comparison to the seeds (125 mg/kg, i.p. and 1000 mg/kg, p.o.) and broccoli heads (250 mg/kg, i.p. and 1000 mg/kg, p.o.). These results resembled the analgesic response observed with the reference drug metamizole (80 mg/kg, i.p.). Chlorogenic acid (CA, 3, 10, 30, and 100 mg/kg, i.p.) and SFN (0.1, 1 and 10 mg/kg, i.p.) were partial responsible antinociceptive metabolites of broccoli. SFN effects involved participation of endogenous opioids, since they were inhibited in the presence of naltrexone (5 mg/kg, s.c.). In the in vitro assay, a significant 80% spasmolytic-like response was reached with SFN alone in comparison to 20% obtained with aqueous extracts of sprouts and seeds. Participation of calcium channels was a mechanism involved in the in vitro response of SFN. In conclusion, broccoli sprouts, SFN and CA are potential nutraceuticals for abdominal pain therapy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Essential oils of herbal origin are widely used in the treatment of diseases of the upper and lower respiratory tract primarily due to their antibacterial and antiviral effects. Menthol, the major component of the essential oil of mint (Mentha) species, exhibits antispasmodic activity, which might result in improved lung function. In a randomized experiment, 106 healthy participants received nebulized peppermint, eucalyptus, or rosemary essential oil for 15 min or no treatment (control). None of the essential oils had an impact on the measured spirometric variables (forced vital capacity, peak expiratory flow, the ratio of the volume of air forcibly blown out in the first second to forced vital capacity). Participants' expectations regarding the effects of essential oils did not affect their objective performance, however, they predicted perceived (subjective) changes. Perceived and measured changes were not connected with each other. In conclusion, inhaled rosemary, peppermint, and eucalyptus essential oils' subjective (perceived) effect on spirometry is mediated at least partly by expectations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To assess the effectiveness of mebeverine 200 mg BID in patients with post-cholecystectomy gastrointestinal spasm not requiring surgical treatment., Materials and Methods: 218 patients were included in 16 clinical centers in 14 cities in Russia. All patients had post-cholecystectomy gastrointestinal spasms, not requiring surgical treatment and received mebeverine (Duspatalin®) 200 mg BID. The observational assessment period lasted from the moment of their inclusion into the study up to 6 weeks post inlusion. The therapy results were evaluated using visual analog scales (GPA and 11-point numeric rating scale) by patient self-assessment of the dynamics of spasm/discomfort and other post-cholecystectomic gastrointestinal symptoms after 2 and 6 weeks of treatment. Gastrointestinal Quality of Life Index (GIQLI) was used to assess patient quality of life., Results: All 218 patients completed the 2-week mebeverine treatment course, 101 of them finished the 6-week course ("prolonged population"). Significant positive changes in the relief of abdominal pain and dyspepsia were noted as well as normalization of stool frequency and consistency. A more marked change in values was observed during prolonged (up to 6 weeks) therapy. Both 2-week and 6-week mebeverine courses led to a normalization of patient quality of life. After 6 week therapy, an effect of mebeverine on the quality of life 91% of patients was observed comparable to cholecystectomy itself, speficially related to the quality of life subscore 'symptoms'., Conclusion: The results of our study demonstrate that mebeverine (Duspatalin®) therapy leads to an effective elimination of clinical symptoms associated with post-cholecystectomy GI-spasm disorders, like abdominal pain, symptoms of dyspepsia and stooldisorders. A more marked change in values was observed during prolonged (up to 6 weeks) therapy.

Importance: Gait impairments are common in patients with chronic supratentorial upper motor neuron lesions and are a source of disability. Clinical management aimed at improving the gait pattern in these patients is generally perceived as a challenging task because many possible abnormalities may interact. Moreover, a multitude of treatment options exist, ranging from assistive devices and muscle stretching to pharmacologic and surgical interventions, but evidence is inconclusive for most approaches and clear treatment guidelines are lacking., Observations: Gait deviations in adults with a chronic supratentorial upper motor neuron lesion can approximately be reduced to the following 3 groups of primary deficits: (1) imbalance of muscle strength, length, and activity around the ankle and tarsal joints leading to pes equinovarus or pes equinus; (2) calf muscle weakness; and (3) overactivity of proximal leg muscles., Conclusions and Relevance: A stepwise treatment algorithm emphasizes medical-technical interventions, which are based on evidence when available and otherwise reflect practice-based experience.

Background: Endoscopic inspection of colonic mucosa is disturbed by colonic folds and peristalsis, which may result in missed polyps. Cimetropium bromide, an antispasmodic agent, inhibits peristalsis and colonic spasms, which may improve polyp detection. The purpose of this randomized, double-blind, placebo-controlled study was to investigate whether cimetropium bromide could improve polyp and adenoma detection in the colorectum and right colon., Methods: Patients undergoing screening or diagnostic colonoscopy were randomized to receive intravenous cimetropium bromide (5 mg) or placebo after cecal intubation. The primary outcomes were the number of polyps per patient (PPP) and adenomas per patient (APP); secondary outcomes were the polyp detection rate (PDR), adenoma detection rate (ADR), and advanced neoplasm detection rate (ANDR)., Results: A total of 181 patients were analyzed; 91 patients received cimetropium bromide and 90 patients received placebo. Cimetropium bromide and placebo groups did not significantly differ in the PPP and APP for the colorectum (1.38 ± 1.58 vs 1.69 ± 2.28, P = .298; 0.96 ± 1.27 vs 1.11 ± 1.89, P = .517, respectively) and right colon (0.70 ± 0.95 vs 0.78 ± 1.21, P = .645; 0.47 ± 0.81 vs 0.51 ± 0.81, P = .757, respectively). Two groups also did not significantly differ in the PDR, ADR, and ANDR for the colorectum and right colon. Furthermore, there were no difference between groups in the PPP, APP, PDR, ADR, and ADNR in a sub-analysis of expert and non-expert endoscopists., Conclusions: Cimetropium bromide did not improve polyp and adenoma detection in the colorectum and right colon during colonoscope withdrawal, regardless of the expertness of the endoscopist. However, its use may be helpful in patients with active peristalsis or for beginning endoscopists during standard colonoscopy without a transparent cap.

Coronary vasospasm can result from silent myocardial ischaemia to sudden death. There are many precipitant factors including different pharmacological agents. Kounis syndrome is defined by acute coronary syndromes associated with anaphylactic or anaphylactoid reactions. We report, to the best of our knowledge, the first paediatric case of Kounis syndrome due to intravenous atropine.

Background/objectives: There are no reliably effective, well-tolerated topical agents for the treatment of hyperhidrosis. We sought to evaluate the efficacy and tolerability of oxybutynin 3% gel in adolescents and young adults with primary focal hyperhidrosis., Methods: Patients with severe axillary hyperhidrosis were treated with topical oxybutynin 3% gel for 4 weeks. Response to treatment was assessed by calculating change in Hyperhidrosis Disease Severity Score from baseline to weeks 1 and 4. Change in health-related quality of life was assessed using the Children's Dermatology Life Quality Index or the Dermatology Life Quality Index. Adverse effects were evaluated using patient diaries, investigator global review, and physical examination., Results: Of 10 patients aged 13-24 enrolled, seven completed the study. Of those who completed the study, four (57.1%) reported reduction in axillary Hyperhidrosis Disease Severity Score at week 1 and all seven (100%) at week 4. Six patients (85.7%) reported reduction in Children's Dermatology Life Quality Index or Dermatology Life Quality Index score. Anticholinergic adverse effects were infrequent. The majority of treatment-related adverse events were mild to moderate in severity. One patient experienced a severe adverse event., Conclusion: Oxybutynin 3% gel reduced hyperhidrosis severity and improved health-related quality of life in this small pilot study. Safety and efficacy should be further evaluated in a large, prospective, placebo-controlled study., (© 2018 Wiley Periodicals, Inc.)

Aim: To evaluate the effect of adding low dose trospium chloride with transcutaneous posterior tibial nerve stimulation (TPTNS) in the treatment of overactive bladder (OAB) in females after failure of behavioral therapy., Methods: We randomized 30 women with OAB, in two groups: G I received 30 min TPTNS, three times a week; GII received TPTNS plus 20 mg trospium chloride daily. OAB Symptom Score questionnaire (OABSS), Incontinence Impact Questionnaire-short form 7 (IIQ-7), 3 day voiding diary and urodynamics at weeks 0 and 8 were evaluated., Results: The groups were similar before treatment. Eight weeks after treatment, the mean OABSS decreased significantly to 8.53 ± 1.30 for group II vs 10.0 ± 2.0 for GI (P < 0.024). The mean IIQ-7 score decreased significantly to 51.86 ± 17.26 in group I vs 31.99 ± 9.26 in group II (P < 0.001). Before treatment, 11 (73.3%) and 4 (26.7%) patients in each group had moderate and poor quality of life (QoL), respectively. After treatment, 6 (40%) and 14 (93.3%) had good QoL, 7 (46.7%) and 1 (6.7%) had moderate QoL in GI and GII, respectively. Two (13.3%) patients in GI had poor QoL. The mean frequency was reduced to 8.60 ± 0.83 vs 10.60 ± 2.32 for GII and GI respectively (P = 0.006). The cystometric capacity increased from 263.40 ± 50.45 to 377.80 ± 112.92 mL (P = 0.001) for GII vs 250.13 ± 56.24 to 296.40 ± 99.0 mL (P = 0.026) for GI., Conclusion: TPTNS combined with low dose trospium chloride proved to be more effective than TPTNS alone in the treatment of OAB in females., (© 2017 Wiley Periodicals, Inc.)

Ethnopharmacology Relevance: Blepharocalyx salicifolius (Kunth) O. Berg (Myrtaceae) is a tree native to Argentina and Uruguay that grows and is cultivated along the riverside of the Rio de la Plata. The leaves of this plant species, locally known as "anacahuita" are used in South America to prepare infusions for the empiric treatment of cough and bronchospasm, as well as diarrhoea and other intestinal disorders. Although previous phytochemical studies have been performed with the essential oil extracted from Blepharocalyx salicifolius, pharmacological evidence supporting its traditional use is still lacking., Aim of the Study: To experimentally evaluate the pharmacological properties of Blepharocalyx salicifolius based on its traditional use. The studies were performed with tincture (T-Bs) and essential oil (EO-Bs) prepared from its leaves, in isolated rat trachea, intestine and heart preparations., Methods: The ex-vivo effects of T-Bs and EO-Bs were evaluated with the agonists carbachol (CCh) and calcium chloride (Ca 2+ ) in the contractile concentration-response curves (CRC) of the isolated intestine. The muscle relaxant effect of EO-Bs was evaluated in the isolated trachea and compared with the effect achieved with papaverine as a positive control. The T-Bs and EO-Bs cardiac effects were analysed by perfusion of an isolated rat heart before a period of ischemia/reperfusion (stunning model). The antitussive effect of both T-Bs and EO-Bs was evaluated in mice exposed to ammonia using codeine as a positive control., Results: Both T-Bs and EO-Bs induced a non-competitive inhibition of the CCh-CRC in the rat intestine, with IC 50 values of 170.3 ± 48.5µg T-Bs/mL (n = 6) and 5.9 ± 1.6µg EO-Bs/mL (n = 6), respectively. EO-Bs also inhibited non-competitively the Ca 2+ -CRC, with IC 50 value of 1.8 ± 0.3µg EO-Bs/mL (n = 8). A similar effect was obtained with the main active component of the EO-Bs 1,8-cineole. In isolated trachea, EO-Bs induced the relaxation of the CCh-contracted tissue (1.7 ± 0.2µg EO-Bs/mL, n = 11) up to a maximal relaxation that was 1.9 times higher than that of papaverine. In the isolated heart, EO-Bs induced a poor negative inotropic response, and did not improve the contractile and energetic recovery after ischemia and reperfusion. In the mouse cough model, EO-Bs (90mg/Kg) was as effective as codeine (30mg/Kg) in reducing cough frequency., Conclusions: The results indicate that the preparations from Blepharocalyx salicifolius leaves were effective as central antitussive, bronchodilating and antispasmodic agents, suggestive of a mechanism associated with the inhibition of Ca 2+ influx into smooth muscle. The EO-Bs displayed only a poor ability to reduce cardiac inotropism, and was devoid of any cardioprotective properties. Thus, the present study validates the traditional use of this South American plant for asthma, cough and bronchospasm, shedding new light into its potency and putative mechanism of action., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To prospectively evaluate the effect of hyoscine butylbromide (HBB) on visualisation of anatomical details and motion-related artefacts in mp-MRI of the prostate at 3.0 Tesla., Methods: One hundred and three consecutive patients (65 ± 10 years) were included in this trial, powered to demonstrate an improvement of image quality after HBB administration, assessed on a 5-point scale by two blinded readers. All patients received high-spatial resolution axial T2-weighted TSE sequences at 3.0 T without spasmolytic agent, repeated after application of 40 mg HBB and followed by routine mp-MRI. Secondary endpoints were (1) susceptibility to side effects, (2) dependence of spasmolytic effect on patients´ weight, and (3) prostate volume., Results: In 68% of patients, HBB significantly improved the anatomic score (mean 3.4 ± 0.9 before and 4.4 ± 0.7 after HBB for both readers, p = <0.001). In 67%, HBB significantly enhanced the artefact score (mean 3.2 ± 1 before and 4.2 ± 0.8 after HBB for reader 1, p = <0.001; 3.2 ± 1 and 4.1 ± 0.8 for reader 2, p = <0.001). Subgroup analysis revealed no statistically significant difference between patients with different bodyweight or prostate volume. Inter-reader agreement was excellent (k = 0.95-0.98)., Conclusions: Hyoscine butylbromide significantly improves image quality and reduces motion-related artefacts in mp-MRI of the prostate independent of bodyweight or prostate volume. No side effects were reported., Key Points: • Hyoscine butylbromide (HBB) improved image quality in over 2/3 of patients. • Severe artefacts were reduced after HBB in more than 20%. • The number of non-diagnostic MRI was reduced to <1% after HBB. • HBB effect was independent of bodyweight and prostate volume. • No side effects of HBB were reported in this study population.

Objective: To determine whether antispasmodic medications are associated with neurological and functional outcomes during the first year after traumatic spinal cord injury (SCI)., Design/methods: Retrospective analysis of prospectively collected data from six inpatient SCI rehabilitation centers. Baseline-adjusted outcomes at discharge and one-year follow-up were compared using analysis of covariance between patients who received antispasmodic medication on at least 5 days during inpatient rehabilitation and patients who did not., Outcome Measures: Rasch-transformed motor subscore of the Functional Independence Measure (FIM); International Standards for Neurological Classification of Spinal Cord Injury motor scores, grade, and level., Results: Of 1,259 patients, 59.8%, 35.4%, and 4.8% were injured at the cervical, thoracic, and lumbosacral levels, respectively. 65.6% had motor complete injury. Rasch-transformed motor FIM score at admission averaged 23.3 (95% confidence interval (CI) 22.4-24.2). Total motor score averaged 39.2 (95% CI 37.8-40.6). 685 patients (54.4%) received one or more antispasmodic medications on at least 5 days. After controlling for demographic and injury variables at admission, Rasch-transformed motor FIM scores at discharge were significantly lower (P = 0.018) in patients receiving antispasmodic medications than in those who did not. This trend persisted in secondary analyses for cervical, thoracic, and lumbosacral subgroups. Multivariate regression showed that receiving antispasmodic medication significantly contributed to discharge motor FIM outcome. At one-year follow-up, no outcomes significantly differed between patients ON or OFF antispasmodics., Conclusions: Antispasmodic medications may be associated with decreased functional recovery at discharge from inpatient traumatic SCI rehabilitation. Randomized prospective studies are needed to directly evaluate the effects of antispasmodic medication on recovery.

Objective: In this study, the aim was to investigate the effect of hyoscine N-butylbromide (HnBB) pretreatment on pain during propofol injection., Subjects and Methods: In this prospective, randomized, placebo-controlled and double-blind trial, 60 patients scheduled to undergo routine outpatient surgery under general anesthesia were randomly allocated to 2 groups, the HnBB (n = 30) and sodium chloride (n = 30) groups. Twenty seconds after the injection of 20 mg HnBB or 0.9 % sodium chloride, a 50-mg dose of propofol was injected in 2-3 s. Ten seconds later, the pain intensity was assessed using a 4-point scale: no pain (0), mild (1), moderate (2), and severe (3) pain. The Student t test was used for the analysis of parametric data and the Pearson χ2 test for categorical data., Results: The occurrence of pain in the HnBB group (43.3%) was significantly lower than the control group (73.3%) (p < 0.018). Of the 30 patients in each group, 10 in the control group and 3 in the HnBB group experienced severe pain (p = 0.001)., Conclusions: Pretreatment with 20 mg HnBB significantly reduced propofol injection pain compared to placebo., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background and Study Aims: Colonoscopy is the cornerstone of diagnosing colonic diseases. Investigators have evaluated the effectiveness of antispasmodic agents in colonoscopy with conflicting evidence. The aim of this study is to determine the efficacy of enteric coated peppermint oil capsules (Colpermin®), an antispasmodic agent, on outcomes during colonoscopy., Patients and Methods: A total of 80 patients undergoing elective colonoscopy were recruited and randomized in a double blinded fashion to receive either placebo or peppermint oil capsules administered 4 h prior to the procedure., Results: Peppermint oil capsules did not affect caecal intubation time when compared with placebo. Patients' tolerance, endoscopist's satisfaction and demand on sedation were also not affected., Conclusion: This randomized controlled trial does not support the routine use of peppermint oil capsules prior to colonoscopy as a tool for procedure optimization, and patients' and endoscopist's satisfaction., (Copyright © 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Objective: Hyoscine butyl bromide (HBB) is known for its antispasmodic action and has been in use for over five decades, there is however no consensus on its effectiveness in the labor process. The aim of this study was to determine the effect of HBB on the duration of the active phase of labor., Materials and Methods: A randomized double-blind placebo-controlled clinical trial involving 160 parturient who received either intravenous Hyoscine butyl-bromide (20 mg in 1 ml; n = 80) or intravenous normal saline (1 ml, n = 80). The mean duration of active phase of labor was compared between the two groups., Results: The observed mean duration of the active phase of labor was significantly shorter (P = 0.001) in the Hyoscine butyl-bromide group (365.11 ± 37.32 min, range = 280-490) than in the Placebo group (388.46 ± 51.65 min, range = 280-525). There was no significant difference between the two groups in the mean duration of the second and third stages of labor (20.46 ± 10.46 vs. 23.38 ± 18.95 min, P = 0.43 and 8.96 ± 4.34 vs. 9.23 ± 5.92 min, P = 0.75, respectively). The mean 1-min APGAR scores were also comparable (8.08 ± 1.54 vs. 7.64 ± 1.60, P = 0.08). The mean postpartum blood loss was significantly less in the Hyoscine butyl-bromide group (303 ± 96.52 vs. 368 ± 264.19 ml, P = 0.04)., Conclusion: Hyoscine butyl-bromide was effective in shortening the duration of the active phase of labor. It was also associated with significantly less postpartum blood loss., (Copyright © 2017. Published by Elsevier B.V.)

Licorice derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch . (Fabaceae), is one of the most widely-used traditional herbal medicines in China. It has been reported to possess significant analgesic activity for treating spastic pain. The aim of this study is to investigate the spasmolytic molecular mechanism of licorice on oxytocin-induced uterine contractions and predict the relevant bioactive constituents in the aqueous extract. The aqueous extraction from licorice inhibited the amplitude and frequency of uterine contraction in a concentration-dependent manner. A morphological examination showed that myometrial smooth muscle cells of oxytocin-stimulated group were oval-shaped and arranged irregularly, while those with a single centrally located nucleus of control and licorice-treated groups were fusiform and arranged orderly. The percentage of phosphorylation of HSP27 at Ser-15 residue increased up to 50.33% at 60 min after oxytocin stimulation. Furthermore, this increase was significantly suppressed by licorice treatment at the concentration of 0.2 and 0.4 mg/mL. Colocalization between HSP27 and α-SMA was observed in the myometrial tissues, especially along the actin bundles in the oxytocin-stimulated group. On the contrary, the colocalization was no longer shown after treatment with licorice. Additionally, employing ChemGPS-NP provided support for a preliminary assignment of liquiritigenin and isoliquiritigenin as protein kinase C (PKC) inhibitors in addition to liquiritigenin, isoliquiritigenin, liquiritin and isoliquiritin as MAPK-activated protein kinase 2 (MK2) inhibitors. These assigned compounds were docked with corresponding crystal structures of respective proteins with negative and low binding energy, which indicated a high affinity and tight binding capacity for the active site of the kinases. These results suggest that licorice exerts its spasmolytic effect through inhibiting the phosphorylation of HSP27 to alter the interaction between HSP27 and actin. Furthermore, our results provide support for the prediction that potential bioactive constituents from aqueous licorice extract inhibit the relevant up-stream kinases that phosphorylate HSP27., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Upper limb spasticity is a common complication following stroke. Cohort studies found 19% of post-stroke patients had upper limb spasticity at 3 months and 38% of patients at 12 months. For focal spasticity, intramuscular injections of botulinum toxin are indicated. In Germany, it is assumed that patients with the described indication are undersupplied with botulinum toxin., Objective: The aim of the present study is to evaluate the medical care of patients with upper limb spasticity post-stroke with the focus on the use of botulinum toxin as one treatment option., Methods: A standardized questionnaire was developed and a postal survey of a representative national random sample of 800 neurologists to capture the actual medical care situation., Results: The response rate amounted to 37% (n = 292). 59% of the neurologists surveyed had never used botulinum toxin. In total, 87% of neurologists noticed barriers regarding the use of botulinum toxin, where the amount of the doctor's remuneration in 40% and the lack of reimbursement of costs in off-label use in 60% were the most commonly used answers. The achievement of an advanced training in using botulinum toxin was also stated as a general obstacle for resident neurologists., Discussion: Due to a response rate of 37% for the postal survey a selection bias cannot be excluded. Although botulinum toxin is recommended in the national treatment guidelines, many neurologists do not use botulinum toxin. The reasons can be seen from the barriers described.

Background: COPD exacerbations are associated with accelerated lung function decline, but whether they are causal is unknown. We evaluated the effect of a single exacerbation on rate of lung function change using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT ® ) trial., Methods: Retrospective analysis of annual rates of decline in FEV 1 and FVC before and after a single (and the only) moderate-to-severe exacerbation in patients during UPLIFT ® (exacerbator subgroup), compared with changes between the first and second half of the study in a non-exacerbator subgroup. A sensitivity analysis examined annual rates of decline in matched pairs of exacerbators and non-exacerbators., Results: Following the single moderate-to-severe exacerbation, mean annual decline in post-bronchodilator lung function increased compared with the rate of decline before the exacerbation (FEV 1 76.5 vs. 39.1 mL/year, p = 0.003; FVC 106.5 vs. 34.7 mL/year, p = 0.011). In non-exacerbators, there were no differences in rates of decline between the first and second halves of the study (post-bronchodilator FEV 1 38.2 vs. 41.8 mL/year, FVC 45.3 vs. 43.9 mL/year. Before the single (moderate-to-severe) exacerbation in the exacerbator subgroup, declines in post-bronchodilator FEV 1 or FVC were similar to non-exacerbators in the first half of the study; after the single exacerbation they were significantly higher than for non-exacerbators in the second half of the study. The sensitivity analysis showed similar results., Conclusion: A single COPD exacerbation may result in significant increase in the rate of decline in lung function., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Proper adaptation of ventricular repolarization (VR) to rapid heart rate (HR) increase is crucial for cardiac electro-mechanical function. The pattern and temporal aspects of this adaptation and its components (duration and dispersion) during normal conduction are, however, incompletely known in humans and were the topic of this study., Methods & Results: The VR duration (QT & QTpeak) and dispersion (Tamplitude, Tarea & ventricular gradient; VG) responses were studied by continuous vectorcardiogram after a bolus injection of atropine 0.04mg/kg b.w. in 31 healthy young adults (16 men). The primary measure (T90 End) was the time to reach 90% change from baseline to end value 300s later. Mean (SD) of T90 End was 23 (9) s for a 41% RR decrease, 130 (35) s for a 16% QTend decrease and 110 (36) s for a 19% QTpeak decrease; the response was single-exponential for these measures. For 35-43% decreases of Tamplitude, Tarea & VG, mean (SD) of T90 End were 21 (10), 38 (20) and 40 (23) s and the response pattern was double-exponential with varying overshoot., Conclusions: VR duration and dispersion responses to a very rapid HR increase during normal conduction differed substantially. In contrast to the well-known single-exponential delay in VR duration adaptation the responses of VR dispersion measures were double-exponential and much more rapid. We describe a new and completely non-invasive phenotypic characterization of different components of VR adaptation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To prospectively investigate how Buscopan affects the diagnosis of bowel inflammation by diffusion-weighted imaging MR enterography (DWI-MRE) in Crohn's disease (CD)., Methods: Thirty CD patients without previous bowel surgery underwent DWI-MRE (b = 900 sec/mm 2 ) before and after intravenous Buscopan. The 30 patients were randomly divided into two groups; using a crossover design, interpretations were made regarding the presence of restricted mural diffusion (i.e., bowel inflammation) in nine bowel segments in two separate reading sessions by two readers. The readers also judged restricted mural diffusion extent in each bowel segment on two side-by-side DWI-MRE images with a random right-to-left order. Ileocolonoscopy and conventional MRE interpreted by an expert panel were reference standards., Results: We analyzed 262 bowel segments. DWI-MRE without Buscopan significantly decreased sensitivity for both readers (58.8 % vs. 72.9 %, P = 0.046; 57.6 % vs. 85.9 %, P = 0.001) and did not significantly increase specificity (P = 0.085 and 0.396). Two readers noted that 28.6 % and 23.3 % of 262 bowel segments had greater diffusion restriction extent on DWI-MRE with Buscopan compared with DWI-MRE without Buscopan (P < 0.001) and 68.7 % and 74 %, respectively, had similar extent between them., Conclusion: Omitting Buscopan caused a greater loss in sensitivity of DWI-MRE than false-positive reduction for diagnosing bowel inflammation in CD., Key Points: • Omitting Buscopan significantly decreases DWI-MRE sensitivity for diagnosing bowel inflammation in CD. • Increase in the corresponding DWI-MRE specificity by omitting Buscopan is less apparent. • DWI-MRE without Buscopan underestimates the extent of bowel inflammation in CD.

Oral baclofen has long been a mainstay in the management of spasticity. This review looks at the clinical evidence for the efficacy and safety of oral baclofen in patients with spasticity of any origin or severity, to determine whether there is a rationale for the use of intrathecal baclofen. Results suggest that oral baclofen may be effective in many patients with spasticity, regardless of the underlying disease or severity, and that it is at least comparable with other antispasmodic agents. However, adverse effects, such as muscle weakness, nausea, somnolence and paraesthesia, are common with oral baclofen, affecting between 25% and 75% of patients, and limiting its usefulness. Intrathecal baclofen may be an effective alternative as the drug is delivered directly into the cerebrospinal fluid, thus bypassing the blood-brain barrier and thereby optimizing the efficacy of baclofen while minimizing drug-related side-effects. Intrathecal baclofen is a viable option in patients who experience intolerable side-effects or who fail to respond to the maximum recommended dose of oral baclofen.

Irritable bowel syndrome (IBS) is heterogeneous. Patients need proper assessment and explanation of IBS pathophysiology and appropriate therapies. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet effectively reduces symptoms in 75% of patients. Best treatment for those nonresponsive will depend on the pathophysiological basis for symptom genesis, with the following possible abnormalities: (i) Visceral hypersensitivity and/or enhanced gut-brain communication: a low FODMAP diet is mainly targeted for this patient group. A dietitian may also recommend antispasmodic agents, including peppermint oil. Another dietary treatment is a low food chemical diet, although this diet is often extremely limited, and therefore, not suited for some populations. Psychological therapies are also clinically beneficial. (ii) Altered motility: in patients with fast transit, a dietitian may recommend a reduction in all FODMAPs or targeted monosaccharides and disaccharides, which are more osmotic in nature. If not effective, patients may benefit from psyllium, which has an exceptional water-holding capacity aimed to promote more formed stools. Patients with slow or uncoordinated transit are often more difficult to treat. Dietary interventions have some success and usually comprise a combination of adequate fiber and fluid, osmotic laxatives, and stimulating agents such as caffeine, senna, and exercise. (iii) Altered microbiome: supplementary probiotics and prebiotics have weak evidence of efficacy with some notable exceptions. A dietitian may trial supplementary Bifidobacterium infantis or oligosaccharides, usually as an adjunct therapy. Guidance from a dietitian will encompass dietary methods to treat IBS but additionally identify where dietary treatment is not indicated to ensure that diet is correctly used and patients are not nutritionally or psychologically compromised., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background  Abdominal pain, cramping, and discomfort (APCD) are experienced by up to 30 % of adults in Europe. Objective  To assess the impact of APCD on quality of life (QoL) and to investigate the effectiveness, tolerability, and impact on QoL of hyoscine butylbromide (HBB, Buscopan ® ) compared with STW 5 (Iberogast ® ) or analgesics in women with APCD. Methods  An internet-based observational pilot study was conducted in Germany in women who had predominantly used HBB, STW 5, or analgesics (n = 240 per treatment) to treat APCD. This online survey included questions on QoL, effectiveness, and tolerability. Results  A total of 720 completed questionnaires was evaluated. APCD had a major impact on QoL, with 96 % of women reporting that daily activities were disrupted at least sometimes, and 44 % at least often. Other aspects of QoL, such as quality of work, eating habits, and social activities, were also affected in most women. After taking their medication of choice, 91 % of women in the HBB group reported they could "very often" or "often" continue with their daily activities, compared with 84 % and 85 % in the STW 5 and analgesic groups, respectively (p < 0.05 for both comparisons). HBB was perceived to be the "best solution" to overcome APCD symptoms "very often" or "often" by more women (86 %) than STW 5 (75 %) and analgesics (74 %) (p < 0.05 for both comparisons). Conclusion  Women with APCD have impaired QoL. All treatments were considered effective by the majority of participants. Compared with STW 5 or analgesics, HBB was reported to facilitate return to daily activities more frequently., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To investigate whether the use of a belladonna and opium (B&O) rectal suppository administered immediately before ureteroscopy (URS) and stent placement could reduce stent-related discomfort., Methods: A randomized, double-blinded, placebo-controlled study was performed from August 2013 to December 2014. Seventy-one subjects were enrolled and randomized to receive a B&O (15 mg/30 mg) or a placebo suppository after induction of general anesthesia immediately before URS and stent placement. Baseline urinary symptoms were assessed using the American Urological Association Symptom Score (AUASS). The Ureteral Stent Symptom Questionnaire and AUASS were completed on postoperative days (POD) 1, 3, and after stent removal. Analgesic use intraoperatively, in the recovery unit, and at home was recorded., Results: Of the 71 subjects, 65 had treatment for ureteral (41%) and renal (61%) calculi, 4 for renal urothelial carcinoma, and 2 were excluded for no stent placed. By POD3, the B&O group reported a higher mean global quality of life (QOL) score (P = .04), a better mean quality of work score (P = .05), and less pain with urination (P = .03). The B&O group reported an improved AUASS QOL when comparing POD1 with post-stent removal (P = .04). There was no difference in analgesic use among groups (P = .67). There were no episodes of urinary retention. Age was associated with unplanned emergency visits (P <.00) and "high-pain" measure (P = .02) CONCLUSION: B&O suppository administered preoperatively improved QOL measures and reduced urinary-related pain after URS with stent. Younger age was associated with severe stent pain and unplanned hospital visits., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Drooling can be a severe disability and have high impact on daily life. Reversible treatment is preferable., Aim: To analyse whether sublingual administration of atropine eyedrops is a useful reversible treatment option for severe drooling in children with disabilities., Design: The study had a prospective, single-system research design. The participants served as their own controls. The study period was 3 weeks without treatment, 4 weeks with atropine eyedrop solution 10 mg/mL one drop a day followed by 4 weeks of one drop twice a day. Parents' rating of their child's drooling was assessed on a 100-mm VAS, and unstimulated salivary secretion rate measurement was performed together with notations about side effects and practicality., Results: Parents' VAS assessment of drooling decreased from a median (range) of 74 (40-98) at baseline to 48 (18-88) (P = 0.05) and 32 (12-85) (P = 0.004) after 4 weeks of atropine once a day and another 4 weeks of atropine twice a day, respectively (n = 11). Unstimulated salivary secretion rates decreased from baseline to end of study (P = 0.032). Several parents complained about difficult administration. No irreversible side effects were noted., Conclusions: Sublingual atropine eyedrops may be an alternative for treatment of severe drooling in children with disabilities., (© 2015 The Authors. International Journal of Paediatric Dentistry published by BSPD, IAPD and John Wiley & Sons Ltd.)

Introduction: Adenoma detection rate (ADR) is the most robust colonoscopy quality metric and clinical studies have adopted it as the ideal method to assess the impact of technical interventions. Areas covered: We reviewed papers focusing on the impact of colonoscopy technical issues on ADR, including withdrawal time and technique, second evaluation of the right colon, patient positional changes, gastrointestinal assistant participation during colonoscopy, water-aided technique, optimization of bowel preparation and antispasmodic administration. Expert commentary: Overall, technical interventions are inexpensive, available worldwide and easy to implement. Some of them, such as the adoption of split dose regimen and slow scope withdrawal to allow a careful inspection, have been demonstrated to significantly improve ADR. Emerging data support the use of water-exchange colonoscopy. According to published studies, other technical interventions seem to provide only marginal benefit to ADR. Unfortunately, the available evidence has methodological limitations, such as small sample sizes, the inclusion of expert endoscopists only and the evaluation of single technical interventions. Additionally, larger studies are needed to clarify whether these interventions might have a higher benefit on low adenoma detectors and whether the implementation of a bundle of them, instead of a single technical maneuver, might have a greater impact on ADR.

Ethnopharmacological Relevance: Morinda citrifolia L. (Noni) is a medicinal plant used in Polynesia for many properties such as anti-inflammatory, anti-diabetic and antineoplastic effects. Recent studies showed that noni juice have anti-oxidant and acute anti-inflammatory activities likely due to polyphenols, iridoids and vitamin C content. The present study was undertaken to evaluate chronic anti-inflammatory and spasmolytic effects of noni juice., Materials and Methods: Therefore, we evaluated the effect of oral or intraperitoneal administrations of noni juice in vivo on the lung inflammation in ovalbumin (OVA) sensitized Brown Norway rat (with prednisolone 10mg/kg intraperitoneously as reference compound) and the ex vivo effect of noni juice on BaCl 2 (calcium signal) or methacholine (cholinergic signal) induced spasms in jejunum segments., Results: We found that noni juice (intraperitoneously 2.17mL/kg and orally 4.55mL/kg) reduced the inflammation in OVA-sensitized Brown Norway rat with regard to the decreased number of inflammatory cells in lung (macrophages minus 20-26%, lymphocytes minus 58-34%, eosinophils minus 53-30%, neutrophils minus 70-28% respectively). Noni juice demonstrated a dose-dependent NO scavenging effect up to 8.1nmol of nitrites for 50µL of noni juice. In addition noni juice inhibited (up to 90%) calcium and cholinergic induced spasms on the jejunum segments model with a rightward shift of the concentration response curve., Conclusion: We describe for the first time that noni juice demonstrate (1) a chronic anti-inflammatory activity on sensitized lungs along with (2) a spasmolytic effect integrating a calcium channel blocker activity component., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Prostaglandin analogs induce miosis and lower intraocular pressure (IOP). As pupils of latanoprost-treated eyes may have to be dilated for ophthalmoscopy or intraocular surgery, we studied whether 0.5% tropicamide or 1% atropine alter the effects of 0.005% latanoprost on pupil diameter (PD) and IOP in healthy dogs., Methods: IOP and PD were measured hourly, 8 AM-4 PM, with the right and left eyes serving as control (CE) and treated (TE) eyes, respectively. Measurements were conducted in ten Labrador retrievers with one-week washout: (i) baseline values, (ii) latanoprost at 8 AM, (iii) tropicamide at 8 AM, (iv) latanoprost at 8 AM and tropicamide at 11 AM, and (v) latanoprost at 8 AM and atropine at 11 AM (n = 4)., Results: At 4 PM, TE PD was 5.88 ± 0.59, 3.62 ± 0.66, 6.33 ± 1.00, 5.42 ± 0.57, and 8.12 ± 1.24 mm in sessions 1-5, respectively. TE PD was significantly different between treatment sessions 2, 4, and 5 (P = 0.018, Friedman), being most mydriatic in session 5. At 4 PM, TE IOP was 11.27 ± 2.07, 7.10 ± 1.07, 11.1 ± 2.21, 7.70 ± 1.85, and 8.87 ± 1.42 mm Hg in sessions 1-5, respectively, with no differences between treatment sessions 2, 4, and 5 (P = 0.105, Friedman)., Conclusions: Tropicamide and atropine counteracted latanoprost's miotic effect, with atropine causing significantly larger mydriasis, sufficient for indirect ophthalmoscopy. Neither drug counteracted the hypotensive effect of latanoprost during this study period. Further studies are necessary to evaluate the potential risks in glaucomatous dogs., (© 2015 American College of Veterinary Ophthalmologists.)

The Chrysactinia mexicana A. Gray (C. mexicana) plant is used in folk medicine to treat fever and rheumatism; it is used as a diuretic, antispasmodic; and it is used for its aphrodisiac properties. This study investigates the effects of the essential oil of C. mexicana (EOCM) on the contractility of rabbit ileum and the mechanisms of action involved. Muscle contractility studies in vitro in an organ bath to evaluate the response to EOCM were performed in the rabbit ileum. EOCM (1-100 µg·mL(-1)) reduced the amplitude and area under the curve of spontaneous contractions of the ileum. The contractions induced by carbachol 1 µM, potassium chloride (KCl) 60 mM or Bay K8644 1 µM were reduced by EOCM (30 µg·mL(-1)). Apamin 1 µM and charybdotoxin 0.01 µM decreased the inhibition induced by EOCM. The d-cAMP 1 µM decreased the inhibition induced by EOCM. l-NNA 10 µM, Rp-8-Br-PET-cGMPS 1 µM, d,l-propargylglycine 2 mM, or aminooxyacetic acid hemihydrochloride 2 mM did not modify the EOCM effect. In conclusion, EOCM induces an antispasmodic effect and could be used in the treatment of intestinal spasms or diarrhea processes. This effect would be mediated by Ca(2+), Ca(2+)-activated K⁺ channels and cAMP.

The prevalence and the incidence of Urinary Incontinence is growing. Women suffer predominantly from stress and mixed urinary incontinence and men from urge incontinence. In elderly people, the pathophysiological and the physiological change in the lower urinary tract system must be considered as well as an underlying multimorbidity. Stress urinary incontinence is among others caused by an insufficient urethral closure mechanism and urge incontinence is followed by unhibited detrusor contractions. Medical treatment is beside other important conservative options only one part of the treatment strategy in incontinence. Duloxetine, a serotonine-norepinephrine reuptake inhibitore can increase activity of the external urethral sphincter and is able to reduce incontinence episodes in up to 64 %. Antagonists of muscarinic receptors can reduce urgency, frequency and urge incontinence as well as increase bladder capacity significantly. In Germany, darifenacin, fesoterodin, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride are available to treat urge incontinence. The efficacy of these agents are almost comparable in the elderly with the exception of oxybutynin IR. However, tolerability is different and not well studied in the elderly population with the exception of fesoterodin. Side effects, especially dry mouth, dizziness and constipation often limit their use. None of the agents show ideal efficacy or tolerability in all patients. Last summer therefore a β3-agonist mirabegron was also introduced in Germany but was withdrawn.

Background: Physicians often diagnose diverticulitis and prescribe antibiotics in outpatients with abdominal pain and tenderness without other evidence., Aim: We investigated the misattribution of irritable bowel syndrome (IBS) symptoms to diverticulitis in outpatients., Methods: In patients diagnosed with diverticulitis and dispensed antibiotics in an integrated healthcare system, we retrospectively compared 15,846 outpatients managed without computed tomography (CT) versus 3750 emergency department/inpatients who had CT. We assessed demographics and past history, including 17 symptom-based somatic and 11 mental disorders and three somatic-mental comorbidity pairs (dyads) coded over 3 years and seven drug classes dispensed over 1 year before diagnosis., Results: Univariate analysis showed small intergroup demographic differences. Outpatients had increases in prior diverticulitis, including outpatient-managed episodes, total somatic diagnoses (p < .0001), eight somatic and three mental disorders (p ≤ .015), all three dyads (p ≤ .05), and dispensing of three drug classes (p ≤ .016). IBS had been diagnosed in 2399 (15.1 %) outpatients versus 361 (9.6 %) emergency department/inpatients (p < .0001), the greatest increase in any comorbidity. Emergency department/inpatients had no somatic comorbidity more often but more alcohol dependence, non-dependent drug abuse, and opioid dispensing (p ≤ .05). Regression analysis revealed outpatient care was independently positively associated with younger age, non-Hispanic white race/ethnicity, less Charlson comorbidity, diverticulitis history, IBS, chest pain, dyspepsia, fibromyalgia, low back pain, migraine, acute reaction to stress, and antispasmodic and anxiolytic dispensing and negatively associated with non-dependent drug abuse and opioid dispensing (p ≤ .0226)., Conclusions: Multiple types of indirect and concordant evidence suggest misattribution of IBS pain to diverticulitis and unnecessary antibiotic therapy in outpatients.

β-Citronellol is an alcoholic monoterpene found in essential oils such Cymbopogon citratus (a plant with antihypertensive properties). β-Citronellol can act against pathogenic microorganisms that affect airways and, in virtue of the popular use of β-citronellol-enriched essential oils in aromatherapy, we assessed its pharmacologic effects on the contractility of rat trachea. Contractions of isolated tracheal rings were recorded isometrically through a force transducer connected to a data-acquisition device. β-Citronellol relaxed sustained contractions induced by acetylcholine or high extracellular potassium, but half-maximal inhibitory concentrations (IC50) for K(+)-elicited stimuli were smaller than those for cholinergic contractions. It also inhibited contractions induced by electrical field stimulation or sodium orthovanadate with pharmacologic potency equivalent to that seen against acetylcholine-induced contractions. When contractions were evoked by selective recruitment of Ca2+ from the extracellular medium, β-citronellol preferentially inhibited contractions that involved voltage-operated (but not receptor-operated) pathways. β-Citronellol (but not verapamil) inhibited contractions induced by restoration of external Ca2+ levels after depleting internal Ca2+ stores with the concomitant presence of thapsigargin and recurrent challenge with acetylcholine. Treatment of tracheal rings with L-NAME, indomethacin or tetraethylammonium did not change the relaxing effects of β-citronellol. Inhibition of transient receptor potential vanilloid subtype 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptors with selective antagonists caused no change in the effects of β-citronellol. In conclusion, β-citronellol exerted inhibitory effects on rat tracheal rings, with predominant effects on contractions that recruit Ca2+ inflow towards the cytosol by voltage-gated pathways, whereas it appears less active against contractions elicited by receptor-operated Ca2+ channels.