Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

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 2xLD50 dose of paraoxon.

Pentoxifylline, a nonselective phosphodiesterase inhibitor, in adjunctive therapy in patients with irritable bowel syndrome treated with mebeverine.

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.

Childhood dystonic reactions in the middle Black Sea region.

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.

Investigation of antinociceptive, antipyretic, antiasthmatic, and spasmolytic activities of Brazilian Cannabis sativa L. roots in rodents.

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.

Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility.

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.

Cannabis roots: Pharmacological and toxicological studies in mice.

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 (LD50) 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.

Effect of hyoscine-N-butylbromide on labor duration among nullipara in a southwestern Nigerian teaching hospital: A randomized controlled trial.

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).

Oral IBGard™ Before Colonoscopy: A Single-Center Double-Blinded, Randomized, Placebo-Controlled Trial.

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.

MR enterocolonography in patients with Crohn's disease and healthy volunteers - Do we achieve diagnostic bowel distension?

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.

Long-term assessment of the cognitive effects of nabiximols in patients with multiple sclerosis: A pilot study.

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.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Malignancies.

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 BRAFV600 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 (Cmax ) 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 Cmax , AUCinf , and AUClast 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.

Coronary stent embolism to the right posterior cerebral artery.

A 57-year-old male was admitted to the emergency room with chest pain that has been present for 3 hours. His blood pressure was 70/50 mmHg and heart rate was 48 bpm. 12-lead surface electrocardiography revealed inferior myocardial infarction and third-degree atrioventricular (AV) block. An emergency coronary angiography showed a 50% stenosis in the middle segment of the left anterior descending artery and 90% in the proximal circumflex (Cx) artery. The right coronary artery was totally occluded. After the predilatation with a 2.0x15 mm compliant balloon at 10 atm, a 3.5x24 mm bare metal stent was implanted. The third-degree AV block improved and a sinus rhythm of 124 bpm was achieved, but hemodynamic stability was not attained. Percutaneous coronary intervention for the Cx artery was performed. Without predilatation, a 3.5x12 mm low profile BMS was easily advanced over the lesion. Just before the stent implantation, asystole developed, followed by convulsions. Blood pressure and heart rate recovered after the administration of 1 mg of atropine. However, during the seizure, the guidewire and coronary stent device fell to the aortic root. Stent struts were not seen on the balloon catheter in a fluoroscopic examination. Fluoroscopic scanning of the vascular system showed that the coronary stent was in the right posterior cerebral artery. There were no symptoms or signs of neurological disorder. Consultant invasive neuroradiologist recommended medical follow-up. Clopidogrel and acetylsalicylic acid were prescribed indefinitely. Two months after the primary PCI, a successful coronary artery bypass graft operation was performed. After 4 years, the patient remained without any symptoms of neurological problems.

Effects of L-Menthol and Carbon Dioxide on the Adenoma Detection Rate during Colonoscopy: L-Menthol and Carbon Dioxide on Colonoscopy.

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.

Evaluation of the Antispasmodic and Antisecretory Activities of the 80% Methanol Extracts of Verbena officinalis L: Evidence From In Vivo Antidiarrheal Study.

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.

A comparison of intravenous sugammadex and neostigmine + atropine reversal on time to consciousness during wake-up tests in spinal surgery.

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 (T2), 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. BIS90, SSEP90, MEP90 was recorded when TOF ratio reached 90, whereas time-to-consciousness (Timecons) was recorded when the patient responded to verbal commands. RESULTS: BIS90 (77.4 ± 4.7, 74.8 ± 3.7), SSEP90(36 ± 9.9, 29.7 ± 8.5), and MEP90 (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). Timecons 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.

The Role of Muscle Relaxants ­ Spasmolytic (Thiocochlicoside) in Postoperative Pain Management after Mastectomy and Breast Reconstruction

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.

Optimising prostate mpMRI: prepare for success.

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.

A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers.

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 (Tmax) 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 (Tlag) 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 Tlag, 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.

Hyoscine Butylbromide for the Management of Death Rattle: Sooner Rather Than Later.

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.

Broccoli sprouts produce abdominal antinociception but not spasmolytic effects like its bioactive metabolite sulforaphane.

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.