Thymol has anticancer effects in U-87 human malignant glioblastoma cells.

BACKGROUND: Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). METHODS AND RESULTS: Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration (IC50) of thymol in the U-87 cells was 230 µM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. CONCLUSIONS: Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.

A trial-based economic evaluation of peppermint oil for the treatment of irritable bowel syndrome.

BACKGROUND: Irritable Bowel Syndrome (IBS) is a prevalent, chronic gastrointestinal disorder that imposes a substantial socioeconomic burden. Peppermint oil is a frequently used treatment for IBS, but evidence about cost-effectiveness is lacking. OBJECTIVE: We aimed to assess cost-effectiveness of small-intestinal release peppermint oil versus placebo in IBS patients. METHODS: In a multicenter randomized placebo-controlled trial, cost-effectiveness was evaluated from a societal perspective. The incremental cost-effectiveness ratios (ICERs) were expressed as (1) incremental costs per Quality Adjusted Life Years (QALY), and (2) incremental costs per successfully treated patient, that is per abdominal pain responder (according to FDA definitions), both after an eight-week treatment period with placebo versus peppermint oil. Cost-utility and uncertainty were estimated using non-parametric bootstrapping. Sensitivity analyses were performed. RESULTS: The analysis comprised 126 patients (N = 64 placebo, N = 62 small-intestinal release peppermint oil). Peppermint oil was a dominant treatment compared to placebo in 46% of bootstrap replications. Peppermint oil was also more effective but at higher cost in 31% of replications. The net-benefit acceptability curve showed that peppermint oil has a 56% probability of being cost-effective at a conservative willingness-to-pay threshold of €10.000/QALY. Peppermint oil was also a dominant treatment per additional successfully treated patient according to FDA definitions, that is in 51% of replications. In this case, the acceptability curve showed an 89% probability of being cost-effective. CONCLUSIONS: In patients with IBS, small-intestinal release peppermint oil appears to be a cost-effective treatment although there is uncertainty surrounding the ICER. When using abdominal pain responder as outcome measure for the ICER, peppermint oil has a high probability of being cost-effective. The use of peppermint oil, which is a low-cost treatment, can be justified by the modest QALY gains and slightly higher proportion of abdominal pain responders. More research and long-term data are necessary to confirm the cost-effectiveness of peppermint oil. NCT02716285.

Cannabinoid Activity-Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. METHODS: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. RESULTS: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies ("enriched" studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3-4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. CONCLUSIONS: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.

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.

The anti-spasmodic effect of peppermint oil during colonoscopy: a systematic review and meta-analysis.

INTRODUCTION: Multiple pharmacological agents have been studied in literature with antispasmodic effect during colonoscopy. Peppermint oil, with its relaxing effect on colon has demonstrated varying results. We therefore conducted a systematic review and meta-analysis of the available literature to evaluate its role during colonoscopy. EVIDENCE ACQUISITION: Literature search of the following databases was undertaken: PubMed\Medline, Embase, Cochrane, Web of Science, and CINAHL. Outcomes that were evaluated included incidence of any spasticity, severe spasticity, and peristalsis during examination. Adenoma detection rate (ADR) was evaluated as a quality outcome metric. Risk ratios (RR), risk difference (RD) and mean difference (MD) were calculated using the DerSimonian-Laird method and random effects where applicable. EVIDENCE SYNTHESIS: Overall, six studies (with one abstract) were included in this review. Peppermint oil resulted in overall lower incidence for spasticity (RD: -0.39, P=0.02), severe spasticity (RD: -0.15, P=0.04), and peristalsis (-0.27, P≤0.001) during colonoscopy examination. An improved ADR (RR: 1.31, P=0.01) was also noted, however only two studies evaluated this effect. CONCLUSIONS: Peppermint oil resulted in relaxation of colon during colonoscopy with decrease incidence of spasticity, severe spasticity, peristalsis and improved ADR. These results are encouraging however results are limited due to significant heterogeneity found in the outcomes. Larger studies with standardized dosing are needed to evaluate this effect. Furthermore, studies evaluating additional colonoscopy outcomes such as polyp detection rate, advanced adenoma detection rate, and serrated adenoma detection rate are needed.

Hydroalcoholic extract of leaves of Arrabidaea brachypoda (DC. ) Bureau present antispasmodic activity mediated through calcium influx blockage

Aim: Since other species of the Bignoniaceae Family presented of antispasmodic activity, it was decided, by chemotaxonomic criterion, to determine the antispasmodic activity of the leaves of Arrabidaea brachypoda. Methodology: the segments of the rat jejunum were suspended in glass vats containing specific saline solution, at an appropriate temperature, and after stabilization period, were stimulated by a contractile agent to observe the inhibitory or relaxing effect of EH-FAB. Results: EH-FAB showed the presence of 10 compounds, mainly rutin and it has an antispasmodic activity as it inhibits the phasic component and relaxes the tonic component of the contraction in isolated rat jejunum. To assess the mechanism of antispasmodic action, cumulative curves to the CCh were performed in which a non-competitive antagonism was observed, due to a displacement of the control curve to the right and reduction of the maximum contraction effect (Emax). Afterward, the participation of the calcium and/or potassium channels was evaluated by increasing the extracellular potassium, and it was observed that the EH-FAB relaxed the rat jejunum, suggesting the participation of the Ca2+ channels. To corroborate that hypothesis, the EH-FAB was tested against cumulative curves to Ca2+ in a free depolarizing solution of Ca2+, and it was observed that there was a shift of the curve to the right with a reduction in Emax. Conclusions: EH-FAB presents antispasmodic activity in isolated rat jejunum and it is suggested to block the influx of Ca2+ through voltage-gated calcium channels, signaling the therapeutic potential for the treatment of colic and/or diarrhea.(AU)

Probióticos en el síndrome de intestino irritable con predominio de diarrea / Probiotics for the treatment of diarrhea predominant irritable bowel syndrome

Una mujer de 36 años, diagnosticada con síndrome de intestino irritable a predominio de diarrea (SII-D) acude a la consulta médica. Ella pregunta si el uso de probióticos sería útil para controlar los episodios de diarrea, ya que los fármacos con los que está siendo tratada no le resultan eficaces. Se realizó una búsqueda bibliográfica con el objetivo de en contrar evidencia en respuesta a su consulta, tras la cual se seleccionaron dos ensayos clínicos y una revisión sistemática. Se evidenciaron diversos resultados en cuanto al uso de probióticos en el SII-D y se discutieron los riesgos y beneficios del tratamiento, así como las implicancias en la vida de la paciente. (AU)

A 36-year-old woman diagnosed with diarrhea predominant irritable bowel syndrome (D-IBS) goes to meet the doctor. She raises whether the use of probiotics would be useful for controlling diarrhea episodes, since the drugs which she is being treated with, are not effective. A bibliographic search was conducted with the objective of finding evidence in response toher query. Two clinical trials and a systematic review were found. Variable results were found regarding the use of probioticsin D-IBS. The risks and benefits of the treatment were discussed, as well as the implications in the patient's lifestyle. (AU)

Pharmacological Strategies for Presbyopia Correction.

PURPOSE: To summarize the pharmacological strategies that are being explored for presbyopia correction. METHODS: The review concentrates on pharmacologically induced pupillary miosis to increase depth-of-focus and lens softening or other measures to restore active accommodation. RESULTS: Several studies suggest that near vision improves and distance vision is unaffected for many hours after either monocular or binocular instillation of any one of several drug combinations that cause miosis. Unfortunately, in most studies, measurements were limited to photopic visual acuity for near and distance vision, whereas it is anticipated that pupil constriction may have adverse effects on mesopic and scotopic vision. It is not clear whether improved near vision was due entirely to increased depth-of-focus, or whether, for example, a drug-induced myopic shift in refraction was also involved. Currently, no study has provided direct evidence for drug-induced restoration/enhancement of true accommodation involving an ocular power change. CONCLUSIONS: Although it is possible that, in the future, pharmacological drops may offer a safe and reliable solution for presbyopia correction, more evidence of their effectiveness and limitations is required. [J Refract Surg. 2019;35(12):803-814.].

Antispasmodic Effect of Essential Oils and Their Constituents: A Review.

The antispasmodic effect of drugs is used for the symptomatic treatment of cramping and discomfort affecting smooth muscles from the gastrointestinal, billiary or genitourinary tract in a variety of clinical situations.The existing synthetic antispasmodic drugs may cause a series of unpleasant side effects, and therefore the discovery of new molecules of natural origin is an important goal for the pharmaceutical industry. This review describes a series of recent studies investigating the antispasmodic effect of essential oils from 39 plant species belonging to 12 families. The pharmacological models used in the studies together with the mechanistic discussions and the chemical composition of the essential oils are also detailed. The data clearly demonstrate the antispasmodic effect of the essential oils from the aromatic plant species studied. Further research is needed in order to ascertain the therapeutic importance of these findings.

Systematic review of interventions for the prevention and treatment of postoperative urinary retention.

Background: Postoperative urinary retention (PO-UR) is an acute and painful inability to void after surgery that can lead to complications and delayed hospital discharge. Standard treatment with a urinary catheter is associated with a risk of infection and can be distressing, undignified and uncomfortable. This systematic review aimed to identify effective interventions for the prevention and treatment of PO-UR that might be alternatives to urinary catheterization. Methods: Electronic databases were searched from inception to September 2017. Randomized trials of interventions for the prevention or treatment of PO-UR were eligible for inclusion. Studies were assessed for risk of bias using the Cochrane (2.0) tool. Two reviewers were involved at all review stages. Where possible, data were pooled using random-effects meta-analysis. The overall quality of the body of evidence was rated using the GRADE approach. Results: Some 48 studies involving 5644 participants were included. Most interventions were pharmacological strategies to prevent PO-UR. Based on GRADE, there was high-certainty evidence to support replacing morphine in a regional anaesthetic regimen, using alpha-blockers (number needed to treat to prevent one case of PO-UR (NNT) 5, 95 per cent c.i. 5 to 7), the antispasmodic drug drotaverine (NNT 9, 7 to 30) and early postoperative mobilization (NNT 5, 4 to 8) for prevention, and employing hot packs or gauze soaked in warm water for treatment (NNT 2, 2 to 4). Very few studies reported on secondary outcomes of pain, incidence of urinary tract infection or duration of hospital stay. Conclusion: Promising interventions exist for PO-UR, but they need to be evaluated in randomized trials investigating comparative clinical and cost effectiveness, and acceptability to patients.

Profound Prolonged Bradycardia and Hypotension after Interscalene Brachial Plexus Block with Bupivacaine.

BACKGROUND: Interscalene brachial plexus blocks have been a routinely performed method of anesthesia for shoulder surgery that decreases the need for general anesthesia, length of stay, and recovery time. We describe a case of bupivacaine toxicity after an interscalene block. CASE REPORT: The patient was a 66-year-old man who presented to our Emergency Department by emergency medical services from an ambulatory surgery center where he had undergone rotator cuff surgery, with bradycardia and hypotension. His symptoms began upon completion of the surgery in which he received interscalene nerve block with bupivacaine and lidocaine. He was given three doses of 0.5 mg atropine and one dose of 1 mg epinephrine for a heart rate of 40 beats/min without any improvement prior to arrival. His bradycardia was refractory to atropine. He was started on a dopamine drip and transferred to the coronary care unit. The timing of his symptoms, minutes after his regional nerve block, and his complete recovery with only supportive care, make the diagnosis of bupivacaine toxicity likely. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Despite the safety profile of local anesthetics, we must be aware of their potential side affects. Whereas most adverse reactions are secondary to misdirection of anesthetic or accidental vascular puncture, local anesthetic systemic toxicity (LAST) is the major cause of significant adverse events with regional anesthesia. As regional anesthesia becomes more common, emergency physicians must be more aware of the potential complications and be able to both diagnose and treat.

Transcutaneous posterior tibial nerve electrostimulation with low dose trospium chloride: Could it be used as a second line treatment of overactive bladder in females.

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.

New therapies in Irritable Bowel Syndrome: what works and when.

PURPOSE OF REVIEW: The purpose of this review is to examine the evidence supporting the use of recently developed pharmacological treatments for IBS together with new evidence supporting more traditional therapies in order to understand where the new agents are best used in the treatment pathway. RECENT FINDINGS: There is evidence to support the use of traditional treatments such as antispasmodics, antidepressants and dietary alteration in IBS. New therapeutic agents such as Linaclotide, Lubiprostone, Plecanatide, Rifaxamin and Eluxadoline are all more effective than placebo in treating symptoms of IBS with Tenapanor being a promising new agent. The majority of patients, however, treated with these medications remain symptomatic and they are not suitable for use in all patients. SUMMARY: Traditional treatments such as antispasmodics, antidepressants, dietary and lifestyle modifications retain their importance in the treatment of IBS with the newer agents to be considered wherever these treatments are ineffective or poorly tolerated.

Pyloric stenosis: an enigma more than a century after the first successful treatment.

Despite hypertrophic pyloric stenosis (HPS) being one of the most frequently treated pediatric surgical conditions, its etiology remains incompletely understood. We review the diagnosis and treatment of this condition with an emphasis on the evolution of surgical techniques that led to laparoscopic pyloromyotomy, the most frequently performed technique for HPS today. In addition, we review key developments in the understanding of HPS etiology and treatment, including the postulated etiology of work-induced hypertrophy of the pylorus, its association with prokinetic macrolide antibiotics, and the emerging role of atropine sulfate as a medical treatment for HPS or a rescue treatment for incomplete myotomy.

Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment.

Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.

[Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy]. / Revisione sistematica sull'efficacia terapeutica e la sicurezza della cannabis per i pazienti affetti da sclerosi multipla, dolore neuropatico cronico e pazienti oncologici che assumono chemioterapie.

BACKGROUND: medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. In the United States, 23 states and Washington DC (May 2015) have introduced laws to permit the medical use of cannabis. Within the European Union, medicinal cannabis laws and praxis vary wildly between Countries. OBJECTIVES: to provide evidence for benefits and harms of cannabis (including extracts and tinctures) treatment for adults in the following indications: control of spasticity and pain in patients with multiple sclerosis; control of pain in patients with chronic neuropathic pain; control of nausea and vomiting in adults with cancer receiving chemotherapy. METHODS: we searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE from inception to September 2016. We also searched for on-going studies via ClinicalTrials.gov and the World Health Organization and International Clinical Trials Registry Platform (ICTRP) search portal. All searches included also non-English language literature. All relevant randomized controlled trials (RCTs) evaluating the safety and efficacy of cannabis (including extracts and tinctures) compared with placebo or other pharmacological agents were included. Three authors independently evaluated the titles and abstracts of studies identified in the literature searches for their eligibility. For studies considered eligible, we retrieved full texts. Three investigators independently extracted data. For the assessment of the quality of evidence, we used the standard methodological procedures recommended by Cochrane and GRADE working Group. RESULTS: 41 trials (4,550 participants) were included; 15 studies considered efficacy and safety of cannabis for patients with multiple sclerosis, 12 for patients with chronic pain, and 14 for patients with cancer receiving chemotherapy. The included studies were published between 1975 and 2015, and the majority of them were conducted in Europe. We judged almost 50% of these studies to be at low risk of bias. The large majority (80%) of the comparisons were with placebo; only 8 studies included patients with cancer receiving chemotherapy comparing cannabis with other antiemetic drugs. Concerning the efficacy of cannabis (compared with placebo) in patients with multiple sclerosis, confidence in the estimate was high in favour of cannabis for spasticity (numerical rating scale and visual analogue scale, but not the Ashworth scale) and pain. For chronic and neuropathic pain (compared with placebo), there was evidence of a small effect; however, confidence in the estimate is low and these results could not be considered conclusive. There is uncertainty whether cannabis, including extracts and tinctures, compared with placebo or other antiemetic drugs reduces nausea and vomiting in patients with cancer requiring chemotherapy, although the confidence in the estimate of the effect was low or very low. In the included studies, many adverse events were reported and none of the studies assessed the development of abuse or dependence. CONCLUSIONS: there is incomplete evidence of the efficacy and safety of medical use of cannabis in the clinical contexts considered in this review. Furthermore, for many of the outcomes considered, the confidence in the estimate of the effect was again low or very low. To give conclusive answers to the efficacy and safety of cannabis used for medical purposes in the clinical contexts considered, further studies are needed, with higher quality, larger sample sizes, and possibly using the same diagnostic tools for evaluating outcomes of interest.