Spasmolytic Drugs Research Articles

New Application of an Old Drug: Anti-Diabetic Properties of Phloroglucinol.

Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG's efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG's full therapeutic potential.

Systematic approach to obtain axillary arterial access for pediatric heart catheterizations.

Axillary arterial access (AAA) in pediatric heart catheterizations is undervalued. We retrospectively reviewed children with congenital heart diseases (CHDs) who received trans-axillary arterial catheterizations between January 2019 and February 2023. We aimed ultrasound-guided punctures in the proximal two-thirds of axillary arteries with diameters ≥2 mm to insert 7 cm/4 Fr short introducers. We administrated intra-arterial verapamil (1.25 mg) and heparin (100 UI/kg). We infiltrated per-operatively 2% lignocaine (10 mg) for arterial spasms, long sheaths use (≥5 Fr), and ≥60 min procedures in <3 kg patients. We identified 30 patients (66.7% males) with a median age of 1.1 months (IQR, 0.3-5.4), and a median weight of 3.1 kg (IQR, 2.7-3.7). 5/30 patients had six redo interventions after a median of 3.9 months (IQR, 1.7-5.1). Overall, 27/36 procedures were interventional, including 6 aortic valvuloplasties, 6 balloon angioplasties, and 15 stenting procedures. The median arterial axillary angiographic diameter was 2.6 mm (IQR, 2.4-3). Access was right-sided in 23/36 (63.9%) procedures and obtained using 21G/2.5 cm bevel needles in 25/36 (69.4%) procedures. No hemodynamical change occurred after introducing spasmolytic drugs. The median fluoroscopy time was 26.1 min (IQR, 19.2-34.8). There were two self-resolving arterial dissections, one sub-occlusive arterial thrombosis (resolved with 6 weeks of enoxaparin), and one occlusive arterial thrombosis (resolved with alteplase thrombolysis and 6 weeks of enoxaparin). Median follow-up was 11.7 months (IQR, 8-17.5). Four patients with complex univentricular hearts died from non-procedural causes at a median of 40 days (IQR, 31-161) postoperative. Systematic approach for AAA is the key to success and unlocks the many potentials of trans-axillary pediatric cardiology interventions.

Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation

The temperature-sensitive Ca2+-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 17.8± 3.5μM. At the single-channel level, flopropione inhibits TRPV3 channel open probability without alteration of its unitary conductance. In an invivo mouse model of skin inflammation induced by the skin sensitizer DNFB, flopropione also alleviates dorsal skin lesions and ear skin swelling. Further molecular docking combined with site-directed mutagenesis reveals that two residues E501 and I505 in the channel S2-helix are critical for flopropione-mediated inhibition of TRPV3. Taken together, our findings demonstrate that the spasmolytic drug flopropione as a selective inhibitor of TRPV3 channel not only provides a valuable tool molecule for understanding of TRPV3 channel pharmacology but also holds repurposing potential for therapy of skin disorders, such as dermatitis and pruritus.

Baclofen - a great chance or danger - discussion of poisoning based on research

Introduction and purpose: Baclofen is a derivative of γ-aminobutyric acid (GABA). It is a spasmolytic drug that reduces skeletal muscle tension and is used in spasticity. Despite its many positive functions, its use is associated with a risk of side effects. The aim of this work is to gain a better understanding of baclofen and to highlight the toxicity and dangers of its misuse.&#x0D; Material and methods: The study was retrospective in nature. It used an analysis of the records of 11648 intoxications in patients hospitalised from 01.04.2013 to 01.04.2023 in the Clinical Toxicology and Cardiology Department of the Stefan Cardinal Wyszyński Provincial Hospital in Lublin, from which a group of baclofen intoxicated patients (T55), consisting of 19 cases, was distinguished.&#x0D; Results: The study population consisted of 10 women (52.63%) and 9 men (47.37%), aged between 16 and 83 years. The largest group consisted of patients aged up to 30 years - 9 patients (47.37%). The majority of patients - 11 patients (59.89%) were in a severe condition. An overwhelming number reported intentional poisoning - 16 cases (84.21%), including five suicide attempts (31.25%). Patients took other drugs and medicines in addition to baclofen. The most common was ethanol - 8 people (42.11%), followed by NSAIDs - 5 people (26.32%).&#x0D; Conclusions: In order to prevent complications following the use of baclofen, it is very important to educate patients, their family members and the general public about the mechanism of action of the drug itself, its function on the body and the risks of taking it. Prophylactic measures and education on how to deal with poisoning situations are necessary, as they are entirely preventable with immediate diagnosis and treatment.

6084 Cases of Adult Tetanus from China: A Literature Analysis.

To describe the clinical characteristics, treatments, and outcomes of tetanus and determine the most appropriate focus for tetanus prevention and treatment to reduce morbidity and mortality in China. Four databases, including the Chinese Bio-Medical Literature Database, Chinese National Knowledge Infrastructure, Chinese Scientific Journal Database, and Wan-fang Data, were searched from 1 January, 2000 to 30 October, 2022. In total, 151 articles including 6084 tetanus patients met the inclusion criteria. Additionally, 5925 patients had their gender recorded in detail, among which 66.67% (3950/5925) were male, and 33.33% (1975/ 5925) were female. The average age in the detailed records was reported in 4773 cases, with an overall average age of 46.69. The number of patients' places of residence was 580. Those from rural areas comprised the highest percentage with 88.62% (514 / 580). The causes of injury were recorded in 1592 cases in total; injuries caused by metals, wood, and wooden spikes accounted for the highest percentage with 54.52% (868/1592). Patient outcomes were recorded in 4305 cases, with a mortality of 9.34% (402/4305). The leading causes of death included treatment terminated by family members, asphyxia due to persistent spasms, respiratory failure, and autonomic dysfunction, family automatic abandonment and asphyxia accounted for the highest percentage, both 24.00% (54/225). The overall success rate of tetanus treatment in China has dramatically improved, but the prevention and control of non-neonatal tetanus is still challenging. Focus should be placed on the prevention of adult tetanus and standardizing the use of sedative and spasmolytic drugs. Additionally, medical professionals should popularize tetanus prevention and treatment knowledge among the people and strengthen training in grass-roots hospitals.

Successful Treatment of Urolith in a Neutered Persian Cat: A Case Report

Introduction: Uroliths or calculi are the formations of stones in the bladder. The formation of stones is influenced by specific metabolic conditions such as nutritional factors (e.g., protein-rich diet), hydration (lack of water), pH modification, low urine volume, hypercalcemia, or hypophosphatemia. In pet medicine, urolithiasis is common, particularly in cats.&#x0D; Case report: In October 2022, a 2-year-old neutered male Persian cat with a weight of 4 kg was referred to Ardebili Veterinary Pet Clinic (Mashhad, Iran) due to urinating outside the litter box, painful urination, and blood in the urine. A physical examination, ultrasonography, and blood analysis were performed. The physical examination included an assessment of the cat’s body temperature, heart rate, respiratory rate, mental state, mucous membrane color, capillary refill time, cardiopulmonary auscultation, and abdominal palpation. The cat appeared to be in good general health. No abnormalities were detected during the palpation of the bladder. Ultrasonography was performed using a real-time scanner with a 7.5-10 MHz broadband curvilinear probe, and the kidney parenchyma was examined. During the examination, a urolith with a size of 1 mm was observed. According to history and ultrasonography, and physical examination, the diagnosis was urolithiasis. To treat intermittent bladder pain, a spasmolytic drug (Prazosin) was administered at a dose of 0.5 mg/kg for 7 days. By the second day, the symptoms of pain had subsided.&#x0D; Additionally, ciprofloxacin at 20 mg/kg was used to combat infections. Fluoxetine at a 1 mg/kg dose was also administered to control inappropriate urination outside the litter box. After 3 days, the owner reported that the pet’s health improved, and most clinical signs disappeared.&#x0D; Conclusion: Administering appropriate medication (spasmolytic drug, antibiotic, and antidepressant in case of depressed animal and behavioral problems) can alleviate the calculi crystals in a cat’s urinary bladder and prevent future recurrences. In this instance, fluoxetine was discovered to be a successful option for managing pain and solving behavioral problems.

Drotaverine Hydrochloride Superporous Hydrogel Hybrid System: a Gastroretentive Approach for Sustained Drug Delivery and Enhanced Viscoelasticity

This study aims to prepare drotaverine hydrochloride superporous hydrogel hybrid systems (DSHH systems) to prolong its residence time in the stomach, provide extended release and reduce its frequency of administration. Drotaverine hydrochloride (DRH) is a spasmolytic drug that suffers from brief residence due to intestinal hypermotility during diarrheal episodes associated with gastrointestinal colics resulting in low bioavailability and repeated dosing. Eight DSHH systems were prepared using gas blowing technique. The prepared DSHH systems were evaluated regarding their morphology, incorporation efficiency, density, porosity, swelling ratio, viscoelastic property, erosion percentage and release kinetics. The FH8 formula containing equal proportion of chitosan (3%) /polyvinyl alcohol (3%) as strengthener and crosslinked with tripolyphosphate showed the highest incorporation efficiency (91.83 ± 1.33%), good swelling ratio (28.32 ± 3.15% after 24 h), optimum viscoelastic properties (60.19 ± 3.82 kPa) and sustained release profile (88.03 ± 2.15% after 24 h). A bioequivalence study was done to compare the bioavailability of the candidate formula versus Spasmocure®. Statistical analysis showed significant (P < 0.05) increase in bioavailability 2.7 folds with doubled Tmax (4 h) compared to the marketed product (2 h). These results declared that the superporous hydrogel hybrid systems could be a potential gastroretentive approach for the sustained delivery of drugs with short residence time with enhanced viscoelasticity.Graphical abstract

Positive Treatment Expectations Shape Perceived Medication Efficacy in a Translational Placebo Paradigm for the Gut-Brain Axis.

Placebo research has established the pivotal role of treatment expectations in shaping symptom experience and patient-reported treatment outcomes. Perceived treatment efficacy constitutes a relevant yet understudied aspect, especially in the context of the gut-brain axis with visceral pain as key symptom. Using a clinically relevant experimental model of visceral pain, we elucidated effects of pre-treatment expectations on post-treatment perceived treatment efficacy as an indicator of treatment satisfaction in a translational placebo intervention. We implemented positive suggestions regarding intravenous treatment with a spasmolytic drug (in reality saline), herein applied in combination with two series of individually calibrated rectal distensions in healthy volunteers. The first series used distension pressures inducing pain (pain phase). In the second series, pressures were surreptitiously reduced, modeling pain relief (pain relief phase). Using visual analog scales (VAS), expected and perceived treatment efficacy were assessed, along with perceived pain intensity. Manipulation checks supported that the induction of positive pre-treatment expectations and the modeling of pain relief were successful. Generalized Linear Models (GLM) were implemented to assess the role of inter-individual variability in positive pre-treatment expectations in perceived treatment efficacy and pain perception. GLM indicated no association between pre-treatment expectations and perceived treatment efficacy or perceived pain for the pain phase. For the relief phase, pre-treatment expectations (p = 0.024) as well as efficacy ratings assessed after the preceding pain phase (p < 0.001) were significantly associated with treatment efficacy assessed after the relief phase, together explaining 54% of the variance in perceived treatment efficacy. The association between pre-treatment expectations and perceived pain approached significance (p = 0.057) in the relief phase. Our data from an experimental translational placebo intervention in visceral pain support that reported post-treatment medication efficacy is shaped by pre-treatment expectations. The observation that individuals with higher positive expectations reported less pain and higher treatment satisfaction after pain relief may provide first evidence that perceived symptom improvement may facilitate treatment satisfaction. The immediate experience of symptoms within a given psychosocial treatment context may dynamically change perceptions about treatment, with implications for treatment satisfaction, compliance and adherence of patients with conditions of the gut-brain axis.

Antispasmodic and antimicrobial activities of pyrazole‐containing ferrocenyl alkanols versus their phenyl analogs, and the entry point to potential multitarget treatment for inflammatory bowel diseases

AbstractInflammatory bowel diseases (IBM), such as Crohn's disease, and their common complications represent a global health challenge. Many pyrazole derivatives, such as the spasmolytic drug metamizole, have already found their place among the frequently used therapeutic agents. Alteration of the structure of established therapeutic drugs by introducing a ferrocene moiety was shown to be a promising way for the discovery of new drugs. Herein, two libraries of analogous ferrocenyl (1a‐1j) and phenyl alkanols (2a‐2j) containing a pyrazole core, among which 17 completely new structures, have been synthesized, and structurally and electrochemically characterized. These compounds, along with the aldehydes used for their synthesis, were tested in parallel for their antispasmodic, acetylcholinesterase‐inhibitory, and antimicrobial activities to evaluate their potential as multitarget IBM drugs. The antispasmodic activity was investigated by assessing their effect on both the amplitude and number of spontaneous contractions of isolated rat ileum. Their antimicrobial effect was evaluated against a panel of Gram‐positive and Gram‐negative bacterial strains and fungi. It was found that several of the evaluated compounds displayed gastrointestinal smooth muscle relaxant activity, among them, 1‐(1H‐3‐ferrocenyl‐1‐phenylpyrazol‐4‐yl)‐3‐methylbutan‐1‐ol (1d) showed a remarkable effect by superseding the activity of papaverine. Together with the fact that it represents one of the most antimicrobially active investigated compounds, 1d is a good candidate for further pharmacological evaluation as a multitarget drug for IBM.

Repair of tophus wound of the heel with sural nerve nutrition flap with peroneal artery perforating branch: a retrospective study.

This study was to investigate the clinical effect of a sural nerve nutrition flap with peroneal artery perforator for repairing tophus wound of the heel. Over a 5-year period, 7 elderly male patients with tophus ulceration of the heel were admitted with exposed Achilles' tendon, and a chronic unhealed wound. Debridement, expansion and vacuum sealing drainage (VSD) lavage were performed initially, with simultaneous uric acid-lowering treatment. A 4×6-8×10 cm sural nerve nutrition flap with peroneal artery perforator was the secondary repair after further debridement of the wound. Preoperative Doppler ultrasound located the penetrating point of the peroneal artery perforator as the rotation point of the flap, and the line between the midpoint of the Achilles' tendon and the lateral malleolus and the midpoint of the popliteal fossa 5° above the front of Achilles' tendon was the axis. The patients were treated postoperatively with anti-inflammatory, anticoagulant and spasmolytic drugs and other rehydration therapy, and allopurinol was continued to control uric acid. The blood supply and temperature of the flap and wound healing were monitored. All 7 flaps survived completely after operation, with 1 case of postoperative wound discharge that finally healed after dressing change and 1 case of skin flap redness and swelling, which improved after strengthening anti-infection treatment. All 7 patients were followed up for 6-12 months (average 10 months). The skin flaps were soft in texture, with good color and appearance, and no recurrence of ulceration. The dorsal extension and plantar flexion of the ankle joint were good, and function was satisfactory. The sural nerve nutrition flap with peroneal artery perforator has double blood supply, strong anti-infective ability, relatively fast tissue healing process, simple operation and high survival rate, making it ideal for repairing tophus wounds of the heel.

Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

Fixed-Dose Combination of NSAIDs and Spasmolytic Agents in the Treatment of Different Types of Pain-A Practical Review.

This review presents the most common disease entities in which combinations of NSAIDs and spasmolytic drugs are used to reduce pain. The benefits of fixed-dose combination products (FDCs) are that they improve the response in people with insufficient monotherapy. Using the synergy or additive effect of drugs, it is possible to obtain a significant therapeutic effect and faster action with the use of smaller doses of individual drugs. In addition, one active ingredient may counteract adverse reactions from the other. Another essential aspect of the use of FDCs is the improvement of medical adherence due to the reduction in the pill burden on patients. It is also possible to develop a fixed-dosed combination product de novo to address a new therapeutic claim and be protected by patents so that the manufacturer can obtain exclusive rights to sell a particular FDC or a formulation thereof. The proposed fixed-dose combinations should always be based on valid therapeutic principles and consider the combined safety profile of all active substances included in the medicinal product. This review aims to identify which combinations of NSAIDs and spasmolytics have been developed and tested and which combinations are still under development.

Healthcare needs, expectations, utilization, and experienced treatment effects in patients with hereditary spastic paraplegia: a web-based survey in the Netherlands

BackgroundWe aimed to identify healthcare needs, expectations, utilization, and the experienced treatment effects in a population of Dutch patients with hereditary spastic paraplegia (HSP).MethodsWe distributed an online questionnaire among 194 adult persons with HSP in the Netherlands, of which 166 returned a fully completed version. After applying predefined exclusion criteria, 109 questionnaires from persons with pure HSP were analysed.ResultsHealthcare needs and expectations were primarily focused on the relief of muscle stiffness and reduction of balance and gait impairments (65–80%), but many participants also expressed needs regarding relief of non-motor symptoms (e.g. pain, fatigue), emotional problems, impaired sleep and self-care capacity, and participation problems (> 60%). Remarkably, despite these frequent needs, relatively few participants (< 33%) expected to be able to improve in these additional domains. Rehabilitation physicians and physiotherapists were more frequently consulted than neurologists and occupational therapists, respectively. Physiotherapy was the most often proposed non-pharmacological intervention (85%), followed by orthopedic footwear (55%) and splints (28%). Approximately one third of the participants was never offered any pharmacological (spasmolytic) treatment. Spasmolytic oral drugs, injections, and intrathecal baclofen were given to 41%, 26%, and 5% of the participants, respectively. Independent of the type of pharmacological intervention, 35–46% of these participants experienced decreased spastiticy and improved general fitness. Other experienced effects differed per type of intervention.ConclusionsBased on this web-based survey in the Netherlands, there seems to be ample room for improvement to meet and attune the healthcare needs and expectations of people with HSP concerning both their motor and non-motor symptoms and functional limitations. In addition, the provision of adequate information about non-pharmacological and pharmacological interventions seems to be insufficient for many patients to allow shared decision making. These conclusions warrant a more pro-active attitude of healthcare providers as well as an interdisciplinary approach for a substantial proportion of the HSP population, also involving professionals with a primary occupational and/or psychosocial orientation.

A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways

Receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) are potential therapeutic targets in the treatment of acute and chronic inflammatory diseases. We previously reported that trimebutine, a spasmolytic drug, suppresses RAGE pro-inflammatory signaling pathway in macrophages. The aim of this study was to convert trimebutine to a new small molecule using in silico 3D pharmacophore similarity search, and dissect the mechanistic anti-inflammatory basis. Of note, a unique 3-styrylchromone (3SC), 7-methoxy-3-trimethoxy-SC (7M3TMSC), converted from trimebutine 3D pharmacophore potently suppressed both high mobility group box 1-RAGE and lipopolysaccharide-TLR4 signaling pathways in macrophage-like RAW264.7 cells. More importantly, 7M3TMSC inhibited the phosphorylation of extracellular signaling-regulated kinase 1 and 2 (ERK1/2) and downregulated the production of cytokines, such as interleukin-6. Furthermore, 3D pharmacophore-activity relationship analyses revealed that the hydrogen bond acceptors of the trimethoxy groups in a 3-styryl moiety and the 7-methoxy-group in a chromone moiety in this compound are significant in the dual anti-inflammatory activity. Thus, 7M3TMSC may provide an important scaffold for the development of a new type of anti-inflammatory dual effective drugs targeting RAGE/TLR4-ERK1/2 signaling.

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.

Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

BackgroundDelayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH.MethodsThis is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints.DiscussionNew approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution.Trial registrationDeutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

Efficacy of mebeverin in treatment of abdominal pain

An original study evaluating the effectiveness and safety of mebeverin in treatment of abdominal pain in patients with irritable bowel syndrome (IBS) are presented. Materials and methods: 40 patients diagnosed with IBS, according to the Rome Criteria IV, were monitored. Patients depending on the type of therapy were divided into two groups: 20 patients of the first group had recommendations for lifestyle modification, a hypocaloric diet and took mebeverin per os at a dose of 135 mg three times a day 20 minutes before meals for a month; 20 patients of the second group received only recommendations for lifestyle modification and a hypocaloric diet. All patients were evaluated before and after treatment using the Gastrointestinal Symptom Rating Scale (GSRS), Visual-Analog Pain Intensity Rating Scale (0–10 points), SF‑36 Quality of Life Assessment Question, adverse events assessment. Colonoscopy was performed before treatment to exclude organic pathology of the colon. Results. After treatment patients in the first group had a faster and more significant relief of complaints compared to the second group, a significant improvement in the quality of life on the scales of physical and mental functioning, as well as almost complete disappearance of pain on a visual-analog scale (7.1 out of 10 points before treatment and 0.4 points after). Conclusions. Mebeverin in a dosage of 135 mg three times a day during a month contributes to a significant improvement in well-being, optimizes the quality of life of this category of patients, is effective and safe, which allows us to recommend its use as a first-line spasmolytic drug in the complex therapy of IBS, as well as in various variants of visceral abdominal pain.

Assessment of Ethanol-Induced Toxicity on iPSC-Derived Human Neurons Using a Novel High-Throughput Mitochondrial Neuronal Health (MNH) Assay.

Excessive ethanol exposure can cause mitochondrial and cellular toxicity. In order to discover potential counteracting interventions, it is essential to develop assays capable of capturing the consequences of ethanol exposure in human neurons, and particularly dopaminergic neurons that are crucial for the development of alcohol use disorders (AUD). Here, we developed a novel high-throughput (HT) assay to quantify mitochondrial and neuronal toxicity in human dopaminergic neuron-containing cultures (DNs) from induced pluripotent stem cells (iPSCs). The assay, dubbed mitochondrial neuronal health (MNH) assay, combines live-cell measurement of mitochondrial membrane potential (MMP) with quantification of neuronal branching complexity post-fixation. Using the MNH assay, we demonstrated that chronic ethanol exposure in human iPSC-derived DNs decreases MMP and neuronal outgrowth in a dose-dependent manner. The toxic effect of ethanol on DNs was already detectable after 1 h of exposure, and occurred similarly in DNs derived from healthy individuals and from patients with AUD. We next used the MNH assay to carry out a proof-of-concept compound screening using FDA-approved drugs. We identified potential candidate compounds modulating acute ethanol toxicity in human DNs. We found that disulfiram and baclofen, which are used for AUD treatment, and lithium caused neurotoxicity also in the absence of ethanol, while the spasmolytic drug flavoxate positively influenced MNH. Altogether, we developed an HT assay to probe human MNH and used it to assess ethanol neurotoxicity and to identify modulating agents. The MNH assay represents an effective new tool for discovering modulators of MNH and toxicity in live human neurons.

HPLC study of phenolic compounds in Mirabilis jalapa raw material

Mirabilis jalapa is a popular decorative plant valued for its beautiful multicolored flowers. Folk medicine in various countries applies Mirabilis jalapa as anti-microbial, anti-inflammatory, diuretic, spasmolytic drug. Chemical composition of different types of Mirabilis jalapa has not yet been adequately studied which is an obstacle for its application in medicine. The qualitative composition and quantitative content of phenolic compounds were studied by the HPLC method. The performed experiment revealed presence of hydroxycinnamic acids, flavonoids, isoflavonoids and coumarins in tested herb. The content of phenolic compounds was the highest in Mirabilis jalapa flowers, counting as much as 2977.41 ± 59.55 µg/mg. Total content of phenolic compounds in Mirabilis jalapa herb was 304.25 ± 6.08 µg/mg, in fruits – 67.92 ± 1.36 µg/mg, and in roots – 12.44 ± 0.25 µg/mg. Quantitatively neochlorogenic acid dominated in flowers, chlorogenic acid in fruits, whereas Mirabilis jalapa herb mostly contained rutin and hyperoside. The obtained results will be useful in the development of quality control methods for Mirabilis jalapa herb and manufacture of drug preparations on its basis.

Methods of Physiotherapy in the Medical Rehabilitation of Children with Primary Arterial Hypertension

Introduction. Arterial hypertension (AH) is a widely occurring disease of the cardiovascular system in the children’s population, which often debuts in childhood, persists into adulthood, which dictates the need for early treatment and prevention of arterial hypertension. The formation of AH is associated with maladaptation of physiological mechanisms of self-regulation, with a complex interaction of psychosocial and genetic factors. The use of non-medicinal agents to reduce blood pressure is a starting approach in the treatment of children and adolescents with hypertension and complements medication therapy. Purpose. analysis of literature sources on the effectiveness of hardware physiotherapy methods in the treatment of hypertension in children. Discussion. In the treatment of children with hypertension, the leading role belongs to hardware physiotherapy technologies. Widely used sedative, hypotensive and vegetative-corrective methods are pathogenetically justified and can be used at all stages of arterial hypertension development. Transcranial pulsed electrotherapy (transcranial electrostimulation, electroson, infitotherapy), darsonvalization, aromafitotherapy and medicinal electrophoresis of sedatives belong sedative methods aimed at enhancing inhibitory processes in the Central nervous system. Amplipulster therapy, intermittent normobaric hypoxytherapy, low-intensity magnetic therapy, medicinal electrophoresis of spasmolytic drugs, EHF therapy, laser therapy, which lead to a decrease in arterial hypertension and improve microcirculation, are hypotensive methods. Bio-controlled aerionotherapy, aimed at correcting vegetative dysfunction, is a vegetative corrective method. Conclusion. Currently, there is a wide range of scientifically-based methods of hardware physiotherapy used in the medical rehabilitation of children with arterial hypertension, allowing to improve cerebral hemodynamics, normalize neurophysiological and hemodynamic processes in the Central nervous system, provide sedative and hypotensive effects, stimulate peripheral vasodepressor mechanisms, normalize neuroendocrine processes. The use of hardware physiotherapy methods in the complex treatment of hypertension can improve the quality of life of patients, achieve stable normalization of blood pressure, and reduce the risk of early cardiovascular diseases.