The analgesic properties of Yu-Xue-Bi tablets in the inflammatory pain mice: By the inhibition of CCL3-mediated macrophage transmigration into the spinal cord.

ETHNOPHARMACOLOGICAL RELEVANCE: Until now, inflammatory pain, especially ones with central sensitization in the spinal cord, is far from effectively treated. Yu-Xue-Bi Tablets (YXB) is a patented medicine, which has been widely applied for inflammatory pain. However, its therapeutic characteristics and mechanism remain unknown. AIM OF THE STUDY: This study is designed to evaluate the analgesic characteristics and explore the underlying mechanism of YXB in the inflammatory pain model induced by Complete Freund's Adjuvant (CFA). MATERIALS AND METHODS: The analgesic effects were measured by Von Frey test. The expression of calcitonin gene-related peptide (CGRP) was quantified by immunofluorescence. The expression of immune factors was analyzed via Luminex assay. The further quantifications of C-C Motif chemokine ligand 3 (CCL3) were verified by Enzyme-linked immunosorbent assay (ELISA). The transmigration of macrophage and activation of microglia were evaluated by immunofluorescence. Spinal injections of purified CCL3, CCR1 antagonist (J113863) and CCR5 antagonist (Maraviroc) were used to clarify roles of CCL3 assumed in the pharmacological mechanism of YXB. RESULTS: In CFA mice, YXB ameliorated the mechanical allodynia in dose and time dependent way, suppressed the central sensitization in dose dependent way. In the L5 spinal cord, YXB downregulated the expression of macrophage M1 pro-inflammatory factors TNFRI and CCL3, inhibited the transmigration of circulating macrophage and the activation of microglia. Purified CCL3 led to the transmigration of macrophage, activation of microglia, central sensitization, and mechanical allodynia in the Sham mice. Inhibitors of CCR1 and CCR5 attenuated above symptoms in CFA mice. Purified CCL3 blocked YXB mediated down regulation of CCL3, inhibition of macrophage transmigration, but not activation of microglia. CONCLUSION: YXB exerts the analgesic effects by inhibiting CCL3-mediated peripheral macrophage transmigrate into spinal cord. This study provided a novel approach for inflammatory pain treatment and new insight into the pharmacological action of YXB.

Minimal Pilonidal Surgery vs. Common Wide Excision Operations: Better Well-Being and Comparable Recurrence Rates.

BACKGROUND: Pilonidal disease in the natal cleft is treated traditionally by a wide and deep excision of the affected area. There is growing awareness, however, to the advantages of minimally invasive surgeries. OBJECTIVES: To compare the efficacy of wide excision operations and minimal trephine surgery in patients with primary pilonidal disease. METHODS: In this retrospective study we examined surgical and inpatient records of 2039 patients who underwent surgery for primary pilonidal disease in five private hospitals between 2009 and 2012. Most procedures were of lay-open, primary midline closure, and minimal surgery types. Pilonidal recurrence rates were evaluated in a subset of 1260 patients operated by 53 surgeons each performing one type of surgery, regardless of patient characteristics or disease severity. RESULTS: With a mean follow-up of 7.2 years, 81.5%, 85%, and 88% of patients were disease-free after minimally invasive surgery, wide excision with primary closure, and lay-open surgery, respectively, with no statistically significant difference in recurrence rates. Minimal surgeries were usually performed under local anesthesia and involved lower pain levels, less need for analgesics, and shorter hospital stays than wide excision operations, which were normally performed under general anesthesia. The use of drainage, antibiotics, or methylene blue had no effect on recurrence of pilonidal disease. CONCLUSIONS: Minimally invasive surgeries have the advantage of reducing the extent of surgical injury and preserving patient's quality of life. They should be the treatment of choice for primary pilonidal disease.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Syzygium cumini (L.) Skeels extracts; in vivo anti-nociceptive, anti-inflammatory, acute and subacute toxicity assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels has been extensively used in the ancient medical system of Pakistan, India, Bangladesh, and Sri Lanka to combat diabetes, inflammation, and renal disorders. These health-promoting aspects of S. cumini are related to bioactive metabolites such as phenolic acids, anthocyanins, tannins, and flavonoids. AIM OF THE STUDY: Earlier to this study, we have reported S. cumini extracts as potential sources of bioactive compounds bearing antioxidant and anti-inflammatory properties. However, prior further suggesting S. cumini fruit extracts for consumption against inflammatory disorders, it was mandatory to validate the claim and explore toxicity of the extracts. This study aims to determine the in vivo anti-nociceptive, anti-inflammatory, acute, and subacute toxicity properties of S. cumini crude extracts, followed by identifying and quantifying bioactive metabolites. MATERIAL AND METHODS: In the present study, the anti-nociceptive and anti-inflammatory potential of S. cumini sequential crude extracts were evaluated using formalin and glutamate-induced paw licking method in mice. The acute and sub-acute toxicity assessment of active extract was performed by oral administration in rats. An acute toxicity trial was performed with two different doses, i.e., 2000 mg/kg and 3000 mg/kg for consecutive 14 days, whereas a sub-acute toxicity study was conducted at doses of 750 mg/kg and 1500 mg/kg for the next 28 days. Identification of bioactive compounds was performed using HPLC, and at the end, in silico docking calculations of identified compounds were performed. RESULTS: The 100% methanolic extract (SCME) protected the mice from painful stimulation of formalin and glutamate in a dose-dependent manner with the maximum effect of 49% and 67% at 200 mg/kg, respectively, followed by moderate and non-influential effects of 50% methanolic extract and dichloromethane (DCM) extracts when compared to control, i.e., normal saline. The results of acute toxicity recorded LD50 of SCME over 3000 mg/kg, and no antagonistic effects were recorded during the subacute study when SCME dispensed at the rate of 750 mg/kg and 1500 mg/kg. SCME was found to induce no adverse effects to kidney, heart, liver, spleen, and paired lungs examined by hematological, serum biochemical, histological analysis. HPLC analysis of S. cumini 100% methanolic extracts revealed the presence of delphinidin 3-glucoside, peonidin-3,5-diglucoside, scopoletin, and umbelliferone at the concentration of 127.4, 2104, 31.3, 10.4 µg/g whereas in 50% methanolic extract, the quinic acid, catechin, and myricetin were present at the concentration of 54.9, 63.7, 12.3 µg/g, respectively. Umbelliferone and scopoletin are newly reported compounds in the present study. In silico docking calculations of these compounds indicated the potential of anti-nociceptive and anti-inflammatory activities. CONCLUSIONS: These findings validate that S. cumini fruit extracts are a rich source of bioactive compounds that needs to be considered to enhance biological activities with lesser side effects.

Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: ECa 233 is a standardized extract of Centella asiatica (L.) Urban, a herb traditionally used to treat a number of diseases including neurological disorders. Accordingly, ECa 233 showed benefits on animal models of cognitive deficits, chronic stress and Parkinson's disease. Analgesic activity of ECa 233 was shown in Tail's flick test in rodent and relieving aphthous ulcer pain in man. Moreover, acute and sub-chronic toxicity testing in rodents and pharmacokinetic study in healthy volunteers, clinical trial phase I demonstrated good safety profiles of ECa 233. AIM OF THE STUDY: This study aims to evaluate the anti-nociceptive effects of ECa 233 and its synergistic effect with gabapentin on chronic neuropathic orofacial pain after 3 weeks infraorbital nerve chronic constriction injury in mice. The peripheral and central nociceptive activities are also examined. MATERIALS AND METHODS: Chronic neuropathic orofacial pain was induced by 3 weeks infraorbital nerve chronic constriction injury. Mice were treated with ECa 233 (30, 100 and 300 mg/kg) and gabapentin (10 mg/kg) by oral gavage starting on day 21 and going on for 14 consecutive days. Mechanical hyperalgesia and allodynia were measured on day 7, 14, 21, 28 and 35 after infraorbital nerve chronic constriction injury. At the end of the experiment, mice were observed for the sedative effect using the locomotor activity, the calcitonin gen-related peptide in trigeminal ganglion and c-fos expression in trigeminal nucleus caudalis were investigated after euthanasia. RESULTS: Infraorbital nerve chronic constriction injury gradually induced marked ipsilateral mechanical hyperalgesia and allodynia. The maximum hyperalgesia and allodynia response presented on day 21 and the response was remained constant until day 35. Treatment with either 300 mg/kg ECa 233 or 10 mg/kg gabapentin were able to attenuate mechanical hyperalgesia and allodynia. The downregulation of calcitonin gen-related peptide on ipsilateral trigeminal ganglion were observed in ECa 233 at 100 and 300 mg/kg and 10 mg/kg gabapentin-treated groups. The c-fos expression on ipsilateral trigeminal nucleus caudalis was also decreased in 300 mg/kg ECa 233 and 10 mg/kg gabapentin-treated groups. CONCLUSION: ECa 233 reduced hyperalgesia and allodynia by modulating the peripheral calcitonin gen-related peptide expression consequently alleviate the nociceptive activity in trigeminal nucleus caudalis. Further clinical trial to proof ECa 233's efficacy in neuropathic pain in man as well as possible attributable mechanism of action should be further investigated.

Effect of intracutaneous pyonex on analgesia and sedation in critically ill patients with mechanical ventilation.

The purpose of this study was to evaluate the effect of intracutaneous pyonex on analgesia and sedation in critically ill patients who underwent mechanical ventilation. A total of 88 critically ill patients were divided into a control group and an intervention group. Critical Care Pain Observation Tool (CPOT) and Richmond Agitation and Sedation Scale (RASS) were used to evaluate pain and agitation. The dosage and treatment period of sedative and analgesic drugs in the intervention group were notably lower than the control group (p < 0.05). Analgesia compliance time in the intervention group was superior to control group (p < 0.05). The shallow sedation compliance rate in the intervention group was significantly higher than the control group (p < 0.01). There was significant difference in blood gas analysis before and after treatment between the two groups (p < 0.05). After 2 h of sedation and analgesia, heart rate in the intervention group was lower than control group, but respiratory rate was higher than the control group (p < 0.05). The traditional analgesia and sedation combined with intracutaneous pyonex reduced the total amount and treatment period of sedative and analgesic drugs in critically ill patients throughout the treatment process, and it also decreased the adverse reactions such as blood pressure drops and respiratory depression.

Evaluation of the anti-inflammatory, antipyretic and antinociceptive activities of the hydroalcoholic extract of Rhynchospora nervosa (Vahl) Boeckeler (Cyperaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Rhynchospora nervosa (Vahl) Boeckeler (Cyperaceae), popularly known as "capim-estrela", is a native species widely distributed in Brazil. The whole plant has been used in local traditional medicine in the form of teas or syrups to treat inflammation, flu, nasal congestion, fever, swelling, and venereal disease. This is the first study to investigate the pharmacological properties of this species. AIM OF THE STUDY: The present study aimed to evaluate the in vivo anti-inflammatory, antipyretic and antinociceptive potential of the lyophilized hydroalcoholic extract of R. nervosa in heterogenic Swiss mice. In addition to pharmacological studies, the total phenol and flavonoid contents of the extract were determined. MATERIAL AND METHODS: The anti-inflammatory effect was evaluated through carrageenan-induced paw edema and peritonitis models. For the antinociceptive assay, the number of acetic acid-induced writhing responses in the animals was counted. Antipyretic activity was tested by yeast-induced pyrexia in mice and evaluated for 4 h. Nitric oxide (NO) concentration and leukocyte migration in the peritoneal fluid were quantified. The acute toxicity of the extract was also calculated. Quantitative analyses of total phenols and flavonoids in the extract were performed by spectrophotometric methods. RESULTS: In short, the lyophilized hydroalcoholic extract of R. nervosa showed low acute toxicity in the preclinical tests (LD50 = 3807 mg/kg). A significant anti-inflammatory effect was observed, with an average reduction of carrageenan-induced paw edema of 96.37%. Comparatively, indomethacin inhibited the development of the carrageenin paw edema by 97.52%. In the peritonitis test, a significant reduction in NO levels was recorded. A reduction in the number of white cells, notably monocytes, was also observed, confirming the anti-inflammatory effect. Writhing was reduced by 86.53%, which indicates antinociceptive activity. As for antipyretic activity, no positive effects of the extract were observed. The lyophilized hydroalcoholic extract of R. nervosa presented a high content of phenolic compounds (322.47 µg GAE/mg) and total flavonoids (440.50 µg QE/mg). CONCLUSION: The lyophilized hydroalcoholic extract of R. nervosa showed significant in vivo anti-inflammatory and antinociceptive activity in mice. These preliminary findings support the indication of the use of this species in folk medicine in Brazil for the treatment of inflammation.

Chemical profiling of Justicia vahlii Roth. (Acanthaceae) using UPLC-QTOF-MS and GC-MS analysis and evaluation of acute oral toxicity, antineuropathic and antioxidant activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Justicia vahlii Roth. (Acanthaceae), also called as kodasoori and bhekkar is an annual therophyte erect or decumbent herb used traditionally in toothache, skin diseases (itching, topical inflammation) and for the treatment of various respiratory disorders. AIM OF THE STUDY: The current study aimed at exploring pain cessation potential of J. vahlii Roth. via murine model of neuropathic pain and its phytochemical, toxicological and antioxidant profiles. MATERIALS AND METHODS: The hydro-alcoholic extract of J. vahlii (HAEJv) prepared by maceration technique was subjected to preliminary phytochemical screening, total bioactive content determination, UPLC-QTOF-MS and GC-MS analysis. Toxicity assessment was carried out by using brine shrimp lethality assay and acute oral toxicity test. Murine model of neuropathic pain was applied to assess the antineuropathic potential of the species. Furthermore effect of the extract on catalase, superoxide oxide dismutase (SOD), Glutathione (GSH), interleukin-1beta (IL-1ß) and total necrosis factor-alpha (TNF-α) was also studied. In vitro antioxidant profile was explored by using four methods; 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis(3-ethylbenothiazoline)-6-sulfonic acid (ABTS), CUPric reducing antioxidant capacity (CUPRAC) and Ferric reducing antioxidant power (FRAP) assay. RESULTS: The phytochemical screening revealed the presence of phenols, flavonoids, coumarins, alkaloids and lignans as the major classes of secondary metabolites. The extract was found rich in total phenolics content (TPC) and total flavonoids content (TFC) with identification of total 59 bioactives in UPLC-QTOF-MS and 40 compounds in GC-MS analysis. The extract was found nontoxic up to 4000 mg/kg (p.o.) in mice and no mortality observed in brine shrimp lethality assay. The HAEJv significantly reduced number of acetic acid induced abdominal constrictions at 100 mg/kg (p < 0.01) and 200 mg/kg (p < 0.001) and increased paw withdrawal threshold p < 0.05 at 100 mg/kg and p < 0.001 at 200 mg/kg, and an increase in tail withdrawal latency time p < 0.001 at 200 mg/kg was observed. The extract significantly increased levels of catalase, SOD and GSH while decreased IL-1ß and TNF-α levels in sciatic nerve tissue of mice. HAEJv showed highest antioxidant activity through CUPRAC method 121.32 ± 1.22 mg trolox equivalent per gram of dry extract (mg TE/g DE) followed by DPPH 81.334 ± 4.35 mg TE/g DE, FRAP 69.89 ± 3.05 mg TE/g DE and ABTS 38.17 ± 2.12 mg TE/g DE. CONCLUSION: The current study back the traditional use of J. vahlii in pain cessation through antioxidant based antineuropathic pain activity and revealed the extract non-toxic with number of functional phytoconstituents and warrants further research on isolation of the compounds and sub-acute toxicity studies.

Effective Dose of Prophylactic Oxytocin Infusion During Cesarean Delivery in 90% Population of Nonlaboring Patients With Preeclampsia Receiving Magnesium Sulfate Therapy and Normotensives: An Up-Down Sequential Allocation Dose-Response Study.

BACKGROUND: Oxytocin administration during cesarean delivery is the first-line therapy for the prevention of uterine atony. Patients with preeclampsia may receive magnesium sulfate, a drug with known tocolytic effects, for seizure prophylaxis. However, no study has evaluated the minimum effective dose of oxytocin during cesarean delivery in women with preeclampsia. METHODS: This study compared the effective dose in 90% population (ED90) of oxytocin infusion for achieving satisfactory uterine tone during cesarean delivery in nonlaboring patients with preeclampsia who were receiving magnesium sulfate treatment with a control group of normotensives who were not receiving magnesium sulfate. This prospective dual-arm dose-finding study was based on a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h, on clamping of the umbilical cord, in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician at 4 minutes after initiation of oxytocin infusion. The dose of oxytocin infusion for subsequent patients was decided according to the response exhibited by the previous patient in the group; it was increased by 2 IU/h after unsatisfactory response or decreased by 2 IU/h or maintained at the same level after satisfactory response, in a ratio of 1:9. Oxytocin-associated side effects were also evaluated. Dose-response data for the groups were evaluated using a log-logistic function and ED90 estimates were derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly greater for the preeclampsia group (n = 27) than for the normotensive group (n = 40) (24.9 IU/h [95% confidence interval {CI}, 22.4-27.5] and 13.9 IU/h [95% CI, 12.4-15.5], respectively); the difference in dose requirement was 10.9 IU/h (95% CI, 7.9-14.0; P < .001). The number of patients with oxytocin-related hypotension, defined as a decrease in systolic blood pressure >20% from baseline or to <90 mm Hg, was significantly greater in the preeclampsia group (92.6% vs 62.5%; P = .030), while other side effects such as ST-T depression, nausea/vomiting, headache, and flushing, were not significantly different. There was no significant difference in the need for additional uterotonic or uterine massage, estimated blood loss, and need for re-exploration for uncontrolled bleeding. CONCLUSIONS: Patients with preeclampsia receiving preoperative magnesium therapy need a greater intraoperative dose of oxytocin to achieve satisfactory contraction of the uterus after fetal delivery, as compared to normotensives.

Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial.

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.

Erding formula and bioactive markers in hyperuricemia: towards rational scientific approaches for the modernization of Traditional Chinese Medicine

Introduction: Traditional Chinese Medicine (TCM) represents one of the first holistic approaches in the world to treat and prevent disease. Herbal medicine is one of the major therapeutic remedy in TCM. It often involves multi-herb therapies instead of single herb preparations. Parallel to western medicine, hundreds of herbal formulas have been made available as finished products. Currently, the use of herbal products is popular as treatment option or to complement western medicine. Indications of the herbal formulas were established by TCM terms such as heat-clearing and/or detoxifying which lack modern pharmacological meanings. It is difficult for people without relevant background to understand such terms and their implications for treatments. Furthermore, due to the quality control issues of herbal medicines which contain multiple constituents, consumers may be confronted with the risk of using unstandardized products. Hence, in this thesis, the modernization of TCM is discussed through employing scientific pharmaceutical approaches to a traditional formula, called Erding formula (EF). The aim was to investigate if a new indication, hyperuricemia, can be assigned to a heat-clearing and detoxifying formula. Our hypothesis was: Can Erding formula be used for hyperuricemia treatment and is esculetin a bioactive marker for this new indication? Methods: A hypoxanthine and potassium oxonateinduced hyperuricemic mouse model, a xyleneinduced inflammatory mouse model, and an acetic acidinduced pain model were used to investigate EF and its constituent herbs. The quantity of esculetin was measured by high-performance liquid chromatography. The therapeutic effect of esculetin was assessed using potassium oxonate induced hyperuricemic mouse model, and esculetin and its metabolites were characterized in serum via ultra-performance liquid chromatographyquadrupole time-of-flight mass spectrometry. To develop a modern dosage form, a laboratory-scale wet bead milling approach was employed to prepare esculetin nanocrystals. The formulation was further optimized by design of experiment, and an optimized formulation was then characterized for its saturation solubility and short-term stability. Results: The study showed that EF and Viola yedoensis Makino (Viola) lowered uric acid (UA) levels, while EF and all four individual herbs had antiinflammatory and analgesic activities. These findings revealed that EF was able to treat hyperuricemia and suggested that Viola was the main herb in EF on reducing UA levels. The study showed that esculetin significantly reduced UA levels and six metabolites of esculetin were identified in serum. This confirms that esculetin was absorbed and is a suitable bioactive and quality control marker for EF in hyperuricemia treatment. An esculetin-Povacoat nanocrystal formulation with a 200 nm particle size was successfully prepared. The formulation presented up to a 1.5-fold increase in saturation solubility compared to the bulk esculetin and it was stable for 180 days. Conclusion: The studies proved that Erding formula can be used for hyperuricemia treatment with esculetin as bioactive quality control marker. As well, a new nano-sized formulation of the bioactive marker, esculetin, was created. This presented the possibility to develop an innovative nanotechnological product of the active substances derived from herbal medicine. The findings facilitated a better understanding of TCM terms and concept through mechanistic scientific experiments. This study revealed a potential pathway and an idea to modernize TCM without setting aside its unique concepts. This might increase the global acceptance of TCM products. Furthermore, the TCM concept might be useful in the development of multi-component drug products

Medicina Tradicional Chinesa (MTC) representa uma das primeiras abordagens holísticas em âmbito global para tratar e prevenir doenças. A fitoterapia consiste na principal terapia na MTC. Frequentemente, envolve terapias com múltiplas ervas em vez de preparações individuais. Paralelamente à medicina ocidental, centenas de fórmulas herbais foram disponibilizadas como produtos acabados. Atualmente, o uso de produtos fitoterápicos é popular como opção de tratamento ou para complementar a medicina ocidental. As indicações das fórmulas fitoterápicas foram estabelecidas pelos termos da MTC, tais como "limpeza pelo calor e / ou desintoxicante", que não têm significados farmacológicos modernos. É difícil para a população em geral e mesmo para profissionais sem histórico relevante na área entender tais termos e suas implicações para os tratamentos. Além disso, devido às questões de controle de qualidade dos medicamentos fitoterápicos que contêm múltiplos constituintes, os pacientes podem ser confrontados com o risco de usar produtos não padronizados. Assim, nessa tese, a modernização da MTC é discutida por meio da utilização de abordagens farmacêuticas científicas para uma fórmula tradicional, denominada fórmula de Erding (FE). O objetivo foi o de investigar se uma nova indicação, a hiperuricemia, pode ser atribuída a uma fórmula desintoxicante e de compensação de calor. Nossa hipótese foi: a fórmula de Erding pode ser usada para tratamento de hiperuricemia e a esculetina é um marcador bioativo para essa nova indicação? Foi empregado modelo de camundongo hiperuricêmico induzido por hipoxantina e oxonato de potássio, outro modelo de camundongo inflamatório induzido por xileno e, adicionalmente, modelo de dor induzida por ácido acético. Esses modelos foram usados para investigar a FE e suas ervas constituintes. A quantidade de esculetina foi determinada por cromatografia líquida de alta eficiência. O efeito terapêutico da esculetina foi avaliado utilizando modelo de camundongo hiperuricêmico induzido por oxonato de potássio, e a esculetina e seus metabólitos foram caracterizados no soro por cromatografia líquida de alto desempenho - espectrometria de massa. Para desenvolver forma farmacêutica moderna, uma abordagem de moagem em escala úmida reduzida foi empregada tendo em vista a preparação de nanocristais de esculetina. A formulação foi ainda otimizada empregado planejamento experimental. Essa fórmula foi caracterizada quanto à sua solubilidade de saturação e estabilidade a curto prazo. O estudo mostrou que a FE e a Viola yedoensis Makino (Viola) reduziram os níveis de ácido úrico (AU), enquanto a FE e as quatro plantas individuais apresentaram atividades antiinflamatória e analgésica. Esses resultados revelaram que a FE foi capaz de tratar a hiperuricemia e sugeriu que a viola foi a principal erva da FE na redução dos níveis de AU. O estudo mostrou também que a esculetina reduziu significativamente os níveis de AU e os seis metabólitos da esculetina foram identificados no soro. Tal resultado confirma que a esculetina foi absorvida e pode ser usada como marcador de controle bioativo e de qualidade para FE, no tratamento da hiperuricemia. A formulação de nanocristais de esculetin-povacoat® apresentou tamanho de partícula de 200 nm. A formulação apresentou aumento de 1,5 vezes na solubilidade de saturação em comparação com a esculetina em escala micrométrica e manteve-se estável durante 180 dias. Os estudos comprovaram que a fórmula de Erding pode ser utilizada no tratamento da hiperuricemia empregando a esculetina como marcador bioativo de controle de qualidade. Além disso, foi desenvolvida formulação inovadora, em escala nanométrica, do marcador bioativo, a esculetina. Esse resultado permitiu desenvolver produto com base nanotecnológica das substâncias ativas derivadas do fitoterápico, assim comol permitiram melhor compreensão dos termos e dos conceitos da MTC por meio de experimentos científicos mecanicistas. Esse estudo revelou potencial para a modernização da MTC sem excluir seus conceitos únicos. Isso pode aumentar a aceitação global dos produtos MTC. Além disso, o conceito de MTC pode ser útil no desenvolvimento de medicamentos de múltiplos componentes

Effect of intraperitoneal local anesthesia on enhanced recovery outcomes after bariatric surgery: a randomized controlled pilot study.

BACKGROUND: Patients with extreme obesity are at high risk for adverse perioperative events, especially when opioid-centric analgesic protocols are used, and perioperative pain management interventions in bariatric surgery could improve safety, outcomes and satisfaction. We aimed to evaluate the impact of intraperitoneal local anesthesia (IPLA) on enhanced recovery after bariatric surgery (ERABS) outcomes. METHODS: We conducted a prospective double-blind randomized controlled pilot study in adherence to an a priori peer-reviewed protocol. Patients undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) with an established ERABS protocol between July 2014 and February 2015 were randomly allocated to receive either IPLA with 0.2% ropivacaine (intervention group) or normal saline (control group). We measured pain scores, analgesic consumption and adverse effects. Functional prehabilitation outcomes, including peak expiratory flow (PEF) and the Six Minute Walk Test (6MWT) and Quality of Recovery Survey-40 (QoR-40) scores, were assessed before surgery, and 1 day and 7 days postoperatively. RESULTS: One hundred patients were randomly allocated to the study groups, of whom 92 completed the study, 46 in each group. There were no statistically significant differences between the 2 groups in baseline characteristics or any primary or secondary outcomes. Pain scores and analgesic consumption were low in both groups. There were no adverse events. Significant declines in PEF and 6MWT and QoR-40 scores were noted on postoperative day 1 in both groups; the values returned to baseline on postoperative day 7 in both groups. CONCLUSION: Intraperitoneal local anesthesia with ropivacaine did not reduce postoperative pain or analgesic consumption when administered intraoperatively to patients undergoing LRYGB. Standardization of the ERABS protocol benefited patients, with functional prehabilitation outcomes returning to baseline postoperatively. Trial registration: ClinicalTrials.gov no. NCT02154763.

Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Extensive evidence suggests that alpha-lipoic acid (ALA) is effective in diabetic neuropathy pain management. However, little is known on its safety and efficacy in reducing idiopathic pain in normoglycemic subjects. The aim of this study was to evaluate ALA food supplement safety and efficacy in the reduction of different forms of idiopathic pain. METHODS: Two-hundred and ten normoglycemic adults suffering from idiopathic pain (i.e. 57 subjects with primitive neuropathic pain, 141 subjects with arthralgia with unknown etiology, and 12 subjects with idiopathic myalgia) were randomized to receive placebo, 400 mg/day, or 800 mg/day of ALA. Participants underwent two visits (at baseline = t0, and after 2 months = t1) in which two validated questionaries for pain (numerical rating scale [NRS] and visual analogue scale [VAS]) were collected; fasting blood glucose assessment, adverse effects, and renal and hepatic toxicity were also monitored. RESULTS: At t1, none of subjects treated with ALA reported a decreased glycemia or adverse effects. The treated subjects showed a significant reduction in NRS (p < 0.001) while the placebo group did not show any NRS reduction (p = 0.86). Similar results were also obtained for VAS. Statistical analysis aimed at detecting possible differences in NRS and VAS scores among treatment groups based on the source of pain did not reveal any significant effect. CONCLUSIONS: Since the management of idiopathic pain is challenging for physicians, the use of ALA food supplements could be a feasible option, based on its safety and efficacy compared to commonly-used analgesic drugs.

Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms.

BACKGROUND: The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain. METHODS: A retrospective, electronic record-based cohort study of StrainprintTM users with self-reported endometriosis was conducted. Self-rated cannabis efficacy, defined as a function of initial and final symptom ratings, was investigated across the included symptom clusters of cramps, pelvic pain, gastrointestinal pain, nausea, depression, and low libido. Cannabis dosage form, dose and cannabinoid ratio information was also recorded. RESULTS: A total number of 252 participants identifying as suffering endometriosis recorded 16193 sessions using cannabis between April 2017 and February 2020. The most common method of ingestion was inhalation (n = 10914, 67.4%), with pain as the most common reported symptom being treated by cannabis (n = 9281, 57.3%). Gastrointestinal symptoms, though a less common reason for cannabis usage (15.2%), had the greatest self-reported improvement after use. Inhaled forms had higher efficacy for pain, while oral forms were superior for mood and gastrointestinal symptoms. Dosage varied across ingestion methods, with a median dose of 9 inhalations (IQR 5 to 11) for inhaled dosage forms and 1 mg/mL (IQR 0.5 to 2) for other ingested dosage forms. The ratio of THC to CBD had a statistically significant, yet clinically small, differential effect on efficacy, depending on method of ingestion. CONCLUSIONS: Cannabis appears to be effective for pelvic pain, gastrointestinal issues and mood, with effectiveness differing based on method of ingestion. The greater propensity for use of an inhaled dosage delivery may be due to the rapid onset of pain-relieving effects versus the slower onset of oral products. Oral forms appeared to be superior compared to inhaled forms in the less commonly reported mood or gastrointestinal categories. Clinical trials investigating the tolerability and effectiveness of cannabis for endometriosis pain and associated symptoms are urgently required.

Lantana canescens (Kunth) inhibits inflammatory and hyperalgesic responses in murine models.

ETHNOPHARMACOLOGICAL RELEVANCE: Lantana canescens is popularly known in Brazil as "cidreirinha" or "chumbinho-branco". It is found in Pantanal biome and its flowers and leaves are used in traditional medicine to treat pain and inflammation. Information about this species is limited to the activity of isolated essential oils. Studies with different extracts, composition, and biological properties are still scarce. AIM OF THIS STUDY: The objective of this study was to evaluate the anti-inflammatory and anti-hyperalgesic activity of the hydroethanolic extract of L. canescens aerial parts. MATERIALS AND METHODS: The hydroethanolic extract L. canescens aerial parts (HELc) was analyzed using HPLC-DAD-EM. Male and female Swiss mice weighing 18-25 g were used in the in vivo assays. Acute toxicity was assessed (2000 mg/kg); anti-inflammatory activity through paw edema, mast cell degranulation and peritonitis, and anti-hyperalgesic activity through abdominal writhing assays induced by acetic acid and formalin sensitization, were evaluated using the doses of 3, 30 and 300 mg/kg. RESULTS: The phytochemical characterization of HELc confirmed the presence of glycosylated iridoids (theveside, theviridoside), verbascosides and flavonoids. The HELc did not present toxicity in the evaluated dose. HELc reduced formation of paw edema, degranulation of peritoneal mast cells and infiltration of polymorphonuclear cells into the animals peritoneal cavity. In addition, HELc decreased the number of abdominal writhing induced by acetic acid and the time of paw licking in the evaluation of formalin sensitization. CONCLUSIONS: These results confirm the anti-inflammatory and anti-hyperalgesic effects of hydroethanolic extract of L. canescens, validating the use of this plant in folk medicine.

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

OBJECTIVE: To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain. METHODS: The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination. KEY FINDINGS: DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively). CONCLUSIONS: All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain.

A Call to Action by the Italian Mesotherapy Society on Scientific Research.

Mesotherapy (local intradermal therapy, LIT) is a technique used to slowly spread drugs in tissues underlying the site of injection to prolong the pharmacological effect with respect to intramuscular injection. Recommendations for proper medical use of this technique have been made for pain medicine and rehabilitation, chronic venous disease, sport medicine, musculoskeletal disorders, several dermatological conditions, skin ageing, and immune-prophylaxis. Although mesotherapy is considered a valid technique, unresolved questions remain, which should be answered to standardize methodology and dosing regimen as well as to define the right indications in clinical practice. New randomized controlled trials are needed to test single products (dose, frequency of administration, efficacy and safety). Even infiltration of substances for dermo-cosmetic purposes must be guided by safety and efficacy tests before being proposed by mesotherapy. In this article, we put forth a preclinical and clinical research plan and a health technology assessment as a call to action by doctors, researchers and scientific societies to aid national health authorities in considering mesotherapy for prevention, treatment and rehabilitation paths.

Comparison between acupuncture therapy and gabapentin for chronic pain: a pilot study.

BACKGROUND: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). METHODS: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. RESULTS: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. CONCLUSION: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. TRIAL REGISTRATION NUMBER: NCT01678586 (ClinicalTrials.gov).

The essential oil from Ferulago angulata (Schltdl.) Boiss. fruits exerting potent analgesic and anti-inflammatory effects.

Ferulago angulata is an aromatic herb that its fruits are utilized widely in Persian traditional medicine as a painkiller and reliving inflammation-based disorders. Considering the higher content of essential oil in the fruits, the oil's anti-inflammatory and analgesic activities were investigated in an animal model in vivo. The analgesic effects of F. angulate fruits essential oil was evaluated via testing the writhing triggered by acetic acid examination and hot plate technique. Moreover, the acute anti-inflammatory effects were studied through the paw edema triggered in mice. Using all examined doses (25, 50, and 100 mg/kg) of the oil revealed an analgesic impact considering the increment in the reaction time needed for the hot plate approach. Furthermore, 50 and 100 mg/kg doses of the oil caused a reduction in the frequency of writhes in the mice. It was observed that all examined doses of the oil (25, 50, and 100 mg/kg) caused inflammatory reduction. The findings indicated that the oil may possess significant activities against acute inflammation. It had both peripheral and central pain-killing impacts. cis-ß-ocimene (58.0%) followed by α-pinene (10.0%) as the main constituents of the oil can be considered as the responsible compounds to manage the inflammation and pain.

Identification of the Active Principle Conferring Anti-Inflammatory and Antinociceptive Properties in Bamboo Plant.

Early plants began colonizing earth about 450 million years ago. During the process of coevolution, their metabolic cellular pathways produced a myriad of natural chemicals, many of which remain uncharacterized biologically. Popular preparations containing some of these molecules have been used medicinally for thousands of years. In Brazilian folk medicine, plant extracts from the bamboo plant Guadua paniculata Munro have been used for the treatment of infections and pain. However, the chemical basis of these therapeutic effects has not yet been identified. Here, we performed protein biochemistry and downstream pharmacological assays to determine the mechanisms underlying the anti-inflammatory and antinociceptive effects of an aqueous extract of the G. paniculata rhizome, which we termed AqGP. The anti-inflammatory and antinociceptive effects of AqGP were assessed in mice. We identified and purified a protein (AgGP), with an amino acid sequence similar to that of thaumatins (~20 kDa), capable of repressing inflammation through downregulation of neutrophil recruitment and of decreasing hyperalgesia in mice. In conclusion, we have identified the molecule and the molecular mechanism responsible for the anti-inflammatory and antinociceptive properties of a plant commonly used in Brazilian folk medicine.