Quasi-Static, Poiseuille Flow of Analgesics from an Elastomeric Pump: Theoretical Determination of Infusion Times and Toxicity Conditions

Background: Elastomeric pumps (elastic balls into which analgesics or antibiotics can be inserted) push medicines through a catheter to a nerve or blood vessel. Since elastomeric pumps are small and need no power source, they fit easily into a pocket during infusion, allowing patient mobility. Elastomeric pumps are widely used and widely studied experimentally, but they have well-known problems, such as maintaining reliable flow rates and avoiding toxicity or other peak-and-trough effects. Objectives: Our research objective is to develop a realistic theoretical model of an elastomeric pump, analyze its flow rates, determine its toxicity conditions, and otherwise improve its operation. We believe this is the first such theoretical model of an elastomeric pump consisting of an elastic, medicine-filled ball attached to a horizontal catheter. Method: Our method is to model the system as a quasi-Poiseuille flow driven by the pressure drop generated by the elastic sphere. We construct an engineering model of the pressure exerted by an elastic sphere and match it to a solution of the one-dimensional radial Navier-Stokes equation that describes flow through a horizontal, cylindrical tube. Results: Our results are that the model accurately reproduces flow rates obtained in clinical studies. We also discover that the flow rate has an unavoidable maximum, which we call the “toxicity bump”, when the radius of the sphere approaches its terminal, unstretched value—an effect that has been observed experimentally. Conclusions: We conclude that by choosing the properties of an elastomeric pump, the toxicity bump can be restricted to less than 10% of the earlier, relatively constant flow rate. Our model also produces a relation between the length of time that the analgesic fluid infuses and the physical properties of the fluid, of the elastomeric sphere and the tube, and of the blood vessel into which the analgesic infuses. From these, we conclude that elastomeric pumps can be designed, using our simple model, to control infusion times while avoiding toxicity effects.

Design, Synthesis of Analgesics and Anticancer of Some New Derivatives of Benzimidazole

This work, contains some new compounds from benzimidazole derivatives, which are synthesized by condensation of Orthophenylene diamine and Carbon disulfide resulting in 2-Mercapto-benzimidazole which is treated by alcoholic potassium hydroxide forming potassium salt of 2-mercaptobenzimidazole which reacts with different substances (alkyl chloroacetates, chloroacetic chloride, alkyl halides) also the ethoxy carbonyl methyl thiobenzimidazole reacts with different amines. In addition to chloromethyl benzimidazole which resulted from the reaction between orthophenylene diamine and chloroacetic acid, which reacted with different amines. The synthesized compound tested as analgesics and anticancer activity the new derivatives revealed moderate, strong and very strong analgesics and moderate and strong anticancer activity.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain(CMP)is a common occurrence in clinical practice and there are a variety of options for the treatment of it.However,the pharmacological therapy is still considered to be a primary treatment.The recent years have witnessed the emergence of opioid crisis,yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly.The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics.The purpose of this consensus is to present the application of nonsteroidal antiinflammatory drugs,serotonin norepinephrine reuptake inhibitors,serotonin and norepinephrine reuptake inhibitors,muscle relaxants,ion channel drugs and topical drugs in CMP.

Research Progresses in Effects of Analgesics and Sedatives on Intracranial Pressure of Neurointensive Care Patients

At present, there are some concerns and problems to treat neurointensive care patients by using analgesics and sedatives. Conditions of neurointensive care patients change quickly. For neurointensive care patients who cannot have auxiliary examination timely, clinicians judge intracranial conditions mainly through relevant monitoring devices and consciousness and pupil changes of patients. The use of analgesics and sedatives is limited due to worry about influences on consciousness evaluation and judgment and different degrees of inhibition on cardiovascular system and respiratory system. Common sedatives (e.g. benzodiazepines) and common analgesics (e.g. morphine, fentanyl and sufentanil) both may inhibit respiration. The specification often provides taboos for the use of drugs by patients with increase intracranial pressure (ICP) and craniocerebral injuries. Through literature review, the author analyzed influences of analgesics and sedatives on ICP of neurointensive care patients comprehensively.

Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healingassociated genes

Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.

Gender Differences in Usage of Over-the-Counter Analgesics among Norwegian Adolescents

Introduction: Usage of over-the-counter (OTC) analgesic has increased among Norwegian adolescents since 2001. It has been noted that females tend to have a higher usage compared to males. In this paper we explore this gender difference. Data: Our dataset consists of 284,674 from Norwegian adolescents attending junior high school and high school between 2014 and 2017. Methods: The econometric approach consists of applying ordered logistic regressions with usage of OTC analgesics as the dependent variable and a dichotomous gender variable as the independent variable. Control variables include variables such as frequency of physical and mental health problems and other sociodemographic variables. Results: Gender, physical and mental health problems and various sociodemographic variables are found to have a significant effect on usage of OTC analgesics. Females are predicted to use significantly more analgesics. A large proportion of the gender difference evaporates when controlling for various other determinants. Conclusion: A considerable part of the observed gender difference in OTC analgesic usage can be traced back to differences in frequency and severity of physical and mental health problems. Part of the gender difference in usage, however remains unexplained.

Analgesic and anti-inflammatory activity of Cotinus coggygria Scop.extracts in vivo

Objective:To assess the analgesic and anti-inflammatory effects of standardized extract of Cotinus coggygria(C.coggygria)in different animal models.Methods:C.coggygria extracts(25,50,and 100 mg/kg)were administered to rats and mice(n=6)during hot plate,tail-flick,acetic acid-induced writhing,and formalin tests to determine its analgesic efficacy.The anti-inflammatory activity of C.coggygria extracts was evaluated by histamine and carrageenan-induced paw edema,cotton pellet-induced granuloma,and acetic acid-induced peritoneal capillary dye leakage tests.Results:C.coggygria extracts(50 and 100 mg/kg)significantly alleviated thermal and chemical-induced pain in rodents(P<0.05).It also demonstrated notable anti-inflammatory properties by mitigating histamine and carrageenan-induced paw edema,granuloma deposits,and vascular permeability(P<0.05).Moreover,C.coggygria extracts remarkably reduced TNF-α,IL-1β,IL-6,COX-2,and oxidative stress in rat paws(P<0.05).Carrageenan-induced histological aberrations in hind paw tissues were effectively(P<0.05)mitigated by treatment with C.coggygria extracts.Conclusions:C.coggygria Scop.extracts show analgesic and anti-inflammatory effects via inhibition of COX-2 and inflammatory and oxidative mediators.

Anticancer,Anti-inflammatory,Analgesic,and Anxiolytic Effects of Koumine and Their Molecular Mechanisms

Koumine is an indole alkaloid monomer extracted from the Chinese herb Gelsemium elegans,which has a variety of pharmacological effects.This paper provides a comprehensive summary of the pharmacological effects and molecular mechanisms of koumine,with a particular emphasis on its mechanisms of action in the context of anticancer,anti-inflammatory,analgesic,and anxiolytic properties.The aim is to provide a theoretical foundation for further research and the application of koumine in clinical practice.

Analgesic Effect of Combined Spinal-Epidural Anesthesia and its Effect on TNF-α and CRP Levels in Elderly Patients with Hip Fracture During Surgical Treatment

Objective:To observe the analgesic effect of combined spinal and epidural anesthesia on older patients undergoing hip fracture surgery.Method:One hundred and twenty elderly hip fracture surgery patients treated in our hospital from January 2021 to December 2022 were selected and randomly divided into two groups,with 60 cases in the experimental group and 60 in the control group.The experimental group was given combined spinal-epidural anesthesia intervention measures,while the control group was given epidural anesthesia intervention measures.The analgesic effect,tumor necrosis factor-alpha(TNF-α),C-reactive protein(CRP)levels,and other observation indicators were analyzed after anesthesia intervention.Result:After the intervention,the analgesic effect and the evaluation results of the subjects in the experimental group were better than those in the control group(P<0.05);the obtained values of TNF-αand CRP levels in the experimental group were higher than those of the control group(P<0.05).Conclusion:The combined spinal-epidural anesthesia intervention demonstrated positive outcomes.The analgesic effect of patients during surgery and their inflammatory factor levels improved,which makes this intervention worthy of clinical application and promotion.

Combining Human and Rodent Genetics to Identify New Analgesics

Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacolog- ically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design： the use of controlled inhibition of peripheral tetrahydrobiopterin （BH4） synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially iden- tified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype （present in 25% of Cau- casians） of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 （GCH1）. Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, target- ing the last enzyme of the BH4 synthesis pathway, sepiapterin reductase （SPR）, allows reduction of patholog- ical BH4 production without completely blocking physio- logical BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarker of target engagement, allowing potential quantification of drug efficacy. The emerging development of therapeutics that target BH4 synthesis to treat chronic pain illustrates the power of combining human and mouse genetics： human genetic studies for clinical selection of relevant targets, coupled with causality studies in mice, allowing the rational engineering of new analgesics.

Epoxymicranthols A-N,5,9-Epoxygrayanane Diterpenoids as Potent Analgesics from Rhododendron micranthum

Main observation and conclusion Fifteen 5,9-epoxygrayanane diterpenoids(1-15)including fourteen new ones,epoxymicranthols A-N(1-14),were isolated from the leaves extract of Rhododendron micranthum.Their structures were elucidated via extensive spectroscopic methods and ^(13)C NMR-DP4+analysis,and the absolute configurations of 1,3-10,14,and 15 were confirmed by single-crystal X-ray diffraction analysis.

Clinical Research on Nourishing Yin and Unblocking Meridians Recipe Combined with Opioid Analgesics in Cancer Pain Management

Objective： To investigate the analgesic effects of Nourishing yin and Unblocking meridians Receipe （NUR） combined with opioid analgesics in managing cancer pain. Methods： All the patients enrolled were differentiated as of yin deficiency and meridian blocked syndrome type of TCM. Forty-one of them in the treated group were treated with NUR combined with opioid analgesics, while 43 of them in the control group were given opioid analgesics alone with successive 14 days as one treatment course for both groups. Results： The indexes of the treated group were superior to those in the control group as to the degree of pain-relieving, the therapeutic effect of analgesia, the occurrence frequency of cancer pain every day and its duration each time, the analgesic initial time, and the quality of life. Conclusion： NUR combined with opioid analgesics in cancer pain management was more effective than opioid analgesics alone. KEY WORDS

Gait Assessment of Pain and Analgesics: Comparison of the DigiGait^(TM) and CatWalk^(TM） Gait Imaging Systems

Investigation of pain requires measurements of nociceptive sensitivity and other pain-related behaviors.Recent studies have indicated the superiority of gait analysis over traditional evaluations(e.g., skin sensitivity and sciatic function index [SFI]) in detecting subtle improvements and deteriorations in animal models. Here,pain-related gait parameters, whose criteria include(1)alteration in pain models,(2) correlation with nociceptive threshold, and(3) normalization by analgesics, were identified in representative models of neuropathic pain(spared nerve injury: coordination data) and inflammatory pain(intraplantar complete Freund’s adjuvant: both coordination and intensity data) in the DigiGait^TM and CatWalk^TM systems. DigiGait^TM had advantages in fixed speed(controlled by treadmill) and dynamic SFI, while CatWalk^TM excelled in intrinsic velocity, intensity data,and high-quality 3 D images. Insights into the applicability of each system may provide guidance for selecting the appropriate gait imaging system for different animal models and optimization for future pain research.

Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain

Osteoarthritis(OA)is the most common musculoskeletal disease,and it is a major cause of pain,disability and health burden.Pain is the most common and bothersome presentation of OA,but its treatment is still suboptimal,due to the short-term action of employed analgesics and their poor adverse effect profile.Due to their regenerative and anti-inflammatory properties,mesenchymal stem cells(MSCs)have been extensively investigated as a potential therapy for OA,and numerous preclinical and clinical studies found a significant improvement in joint pathology and function,pain scores and/or quality of life after administration of MSCs.Only a limited number of studies,however,addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs.In this paper,we review the evidence reported in literature that support the analgesic action of MSCs in OA,and we summarize the potential mechanisms of these antinociceptive effects.

Development and Evaluation of Stable Paracetamol Loaded Solid Dispersion with Enhanced Analgesic and Hepatoprotective Property

Paracetamol (PCM) is enlisted in the WHO model list as an essential medicine for pain and palliative care, but at overdose, it causes hepatic damage. This study was designed to assess the analgesic efficacy and hepatoprotective property of a solid dispersion (SD) loaded with PCM. A number of PCM loaded formulations (PSDs) were fabricated using silica alone or in combination with polyethylene glycol and/or Na-citrate followed by in-vitro dissolution profiling. Selected PSDs with improved dissolution profile were subjected to solid-state characterization (DSC, PXRD, FTIR, and SEM), stability study along with investigation of in-vivo analgesic efficacy and effect on hepatocytes. Among these, PSD10 showed a rapid and significantly higher in-vitro drug release than pure PCM. This improvement was distinct to other PSDs also. Solid-state characterization of PSD10 authenticated the conversion of crystalline PCM to amorphous form upon formulation. Subsequent oral administration of PSD10 in Swiss albino mice showed 1.44-fold greater analgesic efficacy than pure PCM at dose 30 mg/kg. Besides, at acute toxic dose, liver histology of PSD10 mice was comparable with NC mice indicating hepatic protection upon formulation, whereas the PCM mice showed extensive hepatic necrosis which was also endorsed by significantly higher values of SGPT, SGOT, and ALP than PSD10 mice. Finally, an accelerated stability study of PSD10 performed according to the guideline of ICH noticed no remarkable deviation in its dissolution performance as well as crystalline nature. Thus, this newly developed PSD10 may be a safe and promising alternative for pain management and palliative care.

Study on the Anti-Inflammatory and Analgesic Mechanisms of Breast Lump Resolution Detergent in a Rat Model of Breast Hyperplasia

Objective: This study aimed to investigate the anti-inflammatory and analgesic mechanisms of a breast lump resolution detergent in a rat model of breast hyperplasia. Methods: A rat model of breast hyperplasia was established using injections of estradiol benzoate combined with progesterone. The effects of the breast lump resolution detergent on nipple height and diameter in the rat model were observed, along with its impact on serum levels of estradiol (E2), prolactin (PRL), and progesterone (P). Additionally, the study examined the morphological changes in breast tissue. The impact of the breast nodule detergent on blood rheology parameters was also observed. Furthermore, the anti-inflammatory effect of the breast nodule detergent was assessed using the cotton ball granuloma experiment, and the analgesic effect was observed using the writhing test. Results: The breast lump resolution detergent reduced nipple height and diameter in the rat model, decreased serum levels of E2, PRL, and P, and alleviated pathological changes in breast tissue. It also lowered hemorheological parameters including whole blood high, medium, and low shear viscosity, plasma viscosity, red blood cell hematocrit, red blood cell aggregation index, red blood cell deformability index, red blood cell electrophoresis time, and erythrocyte sedimentation rate in the acute “blood stasis” rat model. The detergent reduced the weight of cotton ball granulomas in mice and decreased the number of writhing episodes caused by acetic acid. Conclusion: The breast lump resolution detergent demonstrates favorable therapeutic effects in treating breast hyperplasia, promoting blood circulation and removing blood stasis, exerting anti-inflammatory properties, and providing analgesic effects. The downregulation of serum E2 and PRL levels and the upregulation of P levels may be critical mechanisms underlying its efficacy.

Mechanism of Cinnamomum camphora essential oil for analgesia based on gas chromatography-mass spectrometry integrated network pharmacology

This study aims to explore the analgesic ingredients and mechanism of Cinnamomum camphora essential oil(CCEO).The constituents in CCEO were characterized qualitatively by gas chromatography-mass spectrometry.Targets related to active ingredients were collected by PubChem and Swiss Target Prediction.Targets related to pain were screened by TTD and OMIM database,and compound-target network was established by Cytoscape software.Gene ontology(GO)function and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of targets were carried out by DAVID database.Protein-protein interaction(PPI)network was established and analyzed by STRING database.Molecular docking method was used to verify the interaction between main components and relevant core targets.A total of 13 compounds were identified in CCEO,and 58 related targets were predicted.GO function enrichment analysis revealed that the selected targets were mainly involved in biological processes such as chemical synaptic transmission and molecular function such as neurotransmitter receptor activity;24 signal pathways were screened by KEGG pathway enrichment analysis,including neuroactive ligand-receptor interaction,retrograde endocannabinoid signaling and calcium signaling pathway.Docking results showed that the main constituents had certain affinities with the key targets.The active ingredients in CCEO regulated multiple signaling pathways to ameliorate pain through AR,ACHE,ESR1,GABRG2,PTGS2 and PPARγ.

大麻素1型受体参与疼痛调节机制的研究进展

大麻素1型受体(CB1R)是近年来研究较为广泛的内源性大麻素受体之一,在中枢和外周神经系统均有表达。CB1R位于突触前膜,通过逆行抑制性突触传递调节神经递质的释放,是治疗疼痛的有效靶点。激活CB1R对伤害性、病理性和炎性疼痛均具有镇痛效应,拮抗CB1R可引起疼痛敏化。本文通过对CB1R结构功能、信号转导、镇痛机制方面进行综述,为进一步了解疼痛的病理生理学机制及探索更优疼痛治疗方法提供参考。

Coagulation and analgesic effects of aqueous extract of peanut shells on mice

Background:Peanut shells are a commonly discarded byproduct of peanut processing.However,recent studies have shown that they contain bioactive compounds that have potential health benefits.Specifically,water extract from peanut shells has been identified as a promising source of these compounds.Therefore,investigating the effects of water extract from peanut shells on coagulation and analgesia in mice could have significant implications for human health.Methods:(1)Analgesic experiments:The analgesic effect of the aqueous extract of peanut shells was observed by the hot plate method in mice.The aspirin group was used as a positive control group for analgesic experiments.(2)Coagulation experiment:the coagulation effect of the aqueous extract of peanut shells was observed by the capillary method and slide method.Yunnan Baiyao group was the positive control group of the coagulation test.Results:(1)The analgesic effect of peanut shell water extract on mice was prolonged with the increase in dose.The low,medium,and high dose groups of peanut shell could improve the pain domain of mice induced by the hot plate method in a certain period(P<0.05);with the increase of peanut shell water extract dose,liver weight coefficient increased(P<0.05).(2)Peanut shell water extract coagulated mice,and the high-dose group of peanut shells was the most significant.Within the scope of this study,the higher the concentration,the better the coagulation effect(P<0.05).Compared with distilled water group,the liver weight coefficients of the Yunnan Baiyao group,low,middle,and high dose groups of peanut shells were significantly increased(P<0.05).Conclusion:(1)The aqueous extract of peanut shells has a specific analgesic effect on mice.(2)The aqueous extract of peanut shells promotes coagulation,and the pro-coagulant effect is more significant with increasing dose and the liver weight coefficient increases.

前交叉韧带重建术后三种不同药物镇痛早期疗效的对比

目的:比较去痛片(复方氨基比林、非那西丁片,商品名去痛片)、盐酸曲马多缓释片(商品名:奇曼丁)及盐酸哌替啶(商品名:杜冷丁)在膝关节前交叉韧带自体肌腱单束重建术后早期的止疼效果及安全性。方法:回顾性分析2018年11月至2019年2月,北京大学第三医院连续收治的45例由同一组医师施行膝关节镜下前交叉韧带自体肌腱单束重建术患者,术后疼痛情况和使用药物镇痛情况的临床资料。采用随机区组设计,根据前交叉韧带断裂是否合并半月板损伤将患者分为两组,A组为单纯膝关节前交叉韧带重建的患者24例,B组为前交叉韧带断裂合并半月板损伤的患者21例。两组又根据患者实际使用的术后镇痛药物各分为3组,其中,A组口服去痛片4例、口服奇曼丁11例、肌肉注射(简称肌注)杜冷丁联合盐酸异丙嗪(商品名:非那根)9例;B组口服去痛片3例、口服奇曼丁10例、肌注杜冷丁联合非那根8例。术后早期,患者诉疼痛并主动要求镇痛时随机给予去痛片、奇曼丁或杜冷丁联合非那根这三种不同的止痛药物缓解疼痛,采用疼痛视觉模拟评分(visual analogue scale, VAS)评估疼痛缓解情况,并观察不良反应发生情况。结果:患者在性别、年龄、体重指数、住院时间等基本情况上差异无统计学意义(P>0.05)。应用三种止痛药物缓解疼痛的两组患者,在用药前及用药1 h后通过VAS评分判断结果表明,患者疼痛情况明显缓解,用药前后疼痛差异有统计学意义(P<0.05)。对两组患者应用的三种药物进行两两比较显示,杜冷丁联合非那根组对于疼痛缓解的程度显著高于其余两种药物(P<0.05),用药1 h后,两组差异无统计学意义(P>0.05)。应用杜冷丁患者易出现恶心、呕吐等副反应,但应用杜冷丁的同时使用非那根可减少副反应。在不良反应方面,仅单纯前交叉韧带重建组中应用奇曼丁组的患者出现恶心1例,其余各组患者均未出现严重的并发症及过敏反应。结论:无论是单纯交叉韧带重建,还是合并半月板成型或缝合的交叉韧带重建,患者应用去痛片、奇曼丁、杜冷丁联合非那根这三种药物均能有效缓解疼痛,其中杜冷丁对疼痛的缓解幅度最大。应用杜冷丁的同时,合用非那根可有效减轻患者的呕吐、恶心等不良反应,增加用药安全性。