Reducing the dose of neuromuscular blocking agents with adjuncts: a systematic review and meta-analysis.

BACKGROUND: Acute global shortages of neuromuscular blocking agents (NMBA) threaten to impact adversely on perioperative and critical care. The use of pharmacological adjuncts may reduce NMBA dose. However, the magnitude of any putative effects remains unclear. METHODS: We conducted a systematic review and meta-analysis of RCTs. We searched Medline, Embase, Web of Science, and Cochrane Database (1970-2020) for RCTs comparing use of pharmacological adjuncts for NMBAs. We excluded RCTs not reporting perioperative NMBA dose. The primary outcome was total NMBA dose used to achieve a clinically acceptable depth of neuromuscular block. We assessed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) criteria. Data are presented as the standardised mean difference (SMD); I2 indicates percentage of variance attributable to heterogeneity. RESULTS: From 3082 records, the full texts of 159 trials were retrieved. Thirty-one perioperative RCTs met the inclusion criteria for meta-analysis (n=1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: -1.10 [-1.44 to -0.76], P<0.001; I2=85%; GRADE=moderate), dexmedetomidine (SMD: -0.89 [-1.55 to -0.22]; P=0.009; I2=87%; GRADE=low), and clonidine (SMD: -0.67 [-1.13 to -0.22]; P=0.004; I2=0%; GRADE=low) but not lidocaine (SMD: -0.46 [-1.01 to -0.09]; P=0.10; I2=68%; GRADE=moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30-50 mg kg-1 magnesium preoperatively (8-15 mg kg h-1 intraoperatively) reduces rocuronium dose by 25.5% (inter-quartile range, 14.7-31). CONCLUSIONS: Magnesium, dexmedetomidine, and clonidine may confer a clinically relevant sparing effect on the required dose of neuromuscular block ing drugs in the perioperative setting. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42020183969.

Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease.

There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.

Characterization of a new aerosol antibiotic/adjuvant combination for the treatment of P. aeruginosa lung infections.

The lack of novel classes of antibiotics as well as the constant increase of multidrug resistant bacteria are leaving the clinicians disarmed to treat bacterial infections, especially those caused by Gram-negative pathogens. Among all the investigated solutions, the design of adjuvants able to enhance antibiotics activities appears to be one of the most promising. In this context, a polyamino-isoprenyl derivative has been recently identified to be able to potentiate, at a very low concentration the activity of doxycycline against P. aeruginosa bacterial strains by increasing its intracellular concentration. On the other hand, since aerosol therapy allows a rapid drug administration and targets the respiratory system by avoiding the first pass effect and minimizing undesirable systemic effects, we have developed the first adjuvant/antibiotic combination in an aerosolized form and demonstrated the feasibility of such an approach. Thus, combination aerosol droplets have been demonstrated in sizes suitable for inhalation (3.4 and 4.4 µm mass median aerodynamic diameter and 54 and 60% of the aerodynamic particle size distribution less than 5 µm, as measured for the adjuvant NV716 and doxycycline, respectively and with properties (stoichiometric 1:1 ratio of NV716 salt to drug) that would support further development as an inhaled dosage form. Taken together, our results suggest that these molecules could be successfully delivered at the requested concentration in the lungs and then able to decrease drug consumption as well as increase treatment efficacy.

Comparison of Adrenaline and Dexmedetomidine in Improving the Cutaneous Analgesia of Mexiletine in Response to Skin Pinpricks in Rats.

BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 µmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 µmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 µmol), adding Dex or Adr to Mex (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 µmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 µmol) alone. A high dose of Adr is more effective with Mex 1.8 µmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 µmol combined with any dose of Adr is superior to that of Dex. CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

Compound Kushen injection plus platinum-based chemotherapy for stage IIIB/IV non-small cell lung cancer: A protocol for meta-analysis of randomized clinical trials following the PRISMA guidelines.

BACKGROUND: Compound Kushen injection (CKI) is a commonly used anti-tumor Chinese patent medicine, which is extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae) and has been widely prescribed as an add-on therapy to platinum-based chemotherapy (PBC) for advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain controversial. METHODS AND ANALYSIS: A systematic review and meta-analysis will be performed following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. All randomized controlled trials (RCTs) comparing CKI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. The disease control rate (DCR) will be defined as the primary outcome, and the objective response rate (ORR), quality of life (QOL), survival rate, and toxicities will be the secondary outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of Compound Kushen injection combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results of this study will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review and meta-analysis of eligible randomized controlled trials will evaluate the effects of Compound Kushen injection as adjunctive therapy to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical use of this combination therapy for the specific subsets of patients. PROSPERO REGISTRATION NUMBER: CRD42019134892.

The "nano to micro" transition of hydrophobic curcumin crystals leading to in situ adjuvant depots for Au-liposome nanoparticle mediated enhanced photothermal therapy.

Photothermal therapy (PTT) is emerging as a promising treatment for skin cancer. Plasmon-resonant gold-coated liposome nanoparticles (Au Lipos NPs) specifically absorb Near Infra-Red (NIR) light resulting in localized hyperthermia (PTT). In the current study, curcumin (a hydrophobic anticancer agent) was entrapped in Au Lipos NPs as nanocrystals to act as an adjuvant for the PTT of melanoma. NIR light irradiation on Au Lipos Cur NPs triggered the release of curcumin nanocrystals which coalesce to form curcumin microcrystals (CMCs). An in situ"nano to micro" transition in the crystal state of curcumin was observed. This in situ transition leads to the formation of CMCs. These CMCs exhibited sustained release of curcumin for a prolonged duration (>10 days). The localized availability of curcumin aids in enhancing PTT by inhibiting the growth and mobility of cancer cells that escape PTT. In the in vitro modified scratch assay, the Au Lipos Cur NP + Laser group showed >1.5 fold enhanced therapeutic coverage when compared with the Au Lipos NP + Laser group. In vivo PTT studies performed in a B16 tumor model using Au Lipos Cur NPs showed a significant reduction of the tumor volume along with the localized release of curcumin in the tumor environment. It was observed that the localized release of curcumin enables an immediate adjuvant effect resulting in the enhancement of PTT.

Does the sequence of addition of herbicide and adjuvants to the spray solution influence sicklepod control? / A sequência de adição de herbicida e adjuvantes à calda influencia no controle de fedegoso?

The use of adjuvants associated with herbicides aims at improving the performance of application and the consequent increase in the biological effect of the treatment. However, the sequence of product added to the sprayer tank can influence the phytosanitary spray solution. Thus, this study aimed to evaluate the control of Senna obtusifolia as a function of the sequence of addition of the herbicide aminopyralid + fluroxypyr and adjuvants in the preparation of spray solution. Two herbicide doses (1 and 2 L c.p. ha-1) associated with the adjuvants mineral oil (MO), silicone polyether copolymer (SIL), and a mixture of phosphatidylcholine and propionic acid (LEC), all in the proportion of 0.3% v v-1, with alternate addition to the spray solution to evaluate the effects of the preparation sequence. The spray solution volume considered was 150 L ha-1. Evaluations of spray solution stability were performed from the visual evaluation of homogeneity, electrical conductivity, and pH. The effect of treatment on S. obtusifolia control was measured using a scoring scale and dry matter. Correlation coefficients between the evaluations were also determined. No difference of the preparation sequence of spray solution was observed for stability, pH, and electrical conductivity, but an influence was observed on S. obtusifolia control, without changing dry matter accumulation. The treatment with the adjuvant LEC previously added to the herbicide provided a higher control rate at the highest dose, while the adjuvant SIL had the opposite effect.(AU)

O uso de adjuvantes associados a herbicidas visa melhorar o desempenho da aplicação e o consequente aumento do efeito biológico do tratamento. Porém, a ordem de adição dos produtos ao tanque do pulverizador pode trazer importantes influências à calda fitossanitária. Assim, o objetivo desta pesquisa foi avaliar o controle de Senna obtusifolia em função da sequência de adição do herbicida aminopiralide + fluroxipir e de adjuvantes no preparo das caldas. Foram utilizadas duas dosagens de herbicida (1 e 2 L p.c. ha-1), associadas aos adjuvantes óleo mineral (OM); copolímero de poliéter e silicone (SIL); mistura de fosfatidicolina e ácido propiônico (LEC), todos na proporção de 0,3% v v-1, com adição alternada à calda para avaliar os efeitos da sequência de preparo. O volume de calda considerado foi de 150 L ha-1. Foram realizadas avaliações da estabilidade da calda a partir da avaliação visual de homogeneidade, condutividade elétrica e pH. O efeito do tratamento no controle de S. obtusifolia foi mensurado por meio de uma escala de pontuação e pela massa seca. Também foram determinados os coeficientes de correlação entre as avaliações. Verificou-se que não houve diferença da sequência de preparo da calda para a estabilidade, o pH e a condutividade elétrica. Porém, a sequência de preparo influenciou o controle inicial de S. obtusifolia, sem efeito sobre a massa seca. O tratamento com o adjuvante LEC adicionado ao herbicida proporcionou maior taxa de controle na maior dosagem, enquanto o adjuvante de SIL teve o efeito oposto.(AU)

Coadyuvantes farmacológicos con efecto ahorrador de opioides en el periodo perioperatorio / Farmacologic adyuvants with saving effect of opioids in the perioperative period

En los últimos 15 años, el interés en las vías de recuperación y rehabilitación postoperatorias (ERAS) ha aumentado, ya que los tiempos de recuperación quirúrgica y las estadísticas intrahospitalarias han sido analizados tanto por médicos como por gestores. Aunque el enfoque para reducir la duración de la estancia hospitalaria es multifactorial e incluye objetivos de manejo para varios parámetros como la hemodinámica, administración de fluidos, ventilación, alimentación, motilidad intestinal y movilidad precoz, el manejo del dolor postoperatorio debe ser un área de enfoque fundamental. Los opioides son ampliamente conocidos por tener un perfil de efectos secundarios que ralentiza la recuperación hospitalaria, retrasando tanto el alta hospitalaria como el retorno a la normalidad funcional. Estos efectos secundarios incluyen la disminución de la motilidad intestinal, íleo, náuseas y vómitos postoperatorios, sedación y delirio. Además, se ha sugerido una asociación entre la administración de opioides y la recurrencia del cáncer en la población de oncología quirúrgica, específicamente cáncer de mama y próstata. Los anestesiólogos están bien posicionados para influir en el éxito de los protocolos ERAS para el control adecuado del dolor, teniendo muchas herramientas a su disposición para proporcionar preservación de opioides o incluso libres de ellos durante el periodo perioperatorio. Esta revisión resume la evidencia disponible sobre las terapias farmacológicas para conseguir un ahorro de opioides perioperatorios, exceptuando los antinflamatorios que tienen un efecto demostrado en este campo, y respalda el uso de dexmedetomidina, clonidina, ketamina, pregabalina, lidocaína, magnesio y esmolol como adyuvantes no-opioides dentro de programas multimodales para el tratamiento del dolor postoperatorio. A pesar de ello, se necesitan ensayos adicionales para dilucidar las combinaciones óptimas de estos adyuvantes

In the last 15 years, the interest in the postoperative recovery and rehabilitation pathways (ERAS) has increased since both doctors and managers have analyzed the times of surgical recovery and intrahospital statistics. Although the approach to reduce the length of hospital stay is multifactorial and includes management objectives for various parameters such as hemodynamics, fluid administration, ventilation, feeding, intestinal motility and early mobility, the management of postoperative pain should be an area of basic importance. Opioids are widely known to have a side effect profile that slows down hospital recovery, delaying both hospital discharge and return to functional normalcy. These side effects include decreased bowel motility, ileus, postoperative nausea and vomiting, sedation and delirium. In addition, an association has been suggested between the administration of opioids and the recurrence of cancer in the surgical oncology population, specifically breast and prostate cancer. Anesthesiologists are well positioned to influence the success of ERAS protocols for adequate pain control, having many tools at their disposal to provide opioid preservation or even free of them during the perioperative period. This review summarizes the available evidence on pharmacological therapies to achieve a saving of perioperative opioids, except anti-inflammatories that have a proven effect in this field, and supports the use of dexmedetomidine, clonidine, ketamine, pregabalin, lidocaine, magnesium and esmolol as non opioid adjuvants as agents within multimodal programs for the treatment of postoperative pain Despite this, additional tests are needed to elucidate the optimal combinations of these adjuvants

Sodium Tanshinone II A Sulfonate Injection as Adjuvant Treatment for Unstable Angina Pectoris: A Meta-Analysis of 17 Randomized Controlled Trials.

OBJECTIVE: To systematically evaluate the effectiveness and safety of Sodium Tanshinone II A Sulfonate Injection (STS) as one adjuvant therapy for treating unstable angina pectoris (UAP). METHODS: Randomized controlled trials (RCTs) of UAP treated by STS were searched in the China National Knowledge Infrastructure Database (CNKI), VIP Database for Chinese Technical Periodicals (VIP), Wanfang Database, the Chinese Biomedical Literature Database (CBM), Web of Science, the Cochrane Library, Embase, and PubMed, which from inception to January, 2016. The Cochrane Risk Assessment Tool was used to evaluate the methodological quality of the RCTs. The Review Manager 5.3 software was used to conduct the metaanalysis. RESULTS: The results showed that 17 RCTs involving 1,372 patients were included. The meta-analysis indicated that the combined use of STS and Western medicine (WM) in the treatment of UAP can obviously improve the total effective rate [risk ratio (RR)=1.31, 95% confidence interval (CI) (1.24,1.39), P<0.0001], and the total effective rate of electrocardiogram [RR=1.43, 95% CI (1.30,1.56), P<0.0001], decrease the level of CRP [mean difference (MD)=-3.06, 95%CI (-3.85,-2.27), P<0.00001], fibrinogen [MD=-1.03, 95% CI (-1.16,-0.89), P<0.00001], and whole blood high shear viscosity [MD=-0.70, 95% CI (-0.92,-0.49), P<0.00001]. Additionally, the occurrence of adverse drug reaction of the experimental group was significantly higher than that of the control group [RR=3.57, 95% CI (1.28, 9.94), P<0.05]. CONCLUSIONS: Compared with WM, the combined use of STS was more effective.

Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomiphene citrate, in clomiphene-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effects of short- and long-term treatment with metformin and NAC, in an adjuvant to clomiphene citrate (CC), on the improvement of hormonal profile (SHBG, total testosterone, FBS, and fasting insulin) and fertility status in CC-resistant women with PCOS. MATERIALS AND METHODS: One hundred and eight CC-resistant PCOS patients participated in the study and received either metformin (1500mg/day) or NAC (1800mg/day) with 100mg/day of CC for 8 and 12 weeks. Mean BMI, hirsutism score, LH/FSH ratio, endometrial thickness, mature follicle number, and serum concentrations of LH, FSH, E2, fasting insulin, total testosterone and FBS were evaluated before and after short- and long-term treatment. Furthermore, ovulation and pregnancy rates in the first and second cycles were also determined in treated patients. RESULTS: There was no significant difference in all variables before and 8 weeks after treatment with metformin and NAC. The BMI- and insulin-lowering effects of metformin were significantly higher than NAC after long-term treatment. However, the reducing-effect of NAC on hirsutism score and FBS levels was significantly more than metformin after 12 weeks. Treatment with metformin and NAC significantly increased ovulation and pregnancy rates in CC-resistant PCOS patients. In the first and second cycles, ovulation and pregnancy rates in patients treated with NAC were slightly higher than those received metformin. CONCLUSIONS: Compared with metformin, administration of NAC in an adjuvant to CC is recommended for improving of hormonal profile and treatment of anovulatory infertility in hyperinsulinemic patients especially women with PCOS who are CC-resistant.

The adjuvant value of Andrographis paniculata in metastatic esophageal cancer treatment - from preclinical perspectives.

Esophageal cancer (EC) is the fourth and sixth leading cause of cancer-related deaths in China and United States, respectively. The dismal prognosis of EC is mainly attributed to distant metastases, which may not be overcome by chemotherapy alone. Hence, the use of alternative adjuvant treatments, such as herbal medicines, for metastatic EC remains a great desire of patients. Our previous study demonstrated the in vivo anti-tumor and in vitro anti-invasion activities of Andrographis paniculata (AP) in esophageal cancer. In the present study, the chemical constituents of absorbed AP components through human intestinal Caco-2 cell monolayer were verified for the first time. The anti-migratory activities and suppressive effects on metastasis-related factors such as HER2, MMP2, MMP9, TM4SF3, CXCR4 of the absorbed AP components were revealed in esophageal cancer cells EC-109. The anti-tumor and anti-metastatic effects of AP water extract (1600 mg/kg) were further confirmed in metastatic esophageal xenograft-bearing mice. Besides, AP water extract acted synergistically with cisplatin plus 5-fluorouracil on inhibiting tumor nodule growth (with combination index <0.7). Meanwhile, chemotherapeutics-induced side-effects could also be reduced by AP water extract. The present findings provide evidence on safety and advantages of the combined use of AP with chemotherapeutics in pre-clinical setting.

Rapidly progressive diffuse systemic sclerosis after local vitamins A, D and E complex injections: literature review and report of two cases.

The term autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld's syndrome refers to a wide group of immune-mediated diseases triggered by external agents. Several substances, such as vaccine adjuvants, squalene and silicone implants, are implied in the pathogenesis of ASIA syndrome. Treatment and prognosis of this complex condition are not completely known due to lack of good quality evidence. After a brief introductory literature review on ASIA, we report here two cases of patients that developed rapidly progressive systemic sclerosis clinical features after multiple intramuscular local injections of a substance recommended by a non-medical professional called ADE. ADE is an oily vitamin complex for veterinary use, and it was used in these cases for cosmetic muscular definition and enhancement purpose. To our knowledge, this is the first paper to describe the relation between injections of ADE and the development of ASIA with severe systemic sclerosis phenotype. Further investigation is needed to better understand the pathophysiology and to provide the basis for the treatment of this condition.

Penicillin Encephalopathy: An Unlikely Adversary in the Treatment of Neurosyphilis--Case Report and Review of the Literature.

UNLABELLED: Penicillin encephalopathy is a rare, potentially reversible phenomenon of drug-induced neurotoxicity. CASE: A 65-year-old female with a history of HIV was admitted with a three-day history of worsening headache, confusion, and lethargy. On examination she was awake but confused. Cerebrospinal fluid (CSF) and serum venereal disease research laboratory (VDRL) test returned positive and the patient was started on intravenous penicillin G with probenecid. On the second day of therapy, she developed myoclonic jerking, consistent with penicillin neurotoxicity. Repeat labs also showed new onset renal failure. Penicillin and probenecid therapy were stopped with a resolution of symptoms. Subsequently, therapy without probenecid was reinstituted uneventfully. DISCUSSION: Herein, we describe a female who developed penicillin neurotoxicity after initiation of intravenous penicillin therapy with probenecid for neurosyphilis. It is important that penicillin-induced toxicity be considered if characteristic myoclonic movements accompany encephalopathy. The presence of coexistent renal compromise should heighten the vigilance of clinicians.

Intranasal T-LysYal® as adjunctive therapy for patients after functional endoscopic sinus surgery.

Functional Endoscopic Sinus Surgery (FESS) is a common day surgery technique for upper airway disorders. Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert reparative, anti-inflammatory and immune-modulating activities. Recently, a new intranasal HA formulation has been proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (RinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 83 patients (49 males and 34 females mean age 45.4±6.2 years) treated with FESS. All patients were treated with isotonic saline solution for 4 weeks, and a sub-group (active group) was also treated with intranasal T-LysYal®. Patients were visited at baseline, after treatment, and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells in comparison to isotonic solution. In conclusion, the present study demonstrates that intranasal T-LysYal® is able to significantly improve patients after FESS and its effect is long lasting.

Shenmai injection as an adjuvant treatment for chronic cor pulmonale heart failure: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Shenmai injection (SM), as a traditional Chinese medicine injection, is widely used for chronic cor pulmonale heart failure in mainland China. It is essential to systematically assess the efficacy and safety of SM as an adjuvant treatment for chronic cor pulmonale heart failure. METHODS: Eight English and Chinese electronic databases were searched, from inception to December 2014, to identify randomized controlled trials (RCTs) of SM for chronic cor pulmonale heart failure. The Cochrane Risk of Bias tool was used to evaluate the methodological quality of eligible studies. Meta-analysis was performed by Review Manager 5.2. RESULTS: Twenty-seven RCTs with 2045 participants were identified. The methodological quality of the included studies was generally low. Only one trial reported data on death. None of the included trials reported quality of life. The meta-analysis indicated that compared to conventional treatment, the combination of SM and conventional treatment was more effective in terms of the New York Heart Association classification (RR, 1.26; 95% CI, 1.20-1.32; P < 0.00001), Left Ventricular Ejection Fraction (MD, 11.33; 95% CI, 8.59-14.07; p < 0.00001), partial pressure of oxygen (MD, 1.00; 95% CI, 0.64-1.36; P < 0.00001) and partial pressure of carbon dioxide (MD, 0.83; 95 % CI, 0.58-1.08; p < 0.00001). In addition, two trials reported that SM plus conventional treatment was superior to the conventional treatment alone to reduce B-type natriuretic peptide. No serious adverse drug events or reactions were reported. CONCLUSIONS: SM plus conventional treatment appeared to be effective and relatively safe for chronic cor pulmonale heart failure. However, due to the generally low methodological quality and small sample size, this review didn't find evidence to support routine use of SM as an adjuvant treatment for chronic cor pulmonale heart failure.

Vitamin E as adjuvant treatment for urinary tract infection in girls with acute pyelonephritis.

INTRODUCTION: Vitamin E is a fat-soluble vitamin that functions as an antioxidant. The aim of this study was to investigate the effects of vitamins E supplementation in combination with antibiotics for the treatment of girls with acute pyelonephritis. MATERIALS AND METHODS: This double-blinded randomized controlled trial was conducted on 152 girls aged 5 to 12 years with a first acute pyelonephritis episode based on technetium Tc 99m dimercaptosuccinic acid (99mTc-DMSA). They were randomized to receive a 14-day treatment with only antibiotics (control group; n = 76) and 14-day treatment with supplements of vitamin E (intervention group; n = 76) in addition to the antibiotics. Patients' clinical symptoms were monitored for 14 days and urine culture was performed 3 to 4 days and 7 to 10 days after the start of the treatment and its completion, respectively. All of the girls once underwent DMSA scan 4 to 6 months after the treatment. RESULTS: During the follow-up days, the mean frequency of fever (P = .01), urinary frequency (P = .001), urgency (P = .003), dribbling (P = .001), and urinary incontinence (P = .006) were significantly lower in the intervention group compared to the control group. There was no significant difference in the results of urine culture 3 to 4 days after the start of treatment (P = .16) and 7 to 10 days after its termination (P = .37). There was also no significant difference between the results of DMSA scan 4 to 6 months after the start of treatment (P = .31). CONCLUSIONS: Vitamin E supplementation has a significant effect in ameliorating sign and symptoms of UTI. However, further studies are recommended to confirm these findings.

Non-carrier nanoparticles adjuvant modular protein vaccine in a particle-dependent manner.

Nanoparticles are increasingly used to adjuvant vaccine formulations due to their biocompatibility, ease of manufacture and the opportunity to tailor their size, shape, and physicochemical properties. The efficacy of similarly-sized silica (Si-OH), poly (D,L-lactic-co-glycolic acid) (PLGA) and poly caprolactone (PCL) nanoparticles (nps) to adjuvant recombinant capsomere presenting antigenic M2e modular peptide from Influenza A virus (CapM2e) was investigated in vivo. Formulation of CapM2e with Si-OH or PLGA nps significantly boosted the immunogenicity of modular capsomeres, even though CapM2e was not actively attached to the nanoparticles prior to injection (i.e., formulation was by simple mixing). In contrast, PCL nps showed no significant adjuvant effect using this simple-mixing approach. The immune response induced by CapM2e alone or formulated with nps was antibody-biased with very high antigen-specific antibody titer and less than 20 cells per million splenocytes secreting interferon gamma. Modification of silica nanoparticle surface properties through amine functionalization and pegylation did not lead to significant changes in immune response. This study confirms that simple mixing-based formulation can lead to effective adjuvanting of antigenic protein, though with antibody titer dependent on nanoparticle physicochemical properties.

Incidence of febrile neutropenia in early stage breast cancer patients receiving adjuvant FEC-D treatment.

PURPOSE: The purpose of this study is to determine the incidence of febrile neutropenia (FN) among women receiving FEC-D (flurouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for three cycles followed by docetaxel 100 mg/m(2) every 3 weeks for three cycles) chemotherapy for early stage breast cancer (ESBC) and the impact of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis in a non-clinical trial setting. PATIENTS AND METHODS: A retrospective chart review of women referred for ESBC to The Moncton Hospital between 2005 and 2010 evaluated patient and disease characteristics, adjuvant chemotherapy receipt, G-CSF usage, FN incidence, hospital admission rates, and length of stay. Association of variables with FN was examined, and exploratory multivariable logistic regression modeling examined the impact of baseline variables on risk of FN. RESULTS: Of 520 patients enrolled in the database, 251 (48.3 %) received adjuvant chemotherapy for ESBC. Most (66.9 %) received FEC-D. Overall, 55 (21.9 %) patients developed FN. Forty-four (26.2 %) patients on FEC-D developed FN. Forty of 129 (31.0 %) FEC-D patients who did not receive primary G-CSF prophylaxis developed FN, versus 4 of 39 (10.3 %) receiving G-CSF. Receipt of FEC-D or TC (docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for four or six cycles) was associated with odds ratios of 6.5 or 6.77, respectively, for the development of FN. Receipt of trastuzumab with chemotherapy was associated with an odds ratio of 3.48 for developing FN versus no trastuzumab. Primary G-CSF prophylaxis led to a 63 % reduction in the odds ratio of developing FN. CONCLUSIONS: Incidence of FN with FEC-D treatment is considerably higher in clinical practice than reported in phase III trials. Consistent with ASCO guidelines, prophylactic G-CSF should be considered for all ESBC patients receiving adjuvant FEC-D.

The surface charge of liposomal adjuvants is decisive for their interactions with the Calu-3 and A549 airway epithelial cell culture models.

One of the main reasons for the unmet medical need for mucosal vaccines is the lack of safe and efficacious mucosal adjuvants. The cationic liposome-based adjuvant system composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6'-dibehenate (TDB) is a versatile adjuvant that has shown potential for mucosal vaccination via the airways. The purpose of this study was to investigate the importance of the liposomal surface charge on the interaction with lung epithelial cells. Thus, the cationic DDA in the liposomes was subjected to a step-wise replacement with the zwitterionic distearoylphosphatidylcholine (DSPC). The liposomes were tested with the model protein antigen ovalbumin for the mucosal deposition, the effect on cellular viability and the epithelial integrity by using the two cell lines A549 and Calu-3, representing cells from the alveolar and the bronchiolar epithelium, respectively. The Calu-3 cells were cultured under different conditions, resulting in epithelia with a low and a high mucus secretion, respectively. A significantly larger amount of lipid and ovalbumin was deposited in the epithelial cell layer and in the mucus after incubation with the cationic liposomes, as compared to incubation with the neutral liposomes, which suggests that the cationic charge is important for the delivery. The integrity and the viability of the cells without a surface-lining mucus layer were decreased upon incubation with the cationic formulations, whereas the mucus appeared to retain the integrity and viability of the mucus-covered Calu-3 cells. Our in vitro results thus indicate that DDA/TDB liposomes might be efficiently and safely used as an adjuvant system for vaccines targeting the mucus-covered epithelium of the upper respiratory tract and the conducting airways.

Preparation and in vitro/in vivo evaluation of mucosal adjuvant in situ forming gels with diphtheria toxoid.

Studies on preparation of in situ gel formulations containing diphtheria toxoid as the model active substance and their intranasal administration have been conducted in this study. The objective of mucosal vaccination is to stimulate both systemic and mucosal immune responses. In situ gel formulations were prepared by using, in different ratios, mixtures of Poloxamer 407 and Poloxamer 188 polymers, which gelate in a temperature-dependent manner, and mucoadhesive polymers carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or chitosan. Following pre-formulation studies, F1, F2, F3, F4, F5, F6 and F7 formulations, which gelate at intervals and temperatures in accordance with nasal temperatures, were subjected to more comprehensive studies. For this purpose, organoleptic characteristics of the formulations were identified, their pH and mucoadhesive potencies were measured and rheological behaviors were characterized. Calculated amounts of diphtheria toxoid were added to formulations after optimization of formulations was achieved, and assay and in vitro release studies were carried out. Formulations coded F3 and F7 were considered to be superior to other formulations given the in vitro test results. Therefore, these formulations were tested in guinea pigs to determine immune responses, which they would produce following intranasal and subcutaneous administration. Absorbance values of ELISA tests and antibody neutralization test showed that formulations coded F3 and F7 were unable to stimulate adequate systemic immune response when either of the formulations was administered alone intranasally, whereas F7 resulted in significantly increased neutralizing antibody titers with intranasal administration as a booster dose following subcutaneous administration.