Efficacy of probiotic adjuvant therapy for irritable bowel syndrome in children: A systematic review and meta-analysis.

OBJECTIVE: Irritable bowel syndrome (IBS) affects children's quality of life and learning. The purpose of this research was to systematically evaluate the efficacy of probiotic adjuvant therapy for IBS in children. METHODS: The Web of Science, PubMed, Cochrane Library, EMBASE and Clinical Trials databases were electronically searched for randomized controlled trials (RCTs) published prior to January 2021 exploring the use of probiotic adjuvant therapy for IBS in children. Strict screening and quality evaluations of the eligible articles were performed independently by 2 researchers. Outcome indexes were extracted, and a meta-analysis of the data was performed using RevMan 5.4.1 and STATA 16 software. Finally, the risk of bias in the included studies was assessed with the RCT bias risk assessment tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (5.1.0). RESULTS: A total of nine RCTs were included. In children, probiotics significantly reduced the abdominal pain score (I2 = 95%, SMD = -1.15, 95% (-2.05, -0.24), P = 0.01) and Subject's Global Assessment of Relief (SGARC) score (I2 = 95%, MD = -3.84, 95% (-6.49, -1.20), P = 0.004), increased the rate of abdominal pain treatment success (I2 = 0%, RR = 3.44, 95% (1.73, 6.87), P = 0.0005) and abdominal pain relief (I2 = 40%, RR = 1.48, 95% (0.96, 2.28), P = 0.08), and reduced the frequency of abdominal pain (I2 = 2%, MD = -0.82, 95% (-1.57, -0.07), P = 0.03). However, we found that it might not be possible to relieve abdominal pain by increasing the daily intake of probiotics. CONCLUSIONS: Probiotics are effective at treating abdominal pain caused by IBS in children, however, there was no significant correlation between abdominal pain and the amount of probiotics ingested. More attention should be given to IBS in children, and a standardized evaluation should be adopted.

Physical deterioration and adaptive recovery in physically inactive breast cancer patients during adjuvant chemotherapy: a randomised controlled trial.

Cardiorespiratory fitness is an independent risk factor for cardiovascular disease and shortened life expectancy in breast cancer survivors. This randomised controlled trial (n = 153) was designed for patients with a physically inactive lifestyle prediagnosis and concurrently referred to adjuvant chemotherapy. We compared two 12-week exercise interventions aimed at physiological and patient-reported outcomes (cardiorespiratory fitness, muscle strength, metabolic markers, physical activity, pain, fatigue), including a 39-week follow-up. A supervised hospital-based moderate to high intensity group exercise intervention was compared to an instructed home-based individual pedometer intervention. The two 12-week interventions included oncologists' recommendations and systematic health counselling. Outcomes were measured at baseline and week 6, 12 and 39. Primary outcome cardiorespiratory fitness declined significantly during chemotherapy and was restored in both interventions at follow-up. The interventions effectively engaged breast cancer patients in sustaining physical activities during and following adjuvant treatment. A composite metabolic score improved significantly. Positive cardiorespiratory fitness responders had improved clinical effects on fatigue, pain and dyspnoea versus negative responders. We conclude that a loss of cardiorespiratory fitness among physically inactive breast cancer patients may be restored by early initiated interventions and by adapting to physical activity recommendations, leading to a decreased cardiovascular risk profile in breast cancer survivors.

The efficacy and safety of sulforaphane as an adjuvant in the treatment of bipolar depressive disorder: Study protocol for a randomized, double-blinded, placebo-controlled, parallel-group clinical trial.

BACKGROUND: Bipolar disorder (BD) is a chronic and disabling psychiatric disorder. The treatment of BD still remains a significant clinical challenge due to the complex nature of the disease. Nutraceutical therapy as adjunctive role is a promising therapy for BD. Sulforaphane (SFN), a broccoli extract, was reported to be effective for emotional problems and cognitive impairment. However, clinical research of SFN in the treatment of BD was rare. Therefore, this study is designed to evaluate the adjuvant role of SFN in the treatment of BD. METHODS: This is a randomized, double-blinded, placebo-controlled, parallel-group clinical trial. A total of 100 patients who meet inclusion criteria will be assigned to receive quetiapine plus SFN or quetiapine plus placebo in a 1:1 ratio. The total duration of the study will be 12 weeks including 5 follow ups. The primary outcome is in the Montgomery-Asberg depression rating scale. The secondary outcomes are the quick inventory of depressive symptomatology-self report, Hamilton anxiety rating scale, young mania rating scale, cognitive function, inflammatory factors, and intestinal flora. Any adverse events will be recorded throughout the trial. DISCUSSION: This trial will provide evidences to evaluate the efficacy and safety of SFN combined with quetiapine in the treatment of BD patients, as well as the adjuvant role of SFN in combination. TRIAL REGISTRATION: This study protocol was registered at the Chinese clinical trial registry (ChiCTR2000028706).

Corticosteroids to prevent kidney scarring in children with a febrile urinary tract infection: a randomized trial.

BACKGROUND: To evaluate the efficacy of adjuvant systemic corticosteroids in reducing kidney scarring. A previous study suggested that use of adjuvant systemic corticosteroids reduces kidney scarring in children radiologically confirmed to have extensive pyelonephritis. Efficacy of corticosteroids for children with febrile urinary tract infection (UTI) has not been studied. METHODS: Children aged 2 months to 6 years with their first febrile UTI were randomized to corticosteroids or placebo for 3 days (both arms received antimicrobial therapy); kidney scarring was assessed using 99mTc-dimercaptosuccinic acid kidney scan 5-24 months after the initial UTI. RESULTS: We randomized 546 children of which 385 had a UTI and 254 had outcome kidney scans (instead of the 320 planned). Rates of kidney scarring were 9.8% (12/123) and 16.8% (22/131) in the corticosteroid and placebo groups, respectively (p = 0.16), corresponding to an absolute risk reduction of 5.9% (95% confidence interval: - 2.2, 14.1). CONCLUSION: While children randomized to adjuvant corticosteroids tended to develop fewer kidney scars than children who were randomized to receive placebo, a statistically significant difference was not achieved. However, the study was limited by not reaching its intended sample size. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov , NCT01391793, Registered 7/12/2011 Graphical abstract.

Neuroprotective Agents as an Adjuvant Treatment in Patients With Acute Spinal Cord Injuries: A Qualitative Systematic Review of Randomized Trials.

STUDY DESIGN: This was a systematic literature review. OBJECTIVE: The objective of this study was to evaluate randomized clinical trials that address potential neuroprotective agents used to improve neurological outcome in patients with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Clinical treatment of acute SCI has evolved significantly, but neurological recovery of severely injured patients remains modest. Neuroprotective agents may act to limit secondary damage in the sequence of pathophysiologic insults that occur after primary SCI. METHODS: We performed a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines of all clinical randomized trials that evaluated potential neuroprotective agents (drugs, stem cells, and any type of medicative interventions) in neurological outcome of acute SCI. All the studies were graded according to their level of evidence in accordance with the Oxford Level of Evidence-based Medicine. RESULTS: A total of 16 randomized clinical trials were included and fully analyzed in our review. The following 12 substances/drugs were analyzed: methylprednisolone (MP), naloxone, tirilizad, nimodipine, Sygen, autologous incubated macrophages, autologous bone marrow cells, minocycline, erythropoietin, ganglioside, vitamin D, and progesterone. Modest benefits were attributed to minocycline and Sygen (without statistical significance), and some benefits were obtained with erythropoietin and progesterone plus vitamin D in neurological outcome. For MP, the benefits are also controversial and may be attributed to statistical artifacts and with a high risk of adverse effects. The other substances did not change the final outcome. All studies were considered as grade B of recommendation (100%) and levels of evidences as B2 (81.25%) and B3 (18.75%). CONCLUSIONS: Our review reported some potential substances that may improve neurological outcome in acute SCI: MP, vitamin D associated with progesterone, and erythropoietin. Their potential benefits were modest in the evaluated studies, requiring further randomized clinical trials with large samples of patients, without statistical artifacts, for routine clinical use. Furthermore, potential adverse effects must be considered with the use of neuroprotective agents in SCI. Until then, the use of these substances may be experimental or restricted to specific clinical situations.

Reactogenicity of Bordetella pertussis vaccines formulations using aluminum adjuvants in Sprague Dawley rats / Reactogenicidad de formulaciones de vacunas de Bordetella pertussis utilizando adyuvantes de aluminio en ratas Sprague Dawley

Combined vaccines for childhood are a strategy in the prevention of several diseases. These can maximize protection and decrease immunization schedules in children. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to formulation and regulatory aspects. In addition to being immunogenic and protective must have low reactogenicity when combined with other antigens. Adjuvants are important components in achieving these combinations. Therefore, a reactogenicity study was designed for two Bordetella pertussis formulations containing hydroxide or aluminum phosphate in Sprague Dawley rats. Both formulations dose were administered in 0.2 mL intramuscularly. Clinical evaluations, body weight, water consumption, food, temperature, muscle volume, dermal irritability and pathological studies with special interest at the inoculation site were carried out. Only differences in body temperature and muscle volume were found with a slight increase in values with return to normal. The macroscopic study showed lesions at the site of inoculation, consid­ered characteristics of aluminum adjuvants, such as granulomatous abscesses and the increase in regional lymph nodes near the inoculation site. As conclusion, there are no differences between the formulations of B. pertussis with hydroxide or aluminum phosphate resulted in low reactogenicity.

Las vacunas combinadas resultan una estrategia importante en la obtención de vacunas múltiples para la infancia y el uso de adyuvantes es un componente de gran valor en lograr estas combinaciones, además de ser inmunogénicas y protectoras deben tener baja reactogenicidad, cuando se combinan con diferentes antígenos. Por esta razón, se diseñó un estudio de reactogenicidad a dos formulaciones que contenían hidróxido y fosfato de aluminio con antígenos de Bordetella pertussis en ratas Sprague Dawley. Se administró a cada grupo de ensayo una dosis correspondiente de ambas formulaciones en 0,2 mL por vía intramuscular. Se realizaron observaciones clínicas, comportamiento del peso corporal, consumo de agua, alimentos, temperatura corporal, volumen muscular, irritabilidad dérmica y estudios anatomopatológicos macroscópicos, con especial interés en el sitio de inoculación. No se observaron síntomas, ni muertes en los animales durante el estudio. Tampoco se encontraron diferencias entre los grupos experimentales en cuanto al peso corporal, el consumo de agua y de alimentos; los estudios de temperatura corporal y volumetría muscular evidenciaron un ligero incremento en los valores, los cuales involucionaron rápidamente a la normalidad. En el estudio anatomopatológico macroscópico se observaron lesiones a nivel del punto de inoculación, consideradas propias de los adyuvantes que contienen aluminio, tales como formaciones abscedadas de tipo granulomatosas y el aumento de los ganglios linfáticos regionales cercanos al punto de inoculación. Se concluye que las formulaciones en hidróxido y fosfato de aluminio con antígenos de B.pertussis resultaron ser de baja reactogenicidad.

Mushroom polysaccharide lentinan for treating different types of cancers: A review of 12 years clinical studies in China.

Lentinula edodes has been used to improve general health for thousands of years in Asia. It is the second largest cultivated and the most popular edible mushroom in the world known as "Xianggu" in China and "Shiitake" in Japan. Lentinan is a polysaccharide extracted from Lentinula edodes. ß-Glucan is the major bioactive component in lentinan with immunostimulatory effect. The antitumor property of lentinan was reported in 1960s. Biochemical studies indicate that immunocytes can be activated by lentinan through multiple signaling pathways, such as TLR4/Dectin1-MAPK and Syk-PKC-NFκB pathways. Though it has been approved as an adjuvant therapeutic drug both in China and Japan for treating cancers since 1980s, a systematic review of clinical studies of lentinan has not been conducted elaborately. In this review, over 9474 reported lentinan-associated cancer treatment cases are evaluated and summarized from 135 independent studies in China during the past 12 years (2004-2016) based on CNKI (China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific Journals Database) and Wanfang database. The 9474 reported lentinan-associated cancer treatment cases include lung cancer (3469 cases), gastric cancer (3039 cases), colorectal cancer (1646 cases), ovarian cancer (183 cases), cervical cancer (130 cases), Non-Hodgkin lymphoma (70 cases), pancreatic cancer (15 cases), cardiac cancer (15 cases), nasopharyngeal cancer (14 cases), duodenal cancer (1 case) and 110 cancer cases with no classifying patient information. Overall clinical data show solid effect of lentinan on improving the quality of life and on promoting the efficacy of chemotherapy and radiation therapy during cancer treatment.

Regulatory effects of paeoniflorin-6'-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.

Biodegradable Hyaluronic Acid Modified with Tetraglycine-l-octaarginine as a Safe Adjuvant for Mucosal Vaccination.

We have been investigating the potential use of polymers modified with cell-penetrating peptides as an adjuvant for mucosal vaccination and have already developed nondegradable poly( N-vinylacetamide- co-acrylic acid) (PNVA- co-AA) with which d-octaarginine, a typical cell-penetrating peptide, was grafted. Our previous murine infection experiments demonstrated that immunoglobulin G (IgG) and immunoglobulin A (IgA) were induced in systemic circulation and secreted on nasal mucosa, respectively, through 4-time nasal inoculations with a mixture of influenza viral antigens and d-octaarginine-linked PNVA- co-AA at 7-day intervals, and that immunized mice were perfectly protected from homologous virus infection. In the present study, we designed novel biodegradable polymers bearing cell-penetrating peptides from a perspective of clinical application. Hyaluronic acid whose glucuronic acid was modified with tetraglycine-l-octaarginine at a monosaccharide unit ratio of 30% was successfully developed. The hyaluronic acid derivative exhibited adjuvant activities identical to PNVA- co-AA bearing either d-octaarginine or tetraglycine-d-octaarginine under the above-mentioned inoculation schedule. We further found that there was no difference in humoral immunity between the 4-time inoculations at 7-day intervals and the 2-time inoculations at 28-day intervals. Intranasal IgA induced through the latter schedule with a smaller number of inoculations, which is clinically practical, exhibited cross-reactivity beyond the subtype of viral strains. In vitro toxicity studies demonstrated that the hyaluronic acid derivative was much less toxic than the corresponding PNVA- co-AA derivatives, and that both the polymers and their metabolites did not exhibit genotoxicity. Our results suggested that tetraglycine-l-octaarginine-linked hyaluronic acid would be a clinically valuable and safe adjuvant for mucosal vaccination.

Patient-reported Outcomes in Metastatic Castration-sensitive Prostate Cancer in the Adjuvant Setting.

We review the importance of quality of life (QOL) data from patient-reported outcome measures (PROMs) among men treated with androgen deprivation therapy (ADT) for metastatic castration-sensitive prostate cancer (mCSPC) or localized prostate cancer treated with adjuvant therapy. This information is important for patients as they make treatment choices and for regulatory agencies approving drug therapies. Studies of treatments for mCSPC suggest that the improvements in survival associated with more intensive systemic treatment are accompanied by improvements in QOL. ADT prolongs survival among men with intermediate- or high-risk localized disease in combination with radiation, but the optimal duration is still being defined. For men with biochemical recurrence, starting ADT earlier rather than later had minimal adverse effects on QOL but may not prolong survival. We conclude that rigorous assessment of QOL with validated PROMs must be a priority for clinical trials of novel and more intensive approaches to treatment with ADT. PATIENT SUMMARY: Data on quality of life that are collected using patient-reported outcome measures are important for patients with prostate cancer as they make treatment choices and for regulatory agencies approving drug therapies.

Clinical Profile of Levamisole-Adulterated Cocaine-Induced Vasculitis/Vasculopathy: A 30-Case Series.

OBJECTIVES: The aims of this study were to describe clinical and laboratory manifestations of patients with levamisole-adulterated cocaine-induced vasculitis/vasculopathy and to propose a skin classification according to the distribution and severity of lesions. METHODS: We report the characteristics of 30 patients admitted with levamisole-adulterated cocaine-induced vasculitis/vasculopathy in 4 high-complexity institutions in Colombia, from December 2010 to May 2017. We compare our findings with the main published series. RESULTS: Median age was 31 years (interquartile range, 27-38 years) with a male-to-female ratio of 5:1. Eighty-three percent of the patients had retiform purpura affecting the limbs, buttocks, face, or abdomen; 73% had ear necrosis, 50% cutaneous ulcers, 17% genital necrosis, 13% oral ulcers, and 10% digital necrosis. Cutaneous involvement was classified according to the frequency of the compromised corporal area, and purpuric lesions were stratified in 4 grades of severity. Anti-neutrophil cytoplasmic autoantibodies were positive in 85% of the cases, lupus anticoagulant in 73%, and antinuclear autoantibodies in 57%; rheumatoid factor was negative in all cases. We found nephritis in 17 cases (57%). Prednisolone was used in most of the patients (70%), with other immunosuppressive agents being used in a lower percentage. Improvement was observed in 93% of the patients, but symptoms recurred in 40%, attributed to relapses in consumption. End-stage chronic renal disease developed in 10% of the cases, and 1 patient died. CONCLUSIONS: Because of rising cocaine consumption and levamisole adulteration frequency, levamisole-adulterated cocaine-induced vasculitis/vasculopathy is becoming more common. Detailed characterization of skin involvement coupled with multiple antibody positivity is essential for a diagnosis. Renal involvement is frequent, clinically and histologically heterogeneous, and potentially serious.

ß2-adrenoceptor signaling reduction is involved in the inflammatory response of fibroblast-like synoviocytes from adjuvant-induced arthritic rats.

OBJECTIVE: To investigate the effects of ß-AR signaling on fibroblast-like synoviocytes (FLS) from adjuvant-induced arthritis (AA) rats and the partial mechanisms focused on ß-AR desensitization mediated by GRK2 and ß-arrestin2. METHODS: Animals were divided into a control group and an AA model group, and FLSs were cultured. Arthritis index, histopathology of joints, epinephrine (Epi) and norepinephrine (NE) were detected in vivo. The effect of the ß-AR agonist isoprenaline (ISO) and the ß2-AR agonist salbutamol on FLS cell viability were detected by CCK8. Cytokines TNF-α, IL-1ß, OPG and RANKL were examined by ELISA. The expression of ß2-AR was detected by immunofluorescence and flow cytometry. The cytomembrane expression and desensitization of ß2-AR, GRK2, and ß-arrestin2 were measured by flow cytometry and western blot. RESULTS: The concentration of NE increased to a peak on day 21, which was consistent with the arthritis index. The levels of Epi and NE in synovial tissues were decreased. ISO inhibited FLS cell viability and TNF-α, IL-1ß, and RANKL secretion, and promoted OPG secretion. ß2-AR mediated the effects of ISO on FLS cell viability. ß2-AR signaling was weaker in AA rats compared to the controls. Elevated GRK2 and ß-arrestin2 in cytomembranes promoted ß2-AR desensitization and may decrease the anti-inflammatory effect of ß2-AR signaling. CONCLUSION: The activation of ß2-AR signaling exerts its anti-inflammatory activities on FLS. ß2-AR signaling decreased in the AA model, which might be related to the increased membrane expression of GRK2 and ß-arrestin2, and promoted the excessive desensitization of ß2-AR. Decreased ß2-AR signaling may be relevant to the exacerbation of arthritis inflammation.

Recent advances in experimental polyphosphazene adjuvants and their mechanisms of action.

Vaccination continues to be a very important public health intervention to control infectious diseases in the world. Subunit vaccines are generally poorly immunogenic and require the addition of adjuvants to induce protective immune responses. Despite their critical role in vaccines, adjuvant mechanism of action remains poorly understood, which is a barrier to the development of new, safe and effective vaccines. In the present review, we focus on recent progress in understanding the mechanisms of action of the experimental adjuvants poly[di(carboxylatophenoxy)phosphazene] (PCPP) and poly[di(sodiumcarboxylatoethyl-phenoxy)phosphazene] (PCEP) (in this review, adjuvants PCPP and PCEP are collectively referred to as PZ denoting polyphosphazenes). PZs are high molecular weight, water-soluble, synthetic polymers that have been shown to regulate innate immune response genes, induce cytokines and chemokines secretion at the site of injection and, also, induce immune cell recruitment to the site of injection to create a local immune-competent environment. There is an evidence that as well as its role as an immunoadjuvant (that activate innate immune responses), PZ can also act as a vaccine carrier. The mechanism of action that explains how PZ leads to these effects is not known and is a barrier to the development of designer vaccines.

Alogenosis iatrogénica y enfermedades reumáticas / Latrogenic alogenosis and rheumatic diseases

La aplicación de sustancias con fines estéticos de forma indiscriminada como aceites minerales, hidrocarburos, silicona industrial, entre otros, llevan a producir enfermedades en el organismo bien sea locales y/o sistémicas. La asociación entre el uso de estas sustancias y la aparición de enfermedades autoinmunes aún no está clara. No obstante, se han descrito series de pacientes con antecedentes de inyección por materiales de relleno con fines cosméticos, que posteriormente presentaron patologías autoinmunes como: la esclerosis sistémica, el lupus eritematoso sistémico, la artritis reumatoidea, el síndrome de Sjögren, fibromialgia y presencia aislada de algunos síntomas inespecíficos como artralgias, mialgias, deterioro cognitivo, malestar general y fiebre. La reacción inflamatoria excesiva que pueden desencadenar estas sustancias y sus graves consecuencias para el organismo y teniendo en cuenta el aumento de estas prácticas a nivel global, hace necesario concientizar que sólo a través de una adecuada educación a la comunidad y la preparación del personal de la salud, podrá combatirse el terrible daño que provocan en la población(1)

The application of substances with aesthetic purpose in an indiscriminate way as oils minerals, hydrocarbons, industrial silicon, and others, they take to produce illnesses well in the body it is local and/or systemic. The association between the use of these substances and the appearance of autoimmunity diseases is not still clear. Nevertheless cases series have been described patient with antecedent of injection for filler materials with cosmetics purpose that later presented defined autoimmunity such as systemic sclerosis, lupus, rheumatoid arthritis, Sjögren Syndrome, Fibromyalgia and the isolated presence of some symptoms nonspecific. The excessive inflammatory reaction that can cause these substances and their serious consequences for the organism, and keeping in mind the increase from these practices to global level is necessary to inform that alone through an appropriate education to the community and the preparation of the health professionals will be able to prevent and combat the terrible damage in the population(1)

Antiepileptic drugs as analgesics/adjuvants in inflammatory pain: current preclinical evidence.

Inflammatory pain is the most common type of pain that is treated clinically. The use of currently available treatments (classic analgesics - NSAIDs, paracetamol and opioids) is limited by insufficient efficacy and/or side effects/tolerance development. Antiepileptic drugs (AEDs) are widely used in neuropathic pain treatment, but there is substantial preclinical evidence on their efficacy against inflammatory pain, too. In this review we focus on gabapentinoids (gabapentin and pregabalin) and dibenzazepine AEDs (carbamazepine, oxcarbazepine, and recently introduced eslicarbazepine acetate) and their potential for relieving inflammatory pain. In models of somatic, visceral and trigeminal inflammatory pain, that have a translational value for inflammatory conditions in locomotor system, viscera and head/face, AEDs have demonstrated analgesic activity. This activity was mostly consistent, dependent on the dose and largely independent on the site of inflammation and method of its induction, nociceptive stimuli, species, specific drug used, its route of administration and dosing schedule. AEDs exerted comparable efficacy with classic analgesics. Effective doses of AEDs are lower than toxic doses in animals and, when expressed as equivalent human doses, they are largely overlapping with AEDs doses already used in humans for treating epilepsy/neuropathic pain. The main mechanism of antinociceptive/antihyperalgesic action of gabapentinoids in inflammatory pain models seems to be α2δ-dependent suppression of voltage-gated calcium channels in primary sensory neurons that leads to reduced release of neurotransmitters in the spinal/medullar dorsal horn. The suppression of NMDA receptors via co-agonist binding site primarily at spinal sites, activation of various types of K+ channels at spinal and peripheral sites, and activation of noradrenergic and serotonergic descending pain modulatory pathways may also contribute. Inhibition of voltage-gated sodium channels along the pain pathway is probably the main mechanism of antinociceptive/antihyperalgesic effects of dibenzazepines. The recruitment of peripheral adrenergic and purinergic mechanisms and central GABAergic mechanisms may also contribute. When co-administered with classic/other alternative analgesics, AEDs exerted synergistic/additive interactions. Reviewed data could serve as a basis for clinical studies on the efficacy/safety of AEDs as analgesics/adjuvants in patients with inflammatory pain, and contribute to the improvement of the treatment of various inflammatory pain states.

Adulteration Practices of Psychoactive Illicit Drugs: An Updated Review.

BACKGROUND: Powdery drugs such as cocaine and heroin are frequently adulterated or diluted predominantly to obtain more doses and to increase the drug dealer's profits, but also to enhance, to modify or to oppose drug effects. The aim of this report is to provide an overview of the recent scientific literature on medicines as well as on new psychoactive substances, used as cutting agents (i.e. pharmacologically active adulterants) and on the related adverse health effects on consumers, possibly due to the synergistic effect of the adulterants laced with substances of abuse. METHOD: A literature search up to January 2017 was performed on MEDLINE, Scopus and Web of Science and reports and documents of international agencies or institutions were also searched. RESULTS: Pharmacologically active substances such as: paracetamol, caffeine, dextromethorphan, clenbuterol for heroin; levamisole, phenacetine, lidocaine, hydroxyzine and diltiazem for cocaine; caffeine and phentermine for amphetamine, have been identified over the years. Furthermore, since cocaine and morphine (this latter as a precursor of heroin) are both extracted from natural products, some impurities and minor alkaloids can be present in the final preparation. In this context, it is worth considering that new psychoactive substances are also used as cutting agents. CONCLUSION: The wide availability of illicit psychotropic drugs is the most serious hazard threatening consumers. Indeed emergency departments are often responsible in evaluating damages caused not only by the base substance, but also by other eventual compounds added to mimic or antagonize drug effects or simply dilute the drug amount, with a possible harmful synergic toxic action.