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Introduction: Diabetic neuropathies are the most prevalent chronic complications of diabetes, characterized by pain and substantial morbidity. Although many drugs have been approved for the treatment of this type of pain, including gabapentin, tramadol (TMD), and classical opioids, it is common to report short-term results or potentially severe side effects. TMD, recommended as a second-line treatment can lead to unwanted side effects. Cannabidiol (CBD) has been gaining attention recently due to its therapeutic properties, including pain management. This study aimed to characterize the pharmacological interaction between CBD and TMD over the mechanical allodynia associated with experimental diabetes using isobolographic analysis. Materials and Methods: After diabetes induction by streptozotocin (STZ), diabetic rats were systemically treated with CBD or TMD alone or in combination (doses calculated based on linear regression of effective dose 40% [ED40]) and had the mechanical threshold evaluated using the electronic Von Frey apparatus. Both experimental and theoretical additive ED40 values (Zmix and Zadd, respectively) were determined for the combination of CBD plus TMD in this model. Results: Acute treatment with CBD (3 or 10 mg/kg) or TMD (2.5, 5, 10, or 20 mg/kg) alone or in combination (0.38+1.65 or 1.14+4.95 mg/kg) significantly improved the mechanical allodynia in STZ-diabetic rats. Isobolographic analysis revealed that experimental ED40 of the combination (Zmix) was 1.9 mg/kg (95% confidence interval [CI]=1.2-2.9) and did not differ from the theoretical additive ED40 2.0 mg/kg (95% CI=1.5-2.8; Zadd), suggesting an additive antinociceptive effect in this model. Conclusions: Using an isobolographic analysis, these results provide evidence of additive pharmacological interaction between CBD and TMD over the neuropathic pain associated with experimental diabetes induced by STZ.

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BACKGROUND: An inadequate combination of prescription drugs with food or medicinal plants could cause adverse effects in patients or produce negative therapeutic results. Therefore, this generic systematic review protocol aims to identify and synthesize the literature on clinical characteristics and safety issues of these types of pharmacological interactions occurring in children, adolescents, adults, pregnant/lactating women, and older adults. METHODS/DESIGN: This generic protocol follows the stated guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. A literature search will be performed in PubMed, Scopus, and Virtual Health Library (VHL) electronic databases from 1960 till present for studies reporting clinical characteristics and safety issues associated with pharmacological interactions occurring between prescription drugs and food or medicinal plants in participants from birth-age to ≥ 65-year-old, including pregnant/lactating women. Lateral searching will be carried out in PubMed via related citation. Two reviewers will carry out an independent evaluation of eligible studies as well as the corresponding data extraction of the selected ones. Subsequently, the methodological quality evaluation of the selected articles will be completed using the corresponding Joanna Briggs Institute Checklists. Moreover, the quality of evidence will be graded according to the criteria of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group. Quantitative research in humans comprising clinical trials and clinical, comparative and, observational studies will be included. The main outcomes of this protocol involve reported potential food-drug and herb-drug interactions, associated safety issues, and adverse reactions along with the generic name of the prescribed drug and the scientific name of the food and medicinal plants involved in these types of pharmacological interactions. Finally, findings extracted from the selected studies will be summarized in a narrative synthesis. DISCUSSION: This generic systematic review protocol seeks to synthesize and critically evaluate current knowledge besides to identify any comprehension gaps in the concurrent administration of prescription drugs with food and herbs. By achieving a better understanding of this topic, this information will allow healthcare professionals to develop useful strategies to recognize, manage, and prevent these types of pharmacological interactions at different age stages, including pregnant/lactating women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018117308.

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O objetivo deste estudo foi avaliar latência, duração do efeito, progressão cranial da lidocaína e da bupivacaína isoladas, ou em associação, pela via epidural, em cães, além de mensurar a pressão média do canal epidural antes e após a realização dela. Utilizaram-se 18 cães, alocados em três grupos, os quais receberam, por via epidural: lidocaína 2% (GL) 0,25mL/kg; bupivacaína 0,5% (GB) no mesmo volume, ou a associação de ambas (GLB) na proporção de 1:1. Avaliaram-se as frequências cardíaca e respiratória e a pressão arterial sistólica (PAS) previamente aos tratamentos (M0) e até 60 minutos após a anestesia epidural. Ainda, avaliou-se a pressão no canal epidural antes e após a administração dos tratamentos, o período de latência, a progressão e a duração do bloqueio pelo pinçamento interdigital e do panículo paravertebral. Houve redução de 12% da PAS no GL em todos os momentos e de 16% aos 30 minutos no GLB quando comparados ao basal. A pressão média no espaço epidural antes e após a anestesia epidural foi de -1,5 (±3,9) e 41 (±16) mmHg; 55% apresentaram pressão negativa no espaço epidural. O período de latência não diferiu entre os grupos (GL: 3,5±1,6; GB: 4,5±4,5; e GLB: 2,4±1 minutos) e a duração do bloqueio foi maior no GB em relação ao GL (GL: 125±24; GB: 176±24; e GLB: 153±35 minutos). A progressão máxima dos anestésicos foi até L1-T13 no GL, L4-L3 no GB e L3-L2 no GLB. Conclui-se que a associação de lidocaína com bupivacaína não apresenta vantagens em relação ao uso dos fármacos isolados pela via epidural, tendo a lidocaína progredido mais cranialmente em relação à bupivacaína ou à associação. A lidocaína promoveu redução da PAS, mesmo quando associada à bupivacaína, permanecendo dentro dos valores de referência. Apenas 55% dos cães apresentaram pressão média negativa no espaço epidural antes da administração dos fármacos, dessa forma o teste da gota pendente pode não ser eficiente para localização do espaço epidural em todos os animais.(AU)

The objective of this study was to evaluate the latency, duration of the effect, and cranial progression of lidocaine and bupivacaine alone or in combination, by epidural route in dogs, and measuring the average pressure of the epidural channel before and after the completion thereof. Eighteen dogs were allocated in three groups, which received epidural: lidocaine 2% (GL) 0.25ml / kg; bupivacaine 0.5% (GB) in the same volume, or the association of both (GLB) in a 1: 1 ratio. Heart and respiratory rates and systolic blood pressure (SBP) were evaluated before treatment (M0) and up to 60 minutes after epidural anesthesia. In addition, the pressure in the epidural canal was evaluated before and after the administration of the treatments, latency period, progression and duration of the block by interdigital and paravertebral pannicus clamping. There was a 12% decrease in SBP in the GL at all times and 16% at 30 minutes in GLB when compared to the baseline. The mean pressure in the epidural space before and after epidural anesthesia was -1.5 (±3.9) and 41 (±16) mmHg), 55% presented negative pressure in the epidural space. The latency period did not differ between groups (GL: 3.5±1.6; GB: 4.5±4.5; and GLB: 2.4±1 minutes) and the duration of blockade was higher in GB (GL: 125±24, GB: 176±24, and GLB: 153±35 minutes). The maximum progression of anesthetics was up to L1-T13 in GL, L4-L3 in GB and L3-L2 in GLB. It is concluded that the association of lidocaine with bupivacaine does not present advantages in relation to the use of the drugs isolated by the epidural route, with lidocaine progressing more cranially in relation to bupivacaine or the association. Lidocaine promoted the reduction of SBP, even when associated with bupivacaine, remaining within the reference values. Only 55% of the dogs presented negative mean pressure in the epidural space before administration of the drugs, so the drop test may not be efficient for locating the epidural space in all animals.(AU)

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O objetivo deste estudo foi avaliar latência, duração do efeito, progressão cranial da lidocaína e da bupivacaína isoladas, ou em associação, pela via epidural, em cães, além de mensurar a pressão média do canal epidural antes e após a realização dela. Utilizaram-se 18 cães, alocados em três grupos, os quais receberam, por via epidural: lidocaína 2% (GL) 0,25mL/kg; bupivacaína 0,5% (GB) no mesmo volume, ou a associação de ambas (GLB) na proporção de 1:1. Avaliaram-se as frequências cardíaca e respiratória e a pressão arterial sistólica (PAS) previamente aos tratamentos (M0) e até 60 minutos após a anestesia epidural. Ainda, avaliou-se a pressão no canal epidural antes e após a administração dos tratamentos, o período de latência, a progressão e a duração do bloqueio pelo pinçamento interdigital e do panículo paravertebral. Houve redução de 12% da PAS no GL em todos os momentos e de 16% aos 30 minutos no GLB quando comparados ao basal. A pressão média no espaço epidural antes e após a anestesia epidural foi de -1,5 (±3,9) e 41 (±16) mmHg; 55% apresentaram pressão negativa no espaço epidural. O período de latência não diferiu entre os grupos (GL: 3,5±1,6; GB: 4,5±4,5; e GLB: 2,4±1 minutos) e a duração do bloqueio foi maior no GB em relação ao GL (GL: 125±24; GB: 176±24; e GLB: 153±35 minutos). A progressão máxima dos anestésicos foi até L1-T13 no GL, L4-L3 no GB e L3-L2 no GLB. Conclui-se que a associação de lidocaína com bupivacaína não apresenta vantagens em relação ao uso dos fármacos isolados pela via epidural, tendo a lidocaína progredido mais cranialmente em relação à bupivacaína ou à associação. A lidocaína promoveu redução da PAS, mesmo quando associada à bupivacaína, permanecendo dentro dos valores de referência. Apenas 55% dos cães apresentaram pressão média negativa no espaço epidural antes da administração dos fármacos, dessa forma o teste da gota pendente pode não ser eficiente para localização do espaço epidural em todos os animais.(AU)

The objective of this study was to evaluate the latency, duration of the effect, and cranial progression of lidocaine and bupivacaine alone or in combination, by epidural route in dogs, and measuring the average pressure of the epidural channel before and after the completion thereof. Eighteen dogs were allocated in three groups, which received epidural: lidocaine 2% (GL) 0.25ml / kg; bupivacaine 0.5% (GB) in the same volume, or the association of both (GLB) in a 1: 1 ratio. Heart and respiratory rates and systolic blood pressure (SBP) were evaluated before treatment (M0) and up to 60 minutes after epidural anesthesia. In addition, the pressure in the epidural canal was evaluated before and after the administration of the treatments, latency period, progression and duration of the block by interdigital and paravertebral pannicus clamping. There was a 12% decrease in SBP in the GL at all times and 16% at 30 minutes in GLB when compared to the baseline. The mean pressure in the epidural space before and after epidural anesthesia was -1.5 (±3.9) and 41 (±16) mmHg), 55% presented negative pressure in the epidural space. The latency period did not differ between groups (GL: 3.5±1.6; GB: 4.5±4.5; and GLB: 2.4±1 minutes) and the duration of blockade was higher in GB (GL: 125±24, GB: 176±24, and GLB: 153±35 minutes). The maximum progression of anesthetics was up to L1-T13 in GL, L4-L3 in GB and L3-L2 in GLB. It is concluded that the association of lidocaine with bupivacaine does not present advantages in relation to the use of the drugs isolated by the epidural route, with lidocaine progressing more cranially in relation to bupivacaine or the association. Lidocaine promoted the reduction of SBP, even when associated with bupivacaine, remaining within the reference values. Only 55% of the dogs presented negative mean pressure in the epidural space before administration of the drugs, so the drop test may not be efficient for locating the epidural space in all animals.(AU)

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BACKGROUND: Swietenia humilis seeds are consumed in Mexico to treat type 2 diabetes; the antihyperglycemic effect of this species was previously demonstrated and related to the presence of tetranortriterpenoids of the mexicanolide class. PURPOSE AND STUDY DESIGN: The present investigation was conducted to determine the mechanism of action of selected mexicanolides, including 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), methyl-2-hydroxy-3-ß-tigloyloxy-1-oxomeliac-8(30)-enate (2) and humilinolide H (3), using in vivo experiments with hyperglycemic mice, and cell-based models. METHODS: Nicotinamide-streptozotocin hyperglycemic mice (50-130 mg/kg, i.p.) were used to build antihyperglycemic drug-response curves using an oral glucose tolerance test model. In vitro studies were carried out on INSE1, H4IIE and C2C12 cells to assess insulin secretion, glucose-6-phosphatase inhibition, glucose uptake and mitochondrial bioenergetics, respectively. RESULTS: The combination of the decoction of S. humilis or 2-hydroxy-destigloyl-6-deoxyswietenine acetate (mexicanolide 1) with glibenclamide resulted in a reduction of the antihyperglycemic effect while a significant increase was observed when they were dosed with metformin. These effects were related to KATP SUR blockade, insulin secretion in INSE1 cells, and modulation of 5-HT2 receptors. Furthermore, mexicanolides 1-3 inhibited glucose-phosphatase in H4IIE cells, and enhanced glucose uptake and spare respiratory capacity in C2C12 myotubes. CONCLUSION: S. humilis mexicanolides interact with pharmacological targets at pancreas (KATP channels), liver (glucose-6-phosphatase), and skeletal muscle (mitochondria and possibly glucose transporters) to modulate glucose homeostasis, and could be a promising resource to treat type 2 diabetes.

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Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose-response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED50 of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α2 -adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain.

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Se realizó un estudio descriptivo y prospectivo de 86 trabajadores del Puerto Guillermón Moncada de Santiago de Cuba, quienes recibieron tratamiento quimioprofiláctico con doxiciclina y presentaron reacciones adversas asociadas a dicho tratamiento, en noviembre del 2015, con vistas a caracterizarles y determinar la relación de causalidad existente entre la administración del medicamento, la aparición de efectos indeseables y las posibles interacciones farmacológicas. En esta serie, las reacciones adversas resultaron leves y no graves; las relaciones de causalidad, definitivas en la mayoría de los afectados (65,1 por ciento), aunque se determinaron algunas como probables y posibles, en tanto, las reacciones más frecuentes se presentaron en la esfera gastrointestinal

A descriptive and prospective study of 86 workers from Guillermón Moncada Port was carried out in Santiago de Cuba. They received chemoprophylactic treatment with doxicicline and presented adverse reactions associated with this treatment, in November, 2015, aimed at characterizing them and determining the relationship of causation existing between the administration of medication, emergence of undesirable effects and possible pharmacological interactions. In this series, the adverse reactions were light and no severe; the causation relationships, were definitive in most of the affected patients (65.1 percent), although some were determined as probable and possible, while, the most frequent reactions were presented in the gastrointestinal sphere

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