Juan Gerardo Reyes-García

Antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rodents

BackgroundPainful neuropathy is the most common and debilitating complication of diabetes and results in hyperalgesia and allodynia. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Current therapeutic approaches are only partially successful and they are only thought to reduce the pain associated with peripheral neuropathy. Some natural products offer combined antioxidant, anti-inflammatory and antinociceptive properties that may help to treat in a more integrative manner this condition. In this regard, the purpose of this study was to investigate the antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rats and mice without glucose control as well as the possible mechanism of action involved in this effect.MethodsRats and mice were injected with 50 or 200 mg/kg streptozotocin, respectively, to produce hyperglycemia. The formalin test and von Frey filaments were used to assess the nociceptive activity. Rota-rod was utilized to measure motor activity and malondialdehyde assay to determine anti-oxidative properties.ResultsAfter 3 weeks of diabetes induction, chemical hyperalgesia was observed in streptozotocin-injected rats. Oral acute administration of 7-hydroxy-3,4-dihydrocadalin (0.3–30 mg/kg) decreased in a dose-dependent manner formalin-evoked hyperalgesia in diabetic rats. In addition, methiothepin (non-selective 5-HT receptor antagonist, 1 mg/kg, i.p.) and ODQ (guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (opioid receptor antagonist, 1 mg/kg, s.c.), prevented 7-hydroxy-3,4-dihydrocadalin-induced antihyperalgesic effect. The anti-hyperalgesic effect of 7-hydroxy-3,4-dihydrocadalin was similar to that produced by pregabalin (10 mg/kg, p.o.). Furthermore, oral acute administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) reduced streptozotocin-induced changes in malondialdehyde concentration from plasma samples. Unlike pregabalin, 7-hydroxy-3,4-dihydrocadalin did not affect motor activity. Six weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. At this time, oral administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) or pregabalin (10 mg/kg) reduced in a similar way tactile allodynia in diabetic rats. Finally, chronic oral administration of 7-hydroxy-3,4-dihydrocadalin (30-300 mg/kg, 3 times/week, during 6 weeks), significantly prevented the development of mechanical hyperalgesia and allodynia in streptozotocin-induced diabetic mice.ConclusionsData suggests that 7-hydroxy-3,4-dihydrocadalin has acute and chronic effects in painful diabetic neuropathy. This effect seems to involve antioxidant properties as well as activation of 5-HT receptors and inhibition of guanylyl cyclase enzyme.

Pre-emptive analgesia with the combination of tramadol plus meloxicam for third molar surgery: a pilot study.

The aim of this pilot study was to evaluate pre-emptive analgesia using the combination tramadol plus meloxicam compared with each individual drug alone for the reduction of pain after extraction of third molars. Fifty-one patients were randomised into three groups (n=17 in each), using a series of random numbers: the first group was given tramadol 25mg and meloxicam 7.5mg; the second tramadol 50mg, and the third meloxicam 15 mg, all intramuscularly. Treatments were prepared in identical syringes by an independent investigator and were given immediately. The teeth were removed 50 min after the analgesics had been given. Intensity of pain, consumption of analgesics, and adverse effects were evaluated. The intensity of pain was evaluated using a visual analogue scale (VAS) and the area under the curve of the VAS showed significant differences amongst the groups. In conclusion, the study showed that the combination of tramadol 25mg and meloxicam 7.5mg had an analgesic effect similar to that of meloxicam 15 mg, but both were better than tramadol 50mg for relief of pain after the extraction of mandibular third molars.

Pre-emptive analgesic effectiveness of meloxicam versus tramadol after mandibular third molar surgery: a pilot study.

PURPOSE To compare the pre-emptive analgesic effectiveness of 15 mg of meloxicam and 50 mg of tramadol after mandibular third molar surgery. PATIENTS AND METHODS This pilot study was a double-blind, randomized, parallel-group clinical trial. The patients were randomized into 2 treatment groups, each with 15 patients, by use of a series of random numbers: group A was administered 15 mg of meloxicam intramuscularly (IM) 50 minutes before the surgery and group B was given 50 mg of tramadol IM 50 minutes before the surgery. We evaluated pain intensity, analgesic consumption, swelling, and trismus. RESULTS The group receiving 15 mg of meloxicam IM showed differences in pain intensity evaluated by the area under the curve of the visual analog scale and total analgesic consumption when compared with the group receiving 50 mg of tramadol IM. CONCLUSION The patients receiving 15 mg of preoperative meloxicam had less pain intensity and total analgesic consumption than those receiving 50 mg of preoperative tramadol.

High-fat diet exacerbates pain-like behaviors and periarticular bone loss in mice with CFA-induced knee arthritis.

Our aim was to quantify nociceptive spontaneous behaviors, knee edema, proinflammatory cytokines, bone density, and microarchitecture in high‐fat diet (HFD)‐fed mice with unilateral knee arthritis.

B-vitamin Mixture Improves the Analgesic Effect of Diclofenac in Patients with Osteoarthritis: A Double Blind Study

According to the high consumption of the mixture of B vitamins and diclofenac in several countries, this combination has constituted a frequently used option in pain therapy from inflammatory origin. Although the evidence obtained from inflammatory pain animal models has shown the existence of analgesic synergy between diclofenac and the B vitamins mixture, the corresponding clinical evidence is scarce. A double-blind, randomized clinical trial study was designed to characterize the analgesic effect and safety of diclofenac and B vitamins against diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to total knee arthroplasty with a pain level ≥7 in a 1-10 cm visual analogue scale were allocated to receive a single intramuscular injection of sodium diclofenac (75 mg) alone or combined with thiamine (100 mg), pyridoxine (100 mg) and cyanocobalamin (5 mg), and the pain level was evaluated during 12 h post-injection. Diclofenac+B vitamins mixture showed a superior analgesic effect during the assessed period and also a better assessment of the pain relief perception by patients than diclofenac alone. This study constitutes a clinical support on the improvement of the analgesic effect of diclofenac by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical model of inflammatory pain.

Histopathology of murine toxoplasmosis under treatment with dialyzable leukocyte extract

BACKGROUND Dialyzable leukocyte extracts (DLEs) contain molecules smaller than 10 kDa with biological activity in receptor organisms. Primarily, they participate in the regulation of the Th1 immune response, which is essential for the control of several intracellular infections, such as toxoplasmosis. This disease is associated with congenital infection, encephalitis or systemic infections in immunocompromised individuals. The clinical course of this infection fundamentally depends on a well-regulated immune response and timely treatment with the appropriate drugs. OBJECTIVE The aim of this study was to evaluate the effect of treatment with a leukocyte extract, derived from crocodile lymphoid tissue, on the histopathology and brain parasite load in NIH mice that had been infected with cysts of Toxoplasma gondii (ME-49 strain). METHODS The treatment was applied during the acute and chronic stages of the infection. Histopathological changes were evaluated in the ileum, liver and spleen at one, four and eight weeks after infection and in the brain at week 8. The parasite load was evaluated by counting the cysts of T. gondii found in the brain. FINDINGS Compared to the control mouse group, the mice infected with T. gondii and under treatment with DLE showed less tissue damage, mainly at the intestinal, splenic and hepatic levels. In addition, a greater percentage of survival was observed, and there was a considerable reduction in the parasite load in the brain. CONCLUSIONS The results suggest that DLE derived from crocodile is a potential adjunctive therapy in the conventional treatment of toxoplasmosis.

Adverse Events Reactions Reported With the Use of a Fixed-Dose Combination of Nor-Pseudoephedrine, Triiodothyronine, Atropine, Aloin and Diazepam in Obese Mexican Patients

Background: Obesity is a health problem worldwide. Although the first-line intervention is implementing a comprehensive program of diet, exercise and behavior changes, some patients require additional drug treatment. Among the medications used wide and effectively for obesity in Mexico is found a combination consisting of 5 active ingredients: nor-pseudoephedrine, triiodothyronine, atropine, aloin and diazepam (Redotex®), whose rationality and safety remains controversial. Objective: To analyze the adverse event reports received in the pharmacovigilance unit of the manufacturer company, from 2009 to 2014, in order to assess the existence of related potential safety issues. Method: Adverse events were sorted by frequency and classified by intensity and causality. The groups mainly affected by adverse events by age and sex were determined and the pattern of comorbidities and use of concomitant drugs was defined. Results: The number of reports recorded was 269, which corresponded to 609 adverse events. The greater frequency of reports occurred in the group of female 18-50 years old. The main adverse events were dry mouth and polydipsia. Most adverse events were classified both as mild and probable. Among 132 patients who used concomitant medications, 64 of them corresponded to the use of additional anti-obesity products. Conclusion: Except for some cases of misuse, there were no data to suspect the existence of special safety issues related with the use of the product; thus, considering the high anti-obesity efficacy reported for the study product (Redotex®), its adverse event profile seems acceptable.

Genetic contributors to serum uric acid levels in Mexicans and their effect on premature coronary artery disease

BACKGROUND Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS Only two loci were associated with SUA levels: SLC2A9 (β = -0.47 mg/dl, P = 1.57 × 10-42 for lead SNP rs7678287) and ABCG2 (β = 0.23 mg/dl, P = 2.42 × 10-10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD.

Anorectic efficacy and safety of the diethylpropion-topiramate combination in rats

Preclinical Research & Development

Antiallodynic interaction and motor performance of the pregabalin/thioctic acid and pregabalin/α-tocopherol combinations in neonatal streptozotocin-induced diabetic rats

Painful peripheral neuropathy can be associated with nerve damage caused by diabetes mellitus. Although pregabalin is the first‐line therapy for peripheral neuropathy, it shows substantial discontinuation rates, mainly because of nervous system side effects as motor incoordination. Multimodal therapy may improve the motor side effect profile of pregabalin. The aim of this study was to evaluate the interaction of pregabalin + thioctic acid or pregabalin + α‐tocopherol on allodynia and motor performance in neonatal streptozotocin‐induced diabetic rats. Efficacy of drugs separately or in combination was tested by tactile allodynia using von Frey filaments. Isobolographic and interaction index analysis were used to determine the antiallodynic interaction between pregabalin and either thioctic acid or α‐tocopherol. Motor performance was measured using a rotarod test. Pregabalin, thioctic acid, and α‐tocopherol reduced, in a dose‐dependent fashion, tactile allodynia. Pregabalin + thioctic acid and pregabalin + α‐tocopherol combinations also dose‐dependently reduced allodynic behavior in diabetic rats. Isobolographic analysis revealed an additive interaction for both combinations. Consistently, the interaction indices confirmed the additive effect between pregabalin + thioctic acid and pregabalin + α‐tocopherol. In addition, the administration of either combination improved motor incoordination induced by pregabalin. Data suggests that thioctic acid or α‐tocopherol could positively impact the therapeutic profile of pregabalin, because they might be useful for reducing motor incoordination associated to pregabalin in patients with peripheral neuropathy.