Investigation of the Combination of Pregabalin with Duloxetine or Amitriptyline on the Pharmacokinetics and Antiallodynic Effect During Neuropathic Pain in Rats.

BACKGROUND: Amitriptyline, duloxetine, and pregabalin are among the most pharmacotherapeutic, effective treatments for neuropathic pain control. However, the evaluation of synergism by combining these treatments is still poorly investigated. OBJECTIVES: To evaluate the pharmacokinetics of the combination of pregabalin plus duloxetine and pregabalin plus amitriptyline, as well as the effect of these on neuropathic pain on rodent model. STUDY DESIGN: The experimental study. SETTING: The research took place in the research laboratories at the Federal University of Alfenas after ethics committee approval. METHODS: This study used male Wistar rats weighing between 220 and 250 g. The animals were randomly divided into the following groups: monotherapy (pregabalin, amitriptyline, duloxetine), combined therapy (pregabalin + amitriptyline, pregabalin + duloxetine), and vehicle (ultrapure water). Pharmacokinetic analysis of pregabalin or combination (pregabalin + amitriptyline or pregabalin + duloxetine) in the plasma were performed by ultraperformance liquid chromatography tandem mass spectrometry. Neuropathic pain was induced by sciatic nerve constriction (chronic constriction injury [CCI]) model, and nociceptive threshold was measured by von Frey filaments test. In addition, to evaluate the influence of the treatments on the motor coordination, the rotarod test was used. RESULTS: The pharmacokinetic disposition of pregabalin was changed in the association with amitriptyline, presenting a clearance reduction and consequently an increase in bioavailability. Furthermore, after the 14th day of CCI, pregabalin was administered orally and induced antiallodynic effect after 1, 2:15, 4, and 8 hours of its administration and showed the greatest antiallodynic effect after 4 hours of its administration. Moreover, this effect was prolonged (up to 8 hours) by combination with amitriptyline. Additionally, pregabalin and pregabalin + duloxetine showed a hypoalgesic effect in sham rats. In addition, the rotarod test results showed that drugs did not influence the motor coordination of the rats. LIMITATIONS: Potential competition mechanisms during the excretion of pregabalin, when pregabalin was combined with amitriptyline, were not investigated in this study. CONCLUSIONS: The data demonstrated that combined therapy of pregabalin plus amitriptyline improved the bioavailability of pregabalin and potentiated the efficacy of the antiallodynic effect of pregabalin alone, proving to be advantageous for the treatment of sciatic neuropathic pain.

COVID-19 Pandemic - A Narrative Review of the Potential Roles of Chloroquine and Hydroxychloroquine.

BACKGROUND: Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used against malaria, rheumatism, inflammation in the joints, lupus, among others. These drugs showed positive results in preliminary scientific research for treatment of the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Since the studies with CQ and HCQ are initial with small patient populations, it is not yet known whether there are adverse effects from the use of CQ and HCQ for patients infected with the coronavirus. OBJECTIVES: The aim of this study was to evaluate the evidence regarding the efficacy and safety of CQ and HCQ used against viral infection caused by SARS-CoV-2. STUDY DESIGN: This is a narrative review of the traditional prescriptions of CQ and HCQ efficacy and adverse effects as well as their employment for coronavirus disease 2019 (COVID-19). SETTING: In vitro and clinical studies comparing the antiviral efficacy and adverse effect profile of CQ and HCQ against COVID-19 in adult patients were evaluated. METHODS: A systemic search of reviews, including in vitro and clinical trial studies in English focusing on CQ and HCQ effects and adverse effects against COVID-19 in the adult patient population from PubMed was performed. It included studies reporting chloroquine and hydroxychloroquine effects and adverse effects against COVID-19. RESULTS: A total of 42 articles published between 2004 and April 2020 were reviewed for therapeutic use of CQ and HCQ. Both these drugs showed a significant in vitro potential against coronavirus. Many studies for clinical use of CQ and HCQ showed that patients presented adverse reactions on high doses. LIMITATIONS: Clinical studies have some methodology shortcomings, such as lack of information about the treatment and small number of experimental patients, leading to a misinterpretation of the data. Besides, there are few clinical studies with a limited sample size. Moreover, most of them did not present control groups, and some patients had died during these protocols. DISCUSSION: Despite both CQ and HCQ in vitro antiviral evidence, clinically, both drugs, either alone or combined with other medications, may increase the risk of cardiac arrhythmias, leading to cardiac arrest and sudden death. Besides, a lot of uncertainty still remains, such as starting administration period, dose prescribed, length of treatment, patients' condition, concomitant drug use, among others. CONCLUSION: From the studies reviewed, it is not possible to state the precise efficacy and safety of CQ and HCQ use in the treatment of COVID-19 at any time in the course of the disease. Future studies are warranted.

Effects of Selenium in the Microcirculation of Fructose-Fed Hamsters.

BACKGROUND AND AIMS: Fructose intake is directly related to vascular dysfunction and it is a risk factor for the development of metabolic and cardiovascular diseases, such as obesity, diabetes, and hypertension. Selenium, a component of antioxidant enzymes, improves hyperglycemia and vascular function in diabetic animals. The aim of this study was to evaluate the effects of dietary selenium supplementation on microcirculatory and metabolic parameters of fructose-fed hamsters. METHODS AND RESULTS: Male hamsters (Mesocricetus auratus) had their drinking water substituted or not by 10% fructose solution for 60 days, during which their microcirculatory function was evaluated in the cheek pouch preparation. Blood glucose and serum insulin levels were also tested. Microcirculatory responses to acetylcholine (an endothelium-dependent vasodilator) and to sodium nitroprusside (SNP, an endothelium-independent vasodilator), and macromolecular permeability increase induced by a 30-min ischemia/reperfusion (I/R) procedure, showed that endothelium-dependent and independent vasodilatation was significantly increased in animals that had high selenium supplementation, in both the control and fructose-fed groups. Selenium supplementation protected against plasma leakage induced by I/R in all control and fructose-fed groups. CONCLUSION: Our results indicate that dietary selenium supplementation reduces microvascular dysfunction by increasing endothelial-dependent and independent dilatation and reducing macromolecular permeability increase in fructose-fed animals.

α-Tocopherol Improves Microcirculatory Dysfunction on Fructose Fed Hamsters.

Fructose, an everyday component of western diet associated to chronic hyperglycemia and enhanced free radical production, impairs endothelial function and supplementation with antioxidants might improve it. In this study we investigated if vitamin E could reverse the microvascular damage elicited by fructose. Male Syrian golden hamsters drank either 10% fructose solution (F) or filtered water (C), combined with three concentrations of vitamin E in their chows [zero, normal (VE) or 5X (5XVE)] during 60 days. Microvascular reactivity in response to topical application of acetylcholine (Ach; endothelium-dependent vasodilator) or sodium nitroprusside (SNP; endothelium-independent vasodilator) and macromolecular permeability increase induced by either 30 min ischemia followed by reperfusion (I/R) or topical application of histamine (5 µM) were assessed using the cheek pouch preparation. Compared to controls (drinking filtered water), fructose-drinking animals showed decreased vasodilatation to acetylcholine in all concentrations tested (-56.2% for 10-9M, -53.9% for 10-7M and -43.7% for 10-5M). On the other hand, vitamin E supplementation resulted in increased responses for both water and fructose drinking groups (177.4% for F vs. F/5XVE and 241.6% for C vs. C/5XVE for 10-5M Ach). Endothelial-independent vasodilatation explored by topical application of SNP was restored and even enhanced with the supplementation of 5X vitamin E in both groups (80.1% for F vs. F/5XVE; 144.2% for C vs. C/5XVE; 3.4% of difference for C/5XVE vs. F/5XVE on 10-5M SNP). The number of leaky sites after I/R and histamine stimuli in vitamin E supplemented animals decreased (-25.1% and -15.3% for F vs. F/5XVE; and -21.7% and -16% of leaky sites comparing C vs. C/5XVE, respectively for I/R and histamine stimuli) pointing to tightening of the endothelial barrier for macromolecular permeability. Our results strongly suggest that vitamin E could improve the endothelial function and permeability barrier and also reverse impairments elicited by sugar overload.