Complicaciones cardiovasculares en pacientes COVID-19 hospitalizados en Unidades de Pacientes Críticos en Chile. Registro COVICAR / Cardiovascular complications in COVID-19 patients admitted to intensive care units in Chilean hospitals

BACKGROUND: Patients with a cardiovascular (CV) history may be at greater risk of becoming ill and die due to SARS-CoV-2. AIM: To assess the incidence of CV complications in COVID-19 patients, the type of complication, and their association with CV history. MATERIAL AND METHODS: The clinical course of 1,314 patients with COVID-19 admitted consecutively to critical care units of 10 Chilean hospitals was registered between April and August of 2020. RESULTS: The median age of patients was 59 years and 66% were men. One hundred-four (8%) had a CV history, namely heart failure (HF) in 53 (4.1%), coronary heart disease in 50 (3.8 %), and atrial fibrillation in 36 (2.7 %). There were CV complications in 359 patients (27.3%). The most common were venous thrombosis in 10.7% and arrhythmias in 10.5%, HF in 7.2%, type 2 acute myocardial infarction in 4.2%, arterial thrombosis in 2.0% and acute coronary syndrome (ACS) in 1.6%. When adjusted by age, sex and risk factors, only HF (Odds ratio (OR) = 7.16; 95% confidence intervals (CI), 3.96-12.92) and ACS (OR = 5.44; 95% CI, 1.50-19.82) were significantly associated with CV history. There was no association with arrhythmias, type 2 acute myocardial infarction, arterial or venous thrombosis. CONCLUSIONS: Patients with a history of CV disease are at greater risk of suffering HF and ACS when hospitalized due to COVID-19. Arrhythmias, type 2 AMI, and arterial or venous thrombosis occur with the same frequency in patients with or without CV history, suggesting that these complications depend on inflammatory phenomena related to the infection.

Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose-response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.

[Cardiovascular complications in COVID-19 patients admitted to intensive care units in Chilean hospitals]. / Complicaciones cardiovasculares en pacientes COVID-19 hospitalizados en Unidades de Pacientes Críticos en Chile. Registro COVICAR.

BACKGROUND: Patients with a cardiovascular (CV) history may be at greater risk of becoming ill and die due to SARS-CoV-2. AIM: To assess the incidence of CV complications in COVID-19 patients, the type of complication, and their association with CV history. MATERIAL AND METHODS: The clinical course of 1,314 patients with COVID-19 admitted consecutively to critical care units of 10 Chilean hospitals was registered between April and August of 2020. RESULTS: The median age of patients was 59 years and 66% were men. One hundred-four (8%) had a CV history, namely heart failure (HF) in 53 (4.1%), coronary heart disease in 50 (3.8 %), and atrial fibrillation in 36 (2.7 %). There were CV complications in 359 patients (27.3%). The most common were venous thrombosis in 10.7% and arrhythmias in 10.5%, HF in 7.2%, type 2 acute myocardial infarction in 4.2%, arterial thrombosis in 2.0% and acute coronary syndrome (ACS) in 1.6%. When adjusted by age, sex and risk factors, only HF (Odds ratio (OR) = 7.16; 95% confidence intervals (CI), 3.96-12.92) and ACS (OR = 5.44; 95% CI, 1.50-19.82) were significantly associated with CV history. There was no association with arrhythmias, type 2 acute myocardial infarction, arterial or venous thrombosis. CONCLUSIONS: Patients with a history of CV disease are at greater risk of suffering HF and ACS when hospitalized due to COVID-19. Arrhythmias, type 2 AMI, and arterial or venous thrombosis occur with the same frequency in patients with or without CV history, suggesting that these complications depend on inflammatory phenomena related to the infection.

Experiencia en la práctica clínica real de la efectividad y la tolerabi- lidad de tapentadol de liberación prolongada para el tratamiento de dolor crónico postraumático producido por accidentes de trabajo / Real-world clinical practice experience of the effectiveness and tolerability of pro- longed-release tapentadol for the treatment of chronic post-traumatic pain caused by occupational accidents

Se llevó a cabo un estudio observacional para analizar si tapentadol de liberación prolongada (LP) puede considerarse un tratamiento de primera línea para pacientes con dolor crónico postraumático (DCPT). Métodos: Se presenta una serie de casos de la práctica clínica real de pacientes con DCPT producido por accidentes de trabajo. Antes de ingresar al estudio, todos los pacientes recibían tramadol, que se interrumpió cuando se inició la administración de tapentadol LP. Las evaluaciones de dolor incluyeron una escala de valoración numérica, el cuestionario DN4 y la escala de Impresión Global de Cambio del Paciente (PGIC, Patients' Global Impression of Change). Se recuperaron y registraron los eventos adversos. Resultados: 94 pacientes participaron en el estudio y 77 (82 %) completaron todas las visitas predefinidas. Cerca de la mitad de los pacientes informaron dolor crónico que tenía una duración de al menos 3 años; se observó un componente neuropático en el 87 % de los pacientes. El puntaje de dolor se redujo en 1,5 puntos luego del primer mes de tratamiento con tapentadol LP y en 2,48 puntos luego de 4 meses (p<0,05). También se asoció la administración de tapentadol LP con una reducción del 28,9 % de la dosis concomitante de pregabalina (p<0,01). De acuerdo con el cuestionario PGIC, el 74 % y el 77,9 % de los pacientes informó mejoría luego de uno y cuatro meses de tratamiento, respectivamente. El perfil de seguridad fue consistente con los datos actuales sobre tapentadol LP. Conclusión: El dolor osteomuscular crónico es una enfermedad prevalente que se caracteriza por tener resultados terapéuticos deficientes y se asocia a una mayor discapacidad y una mala calidad de vida. En este estudio de la práctica clínica real en pacientes que trabajan y que cuentan con un componente de dolor neuropático elevado, se observó que tapentadol LP produce efectos beneficiosos en términos del control del DCPT, y se obtuvieron índices altos de eficacia y seguridad.

An observational study was carried out to analyze whether prolonged-release (PR) tapentadol may be considered a first-line treatment for patients with chronic post-traumatic pain (PTD). Methods: A case series of cases of patients with PTFE caused by work accidents in a real clinical practice setting is described. Before entering the study, all patients were receiving tramadol, which was discontinued when PR tapentadol was started. Pain assessments included a numerical rating scale, the DN4 questionnaire, and the Patients' Global Impression of Change (PGIC) scale. Adverse events were retrieved and described. Results: 94 patients participated in the study and 77 (82%) completed all the predefined visits. About half of the patients reported chronic pain that lasted for at least 3 years. A neuropathic component was reported in 87% of patients. The pain score was reduced by 1.5 points after the first month of treatment with PR tapentadol and by 2.48 points after 4 months (p < 0.05). Administration of PR tapentadol was also associated with a concomitant reduction of pregabalin dose of 28.9% (p < 0.01). According to the PGIC questionnaire, 74% and 77.9% of patients reported improvement after one and four months of treatment, respectively. The safety profile was consistent with current data on PR tapentadol. Conclusion: Chronic musculoskeletal pain is a prevalent disease characterized by poor therapeutic results and associated with increased disability and poor quality of life. In our study in a real clinical practice setting with patients with a high neuropathic pain component, PR tapentadol produced beneficial effects in terms of DCPT control, and high efficacy and safety rates were obtained. Keywords: tapentadol, chronic pain, pain caused by work accidents, chronic post-traumatic pain, evidence from real clinical practice.

The Antinociceptive Activities of Certain NSAIDS Combinations in Murine Orofacial Test.

Pain models are mostly in rodents and between them formalin orofacial test allow discrimination among antinociception and anti-inflammation. This assay use a formalin solution injected into the upper right lip of each mouse which produces two periods of pain separated by an inactive period. The aims of the present study were to evaluate, by means of the isobolographic analysis, the antinociception and anti-inflammatory activities of the following NSAIDs: dexketoprofen, diclofenac, piroxicam and metamizole in an orofacial. The NSAIDs administered intraperitoneally produced a dose-dependent activity with the following order of potency of the rubbing behavior, in phase I: diclofenac>dexketoprofen>piroxicam>metamizole and in the phase II: metamizole>diclofenac>piroxicam>dexketoprofen. The coadministration of NSAIDs resulted in a synergistic interaction, which according to the value of the potency of the combination (II) presents the following range: dexketoprofen plus metamizole>dexketoprofen plus diclofenac>dexketoprofen plus piroxicam, in phase I and dexketoprofen plus metamizole>dexketoprofen plus piroxicam>dexketoprofen plus diclofenac, on the phase II. Data obtained in this work corroborate that NSAIDs alone or in combination inducing activities by additional mechanism of action supplementary to inhibition of COXs. This fact represent a novel approach that could be used as multimodal management of orofacial pain, since with this treatment strategies, by the reduction of doses, can help to diminish side effects of other dugs such opioids.

Involvement of NO in Antinociception of NSAIDS in Murine Formalin Hind Paw Assay.

There are different animal models to evaluate pain among them the formalin hind paw assay which is widely used since some of its events appear to be similar to the clinical pain of humans. The assay in which a dilute solution of formalin is injected into the dorsal hindpaw of a murine produces two 'phases' of pain behavior separated by a inactive period. The early phase (Phase I) is probably due to direct activation of nociceptors and the second phase (Phase II) is due to ongoing inflammatory input and central sensitization. Mice were used to determine the potency antinociceptive of piroxicam (1,3,10,and 30 mg/kg), parecoxib (0.3, 1,3,10 and 30 mg/kg), dexketoprofen (3,10,30 and 100 mg/kg) and ketoprofen (3,10,30 and 100 mg/kg). Dose-response for each NSAIDs were created before and after 5 mg/kg of L-NAME i.p. or 5 mg/kg i.p. of 7-nitroindazole. A least-squares linear regression analysis of the log dose-response curves allowed the calculation of the dose that produced 50% of antinociception (ED50) for each drug. The ED50 demonstrated the following rank order of potency, in the phase I: piroxicam > dexketoprofen > ketoprofen > parecoxib and in the phase II: piroxicam > ketoprofen > parecoxib > dexketoprofen. Pretreatment of the mice with L-NAME or 7-nitroindazol induced a significant increase of the analgesic power of the NSAIDs, with a significant reduction of the ED50. It is suggested that NO may be involved in both phases of the trial, which means that nitric oxide regulates the bioactivity of NSAIDs.

Nitric Oxide and Opioids Involvement in Isobolographic Nsaids Antinociception.

Different NSAIDs are used as antinociceptive in various analgesic assays, among which should be mentioned: ibuprofen, ketorolac , ketoprofen, meloxicam , paracetamol and others. It has been shown that NSAIDs possess antinociceptive activity by blocking cyclooxygenase enzymes (COXs). The present study was designed to evaluate the possible involvement of the nitridergic pathway due to L-NAME and the opioidergic route by NTX in the antinoception induced by NSAIDs using a murine pain model the tail flick test in an automatic tail flick algesiometer. The antinociception was evaluated by means of isobolographic analysis. The interaction between the combination of NSAIDs, via i.p., on basis of their ED25, demonstrated that the coadministration of the drugs were synergistic with the exception of the lack of effect in combination of meloxicam with ibuprofen and with ketorolac, since the result was additive. These data validate that the NSAIDs administered alone or in combinations produce antinociception in which other mechanisms of action must be added to the simple inhibition of COXs. In addition, the pretreatment of the mice with L-NAME and NTX does not change previous isobolographic parameters of the mixture of NSAIDs.

Non-steroidal Anti-inflammatory Drugs in Tonic, Phasic and Inflammatory Mouse Models.

The principal mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of ciclooxigenases. In this study was evaluated if NSAIDs could induce antinociceptive differences according to the type of murine pain model. Male mice were injected intraperitoneally with meloxicam, diclofenac, piroxicam, metamizol, ibuprofen, naproxen and paracetamol in the writhing, tail flick and formalin orofacial tests and dose-response were analyzed to obtain the ED50 of each drugs. Administration of NSAIDs produced in a dose-dependent antinociception with different potency in the tests. The relative potency of NSAIDs among the tests shows a value of 5.53 in the orofacial formalin test in phase I and 6.34 in phase II between meloxicam and paracetamol; of 7.60 in the writhing test between meloxicam and paracetamol and of 8.46 in the tail flick test between ibuprofen and paracetamol. If the comparison is made for each NSAID in the different tests, the minimum value was 0.01 for between writhing and phase II of the orofacial formalin. Meanwhile, the highest power ratio was 11.71 for diclofenac between writhing and tail flick tests. In conclusion, the results suggests that intraperitoneal NSAIDs administration induce antinociceptive activity depending on the type of pain. The results support that NSAIDs administration, induce a wide variety of antinociceptive effect, depending on the type of pain. This suggest the participation of different mechanisms of action that can be added to the simple inhibition of COXs controlled by NSAIDs.

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain.

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.

Synergism between gabapentin-tramadol in experimental diabetic neuropathic pain.

Neuropathic pain is associated with several conditions such as surgery, cancer, and diabetes and can be induced experimentally. Among the drugs used as monotherapy are gabapentin and tramadol. The purpose of this study was to evaluate the coadministration of gabapentin and tramadol, by isobolographic analysis, in three different algesiometric assays in experimental diabetic neuropathic pain induced by streptozocin in mice. In all the behavioral tests, gabapentin or tramadol produced a dose-dependent antinociception and their coadministration resulted in a positive interaction. This effect can be explained by principles of multimodal analgesia, whereby the different mechanisms of action of each drug contribute to the combined effect in a supra-additive manner. The findings of the present study suggest that the combination of gabapentin and tramadol could be a useful strategy for the treatment of pain induced by diabetic neuropathy.

Antinociception induced by rosuvastatin in murine neuropathic pain.

BACKGROUND: Neuropathic pain, and subsequent hypernociception, can be induced in mice by paclitaxel (PTX) administration and partial sciatic nerve ligation (PSNL). Its pharmacotherapy has been a clinical challenge, due to a lack of effective treatment. In two models of mouse neuropathic pain (PTX and PSNL) the antinociception induced by rosuvastatin and the participation of proinflammatory biomarkers, interleukin (IL)- 1ß, TBARS and glutathione were evaluated. METHODS: A dose-response curve for rosuvastatin ip was obtained on cold plate, hot plate and Von Frey assays. Changes on spinal cord levels of IL-1ß, glutathione and lipid peroxidation were measured at 7 and 14days in PTX and PSNL murine models. RESULTS: PTX or PSNL were able to induce in mice peripheral neuropathy with hypernociception, either to 7 and 14days. Rosuvastatin induced a dose dependent antinociception in hot plate, cold plate and Von Frey assays. The increased levels of IL-1ß or TBARS induced by pretreatment with PTX or PSNL were reduced by rosuvastatin. The reduction of spinal cord glutathione, by PTX or PSNL, expressed as the ratio GSH/GSSG, were increased significantly in animals pretreated with rosuvastatin. The anti-inflammatory properties of statins could underlie their beneficial effects on neuropathic pain by reduction of proinflammatory biomarkers and activation of glia. CONCLUSION: The findings of this study suggest a potential usefulness of rosuvastatin in the treatment of neuropathic pain.

Effects of a novel ascorbate-based protocol on infarct size and ventricle function in acute myocardial infarction patients undergoing percutaneous coronary angioplasty.

INTRODUCTION: This study was designed to test the hypothesis that high-dose ascorbate prior to reperfusion followed by low chronic oral doses ameliorate myocardial reperfusion injury (MRI) in acute myocardial infarction patients subjected to primary percutaneous coronary angioplasty (PCA). MATERIAL AND METHODS: A randomized double-blind placebo-controlled and multicenter clinical trial was performed on acute myocardial infarction (AMI) patients who underwent PCA. Sodium ascorbate (320 mmol/l, n = 53) or placebo (n = 46) was infused 30 min prior to PCA. Blood samples were drawn at enrolment (M1), after balloon deflation (M2), 6-8 h after M2 (M3) and at discharge (M4). Total antioxidant capacity of plasma (ferric reducing ability of plasma - FRAP), erythrocyte reduced glutathione (GSH) and plasma ascorbate levels were determined in blood samples. Cardiac magnetic resonance (CMR) was performed at 7-15 days and 2-3 months following PCA. Ninety-nine patients were enrolled. In 67 patients, the first CMR was performed, and 40 patients completed follow-up. RESULTS: The ascorbate group showed significantly higher ascorbate and FRAP levels and a decrease in the GSH levels at M2 and M3 (p < 0.05). There were no significant differences in the infarct size, indexed end-systolic volume and ejection fraction at both CMRs. There was a significant amelioration in the decreased ejection fraction between the first and second CMR in the ascorbate group (p < 0.05). CONCLUSIONS: Ascorbate given prior to reperfusion did not show a significant difference in infarct size or ejection fraction. However, it improved the change in ejection fraction determined between 7-15 days and 2-3 months. This result hints at a possible functional effect of ascorbate to ameliorate MRI.

Pharmacological profile of dexketoprofen in orofacial pain.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may act through others mechanisms, in addition to inhibition of prostaglandin synthesis. These includes cholinergic, NO, serotonergic and opioids pathways. METHODS: The aim of this work was to evaluate the effect of systemic action of (S)-+-ketoprofen (dexketoprofen, DEX) on pain behaviors using the orofacial formalin test in mice and the potential involvement of cholinergic, NO, serotonergic and opioids pathways. RESULTS: The pretreatment of the mice with 1mg/kg ip of atropine or opoid antagonists: 1mg/kg, ip of NTX or 1mg/kg ip of NTI or 1mg/kg of NOR-BNI ip, did not produce significant change in the ED50 values of the antinociception to orofacial test induced by DEX. The pretreatment of the mice with 0.5mg/kg ip tropisetron, increased in a significant fashion the values of ED50 of DEX. When the mice were treated with 5mg/kg ip of L-NAME or 25mg/kg ip of aminoguanidine or 50mg/kg ip of 7-nitroindazole reversed the antinociception of DEX. CONCLUSION: The findings of this study demonstrate activation of NO and 5-HTpathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain.

Antinociceptive Interaction of Tramadol with Gabapentin in Experimental Mononeuropathic Pain.

Neuropathic pain is the result of injury to the nervous system, and different animal models have been established to meet the manifestations of neuropathy. The pharmacotherapy for neuropathic pain includes gabapentin and tramadol, but these are only partially effective when given alone. The aim of this study was to assess the antinociceptive interaction between both drugs using the isobolographic analysis and changes of the IL-1ß concentration in a mouse model of neuropathic pain (partial sciatic nerve ligation or PSNL). The i.p. administration of gabapentin (5-100 mg/kg) or tramadol (12.5-100 mg/kg) displayed a dose-dependent antinociception in the hot plate assay of PSNL mice, and effects induced by gabapentin with tramadol were synergistic. Administration of gabapentin or tramadol reversed significantly the increase in the concentration of IL-1ß induced by PSNL after either 7 or 14 days and their combination was significantly more potent in reversing the elevated concentration of IL-1ß. The synergism obtained by the co-administration of gabapentin and tramadol is proposed to result from action on different mechanisms in pain pathways. Gabapentin or tramadol or their combination modulates the expression of pro-inflammatory cytokine, IL-1ß, in a model of mice PSNL which could be due to an inhibition of glial function.

Amelioration of persistent left ventricular function impairment through increased plasma ascorbate levels following myocardial infarction.

PURPOSE: Percutaneous coronary angioplasty (PCA) has been demonstrated to reduce mortality and morbidity and thereby improve the prognosis of patients undergoing acute myocardial infarctions (AMIs). However, this procedure paradoxically increases the initial damage as the result of a condition known as 'myocardial reperfusion injury'. Oxidative stress may contribute to the mechanism of this injury. The goal of the present study was to ascertain whether high plasma ascorbate levels could ameliorate the reperfusion injuries that occur after the successful restoration of blood flow. METHODS: Patients from three clinical centers of the public health system were included in the study. The groups were formed by either-sex patients with a diagnosis of ST-segment elevation myocardial infarction with an indication for primary PCA. Only the patients who presented with their first myocardial infarction were enrolled. Ascorbate was administered through an infusion given prior to the restoration of the coronary flow, which was then followed by oral treatment with vitamin C (500 mg/12 hours) plus vitamin E (400 IU/day) for 84 days. The left ventricular ejection fraction (LVEF) was determined by using cardiac magnetic resonance on days 6 and 84 following the onset of the reperfusion. In addition, the microvascular function was assessed by an angiographic evaluation using the Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG). The results were grouped according to the plasma ascorbate concentration achieved immediately following the onset of reperfusion into either the HA group (high ascorbate, >1 mmol/l) or the LA group (low ascorbate, <1 mmol/l). The biochemical parameters were analyzed throughout the protocol. RESULTS: The LVEF of the HA group was significantly higher than that of the LA group, values on day 84 in the HA group were 33% higher than those of the LA group. The amelioration of the LVEF was accompanied by an improvement in the microvascular dysfunction, after PCA, 95% of the patients in the HA group achieved a TMPG of 2-3, in the LA group only 79% of patients showed a TMPG of 2-3. CONCLUSIONS: These data are consistent with the protective effect of high plasma levels of ascorbate against the oxidative challenge caused by reperfusion injury in patients subjected to PCA following an AMI. Further studies are needed to elucidate the mechanism accounting for this beneficial antioxidant effect.

"How and when Chilean Pharmacology started to be experimental and became a science".

Pharmacology in Chile has about 75 years of history and from its beginning until today has grown exponentially. Today, pharmacology is taught in the biomedical careers of the main Chilean universities and research centers in pharmacology are in the north, central and south of Chile. This editorial offers an overview of the main milestones that have led to the consolidation of Chilean pharmacology in Latin America and the world.