Safety and Efficacy of Oral Mirodenafil in Mexican with Erectile Dysfunction

Abstract Erectile dysfunction is treated with 5-phospodiesterase inhibitors as Mirodenafil, which has shown its efficacy and safety in Koreans, however; no information in other populations is available. An open clinical trial study was designed to evaluate the efficacy and safety in real life of a fixed-dose of Mirodenafil in Mexican patients with erectile dysfunction. Forty-seven male patients received a 100 mg tablet of Mirodenafil, during 12 weeks. Primary outcome efficacy measure was the percentage of male patients with successful intercourse. Secondary outcomes measures included patient satisfaction, mood and self-esteem level. Safety assessments included laboratory tests, vital signs, physical examination, 12-lead electrocardiogram recordings, and incidence of adverse events by patients. Oral administration of Mirodenafil improved in an 80% -90% the number of successful intercourses from 7 to 84 days of treatment. Moreover, patients reported a significant increment in their sexual satisfaction, mood and self-esteem. Mirodenafil treatment did not modify vital signs nor anthropometric parameters during 84 days. Mild headache was the most frequent adverse event (17.0%) and there were no severe adverse events during pharmacological treatment. Data suggest that oral Mirodenafil is safety, well tolerated and effective in the Mexican population with erectile dysfunction

N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception

Main methods: The formalin test was used to assess the antinociceptive activity of HD in vivo. The hydrolysis of anandamide catalyzed by fatty acid amide hydrolase (FAAH) was used to determine the action of HD on FAAH activity in vitro. Key findings: Local peripheral ipisilateral, but not contralateral, administration of HD (10-100 μg/paw) produced a dose-dependent antinociceptive effect in rats. The CB 1 and CB 2 receptor antagonists AM281 (0.3-30 μg/paw) and SR144528 (0.3-30 μg/paw), respectively, reduced the antinociceptive effect of HD (100 μg/paw). In addition, methiothepin (0.03-0.3 μg/paw) and naloxone (5-50 μg/paw) significantly reduced HD-induced antinociception (100 μg/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH. Significance: HD local administration produces antinociception that probably results from an indirect activation of peripheral CB 1 and CB 2 cannabinoid receptors. Data suggest that 5-HT 1 and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug

Efficacy and safety of the metformin-mazindol anorectic combination in rat

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student´s t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors

Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively

[Saturation index and fraction of inspired oxygen as a predictor in COVID-19]

<p><strong>Abstract</strong></p><p><strong>Background:</strong> Coronavirus disease leads to silent hypoxia, ARDS, and organ failure. The saturation and fraction of inspired oxygen have been related to the degree of lung damage, can be considered as a monitoring tool for lung function during hospitalization and a predictor of mortality in patients with pneumonia by COVID-19.</p><p><strong>Objective:</strong> To evaluate the usefulness of the oxygen saturation index and fraction of inspired oxygen as a predictor of mortality in patients with COVID-19 pneumonia.</p><p><strong>Material and methods:</strong> A retrospective, longitudinal, analytical study. Files of eligible patients with a diagnosis of SARS-CoV-2 pneumonia were admitted to HGR No.2, complete file, recording of oxygen saturation and inspired fraction of oxygen, were included. Patients dependent on supplemental oxygen, who did not require supplemental oxygen during their hospitalization, incomplete records, patients who have died from non-pulmonary causes, were excluded.</p><p><strong>Results:</strong> A sample of 175 files with a diagnosis of pneumonia with SARS-CoV-2 was obtained. A logistic regression model was performed including age over 60 years BE of 2.68, with CI (1.09-6.5), DM2 with a BE of 2.35 with CI (0.99-5.59), HTA with a BE of 0.80, with CI (0.32-2.02), SAFI index less than 310 with a BE of 6.63, with a CI (2.64-16.65), endotracheal intubation with a BE 48.43, and a CI (2.64-16.65).</p><p><strong>Conclusion:</strong> The SpO2/Fio2 index can be used for continuous monitoring of lung function in patients with COVID-19 pneumonia, in an accessible, easy and economical way. A relationship with mortality was obtained in patients with SpO2/FiO2 less than 310 associated with other factors.</p><p><strong>Introducción: </strong>la enfermedad por coronavirus conduce a hipoxia silenciosa, síndrome de insuficiencia respiratoria aguda (SDRA) y falla orgánica múltiple. El índice de saturación y fracción inspirada de oxígeno se ha relacionado con el grado de daño pulmonar en pacientes con SDRA, por lo que puede ser considerado como una herramienta de vigilancia para la función pulmonar durante la hospitalización y como predictor de mortalidad en pacientes con neumonía por COVID-19.</p><p><strong>Objetivo:</strong> evaluar la utilidad del índice saturación y fracción inspirada de oxígeno como predictor de mortalidad en pacientes con neumonía por COVID-19.</p><p><strong>Material y métodos:</strong> se realizó un estudio retrospectivo, longitudinal, analítico. Se incluyeron expedientes de pacientes derechohabientes, hombres y mujeres, con diagnóstico de neumonía por SARS-CoV-2 que ingresaron al Hospital General Regional No. 2, con expediente completo y registros de saturación y fracción inspirada de oxígeno. Se excluyeron los expedientes de pacientes dependientes de oxígeno suplementario por patología de base que no ameritaron oxígeno suplementario durante su hospitalización, así como aquellos expedientes incompletos y los de pacientes que hayan fallecido por causas no pulmonares. </p><p><strong>Resultados:</strong> se obtuvo una muestra de 175 expedientes de pacientes con diagnóstico de neumonía por SARS-CoV-2. Se realizó un modelo de regresión logística incluyendo: edad mayor a 60 años, DM2, HAS, índice de SAFI e intubación endotraqueal.</p><p><strong>Conclusiones:</strong> el índice de SpO2/FiO2 se puede utilizar para la monitorización continua de la función pulmonar en pacientes con neumonía por COVID-19, de manera accesible, fácil y económica. Se obtuvo una relación con mortalidad en pacientes con SpO2/FiO2 menor a 310 asociado a otros factores.</p&gt

Formulations of Amlodipine: A Review

Amlodipine (AD) is a calcium channel blocker that is mainly used in the treatment of hypertension and angina. However, latest findings have revealed that its efficacy is not only limited to the treatment of cardiovascular diseases as it has shown to possess antioxidant activity and plays an important role in apoptosis. Therefore, it is also employed in the treatment of cerebrovascular stroke, neurodegenerative diseases, leukemia, breast cancer, and so forth either alone or in combination with other drugs. AD is a photosensitive drug and requires protection from light. A number of workers have tried to formulate various conventional and nonconventional dosage forms of AD. This review highlights all the formulations that have been developed to achieve maximum stability with the desired therapeutic action for the delivery of AD such as fast dissolving tablets, floating tablets, layered tablets, single-pill combinations, capsules, oral and transdermal films, suspensions, emulsions, mucoadhesive microspheres, gels, transdermal patches, and liposomal formulations

Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 ± 9.3 and 39.8 ± 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 ± 0.5 vs. 7.7 ± 0.6 mg/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac

Efficacy and safety of the metformin-mazindol anorectic combination in rat

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student′s t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors

GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats

Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats

Abstract Background Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H2S-induced hyperalgesia in diabetic rats. Results Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H2S, 3–100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3–3 µg/paw), HC-030031 (100–316 µg/paw) and SKF-96365 (10–30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3–30 µg/paw), HC-030031 (100–1000 µg/paw) and SKF-96365 (10–100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-β-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons. Conclusions Our data suggest that H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy