Opioids in COVID-19: Two Sides of a Coin

Introduction: The treatment of most severe COVID-19 patients included the large-scale use of sedatives and analgesics–possibly in higher doses than usual–which was reported in the literature. The use of drugs that decrease mortality is necessary and opioids are important agents in procedures such as orotracheal intubation. However, these drugs seem to have been overestimated in the COVID-19 pandemic. We performed a review of the PubMed-Medline database to evaluate the use of opioids during this period. The following descriptors were used to enhance the search for papers: “Opioids”, “COVID-19,” “COVID-19 pandemic,” “SARS-CoV-2,” “Opioid use disorder,” “Opioid dependence” and the names of the drugs used. We also evaluated the distribution of COVID-19 patients in Brazil and the applicability of opioids in our country during the COVID-19 pandemic.Results: Several positive points were found in the use of opioids in the COVID-19 pandemic, for instance, they can be used for analgesia in orotracheal intubation, for chronic pain management, and as coadjutant in the management of acute intensification of pain. However, high doses of opioids might exacerbate the respiratory depression found in COVID-19 patients, their chronic use can trigger opioid tolerance and the higher doses used during the pandemic might result in greater adverse effects. Unfortunately, the pandemic also affected individuals with opioid use disorder, not only those individuals are at higher risk of mortality, hospitalization and need for ventilatory support, but measures taken to decrease the SARS-CoV-2 spread such as social isolation, might negatively affect the treatment for opioid use disorder. In Brazil, only morphine, remifentanil and fentanyl are available in the basic health care system for the treatment of COVID-19 patients. Out of the 5,273,598 opioid units used in this period all over the country, morphine, fentanyl, and remifentanil, accounted for, respectively, 559,270 (10.6%), 4,624,328 (87.6%), and 90,000 (1.8%) units. Many Brazilian regions with high number of confirmed cases of COVID-19 had few units of opioids available, as the Southeast region, with a 0.23 units of opioids per confirmed COVID-19 case, and the South region, with 0.05 units. In the COVID-19 pandemic scenario, positive points related to opioids were mainly the occurrence of analgesia, to facilitate intubation and their use as coadjutants in the management of acute intensification of pain, whereas the negative points were indiscriminate use, the presence of human immunosuppressor response and increased adverse effects due to higher doses of the drug.Conclusion: The importance of rational and individualized use of analgesic hypnotics and sedative anesthetics should be considered at all times, especially in situations of high demand such as the COVID-19 pandemic.

Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide DDT, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking. This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 yrs). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose-ratios as well as time-in-range in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane time-in-range was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

Prescription Dose Analysis of Quetiapine in the Elderly and Insomnia

Objective: The purpose of this study is to investigate the appropriate dose of quetiapine in clinical psychiatric diseases by examining the drug prescription dose in the elderly and insomnia group through an analysis of the tendency of quetiapine dose prescribed by psychiatric diagnosis.Methods: Among the patients who had been taking outpatient treatment to the mental health department for about 7 years and 8 months from May 1, 2010 to December 31, 2017, 2,794 patients who were continuously taking quetiapine immediate-release form drugs were retrospectively tested. In addition, all subjects were classified into a total of four groups according to their maintenance dose, four mental diseases that most commonly prescribe quetiapine were selected and grouped, and further analyzed whether there was a difference in prescription capacity by age and comorbidities for the insomnia group.Results: Prescription dose of quetiapine was found to be less than 50 mg in depressive disorders and insomnia, which is a relatively low dose prescribed compared to schizophrenia and bipolar disorder. In the case of insomnia, quetiapine prescribed in the elderly patient group was 30.03±9.14 mg, which was relatively high compared to the non-elderly group. And in the case of insomnia accompanied by depressive disorder, 50.28±11.41 mg was prescribed, more than 60% higher doses than that of primary insomnia.Conclusion: In the case of primary insomnia, quetiapine dose prescribed in the elderly patient group is higher than that in the non-elderly patient group.

Male Monsters Still Stalk, Yet More Violent: A Comparative Analysis of Original Slasher Films and Their Remakes

Since its origins in the mid-1970s, the slasher has been defined as a subgenre of horror in which a serial or mass killer stalks and massacres middle-class youngsters, and preferably attractive young women, using cutting weapons or projectiles. In that regard, the twenty-first century has seen a revival of the slasher, combining the release of original movies with remakes of classic films, adapting the traditional plots to the current context. In this paper, a comparative content analysis is performed on 13 slasher films made during the 1970s and the 1980s and 13 remakes premiered in the new millennium, focusing on the differences stemming from the adaptation of the latter to the new sociocultural context. The results indicate that, although there have been a number of changes, such as higher doses of explicit violence and profanity and in the fight responses of the victims, most of the subgenre’s defining traits have remained intact, whereas others, such as those relating to the defining traits of the victims, should be questioned. The limited differences found between the original films and the remakes provide the basis for drawing interesting conclusions about the subgenre itself, as well as to raise discussions about the different contexts of production and reception.

Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials

<b><i>Introduction:</i></b> Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. <b><i>Objective:</i></b> This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. <b><i>Methods:</i></b> A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers’ product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). <b><i>Results:</i></b> From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of –0.06 (–0.16 to 0.04) and –0.06 (–0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. <b><i>Conclusion:</i></b> Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

Addressing Dual Disorders in a Medium-Term Admission Unit

Due to the significant functional repercussions suffered by patients with dual disorder, we must evaluate which ones can benefit from intensive rehabilitative therapies in medium-stay psychiatric units. This was a retrospective study of patient medical records which intended to analyze sociodemographic and clinical variables and parameters related to the hospitalization and discharge of patients admitted to the Medium-Stay Unit (MSU) at the Castellón Provincial Hospital Consortium over 2 years (2017 and 2018), according to the presence or absence of dual disorders in these patients. Patients with a dual disorder represented 55.2% of the hospitalized patients. A higher proportion of them were male, were relatively younger, and had an earlier onset of mental illness, fewer associated medical pathologies, and shorter hospital admission times to the Short-Term Hospitalization Unit than those who did not present a dual disorder. A diagnosis on the schizophrenia spectrum with cannabis use or polyconsumption was the most common diagnosis; 98.2% of all the patients responded adequately to admission to the MSU. This work highlighted the need for higher doses of depot paliperidone in patients with dual disorders.

Protective Immunization of Atlantic Salmon (Salmo salar L.) against Salmon Lice (Lepeophtheirus salmonis) Infestation

Vaccination against salmon lice (Lepeophtheirus salmonis) is a means of control that averts the negative effects of chemical approaches. Here, we studied the immunogenicity and protective effect of a vaccine formulation (based on a salmon lice-gut recombinant protein [P33]) against Lepeophtheirus salmonis infestation in Atlantic salmon in a laboratory-based trial. Our findings revealed that P33 vaccine can provide a measure of protection against immature and adult salmon lice infestation. This protection seemed to be vaccine dose-dependent, where higher doses resulted in lower parasitic infestation rates. We also provide immunological evidence confirming that P33-specific immune response can be triggered in Atlantic salmon after P33 vaccination, and that production of P33-specific antibodies in blood can be detected in vaccinated fish. The negative correlation between P33-specific IgM in salmon plasma and salmon lice numbers on vaccinated fish suggests that protection against lice can be mediated by the specific antibody in salmon plasma. The success of P33 vaccination in protecting salmon against lice confirms the possibility of employing the hematophagous nature of the parasite to deliver salmon-specific antibodies against lice-gut proteins.

Brief Report: Higher Fentanyl Exposures Require Higher Doses of Naloxone for Successful Reversals in a Quantitative Systems Pharmacology Model

Background: Previously, we reported on an opioid receptor quantitative systems pharmacology (QSP) model to evaluate naloxone dosing. Methods: In this study we extended our model to include higher systemic levels of fentanyl (up to 100 ng/ml) and the newly approved 8mg IN naloxone dose (equivalent to 4 mg)Results : As expected, at the lower peak fentanyl concentrations (25 ng/ml and 50 ng/ml), the simulations predicted that 2 mg, 4 mg, 5 mg, and 10 mg IM doses of naloxone displaced fentanyl and reached below the 50% receptor occupancy within 10 minutes. However, at the concentration of 75 ng/ml, the simulation predicted that the 2 mg dose of naloxone failed to reach below the 50% occupancy within 10 minutes. Interestingly, at the highest peak concentration of fentanyl studied (100 ng/ml), the model predicted that the 4 mg of naloxone IM (equivalent to 8 mg IN) failed to reach below the threshold of 50 % occupancy within 10 minutes or even within 15 minutes (Data not shown). In contrast, the model predicted successful reversals when 5 and 10 mg IM doses were utilized. Conclusion:These results support the notion that acutely administered higher doses of naloxone are needed for rapid and adequate clinical reversal, particularly when higher systemic exposure of the potent synthetic opioids occur.

The Effect of Dietary Dry Distilled Rose Petals or Dihydroquercetin Supplementation on the Oxidative Stability and Quality of Lamb Muscles and Fat

The study's objective was to determine the changes in oxidative stability of m. Longissimus dorsi, m. Semimembranosus and perirenal adipose tissue from lambs fed a diet supplemented by 7.5 mg dihydroquercetin/kg life wight/d or 545 mg dry distilled rose petals (DDRP)/kg life wight/d.The experiments were performed with 30 male lambs aged 65 days. They were divided into three groups of 10 animals fed 50 days ad libitum: the control group (with ground alfalfa + granulated compound feed) and two experimental ones (with the same diet + phytonutrients). Samples stored 7 days at 0-4°C were examined. After 7 d of storage in both muscles, the addition of 545 mg DDRP/kg life wight/d contributed to the reduction of α-aminoacidic nitrogen with approximately 0.5 mg Leu/g and the FFA with 0.5-2%. The addition of 7.5 mg dihydroquercetin contributed to the reduction of TBARS with 0.14-0.21 mg MDA/kg, the total color difference, and a slight increase in the share of the MUFA more pronounced in m. Longissimus dorsi. The reduction of aerobic plate count and total yeasts and molds count were determined too. Further studies with higher doses of phytonutrient’s supplementation are needed to determine if it will provoke a more pronounced oxidative stability.