COMT genetic variation may influence opioid dosing requirements in the treatment of cancer-related pain

Background: Opioid analgesics are the mainstay treatment for moderate to severe cancer-related pain. However, clinical studies suggest that genetic variability may result in significant differences in response to opioids. The m-opioid receptor (OPRM1) is the primary site of action for opioids. The polymorphism A118G is relatively frequent in Caucasians and causes an amino acid change from asparagine to aspartatic acid. This polymorphism seems to influence opioids action, with homozygous for A allele requiring lower doses of opioids. Catechol-O-methyltransferase (COMT) is involved in the metabolism of catecholamines, which have a role in the nociception mechanism. The functional polymorphism Val158Met codes the substitution of valine (Val) by methionine (Met). Individuals with the Met/Met genotype have the lowest activity of COMT and have been related to increased pain sensitivity and lower m-opioid system activation. Polymorphisms in multidrug resistance protein (MDR1) can have pharmacologic consequences after opioids administration. Two of the most frequent polymorphisms are C3435T and C1236T. Homozygous individuals for T allele of the C3435T have lower mRNA expression. C1236T was found to be in linkage disequilibrium with C3435T and was also related to different opioid doses, higher in TT individuals. Our purpose was to investigate the effects of these polymorphisms on several pain-related parameters in Caucasian cancer patients. Material and Methods: DNA samples from 30 cancer patients were genotyped for polymorphisms in OPRM1 (rs1799971), COMT (rs4680), and MDR1 (rs1128503, rs1045642) with Real-Time PCR. Daily doses were re-expressed as oral morphine equivalents. We examined the relation between the polymorphisms and opioid dose, pain intensity, performance status, adverse effects, age, gender, bone or CNS metastases and breakthrough pain. Results: Total morphine consumption was related to the polymorphism Val158Met in COMT gene, with carriers of Met allele showing to be significantly associated with higher dose of opioids (p = 0.004, Pearson c2 test), which was also confirmed by logistic regression adjust to age and gender (p = 0.013). All the other polymorphisms and parameters revealed no statistically significant association. Conclusion: This preliminary result indicates that genetic variation at COMT enzyme may influence opioid dosing requirements in the treatment of cancerrelated pain

Interleukin-1β genotype and circulating levels in cancer patients: Metastatic status and pain perception

Objectives: Proinflammatory cytokines released during inflammation can cause hyperexcitability in pain transmission neurons, leading to hyperalgesia and allodynia. Polymorphisms in interleukin 1 (IL-1) family of genes (IL1A, IL1B) and in IL-1 receptor antagonist (IL-1Ra, coded by IL1RN) may therefore induce alterations in cytokine levels/effects and pain related response. Our purpose was to investigate the influence of polymorphisms in IL1A/B/RN on cytokine serum levels and its correlation with pain intensity, performance status, adverse effects, metastases and breakthrough pain in Caucasian cancer patients. Design and methods: Serum IL-1α/β levels of 74 cancer patients were measured by competitive enzyme immunosorbent assay. All patients were also genotyped for the polymorphisms in IL1A (rs17561), IL1B (rs1143634) and IL1RN (rs419598) with Real-Time PCR. Results were then correlated to the appearance of bone or CNS metastases and several pain-related parameters. Results: IL-1β rs1143634 homozygous for T allele were associated with lower levels of IL1-β (p = 0.032, Mann–Whitney test) and presented a trend for lower levels of pain (p = 0.06, Fisher's Exact Test). Also, IL1-β levels were related with cancer onset status, since a four-fold increase probability of metastatic disease was observed in high IL-1β individuals (OR = 4.074, p = 0.010, Pearson χ2 test). Among the female patients presenting metastatic disease and carriers of the TT genotype we observed a trend to lower levels of IL1-β (p = 0.053, Pearson χ2 test). Conclusions: Our results indicate that genetic variation at IL1-β gene may influence serum levels of IL1-β, with proportional consequences in cancer-related pain

Improved Morphine-Loaded Hydrogels for Wound-Related Pain Relief

The use of morphine applied topically to painful wounds has potential advantages, such as dose reduction, fewer side effects and compound formulations, have been proposed for this purpose. Given the potential high impact of drug product quality on a patient’s health, the aim of the present study was to develop two stable sterile hydrogels containing morphine hydrochloride, intended for topical application on painful wounds. Two carboxymethylcellulose sodium-based hydrogels were prepared containing 0.125% w/w (F1-MH semi-solid formulation) and 1.0% w/w (F2-MH fluid formulation) morphine hydrochloride (MH), respectively. Studies included a risk assessment approach for definition of the quality target product profile (QTPP) and assessment of critical quality attributes (CQA) of the hydrogels to support product quality and safety. Safe, odourless, yellowish, translucent and homogeneous gels were obtained, with suitable microbiological and pharmaceutical characteristics. The active substance concentration was adapted according to the characteristics of the dose-metering device. Release profiles were investigated using Franz diffusion cells, and characterised by different kinetic models. Increasing gel viscosity prolonged drug release, with rates of 17.9 ± 2.2 μg·cm−2·h−1 (F1-MH) and 258.0 ± 30.4 μg·cm−2·h−1 (F2-MH), allowing for the reduction of the number of applications and improving patient compliance. The gels proved to be stable for up to 60 days at room temperature. The semi-solid and fluid MH-containing hydrogel formulations are safe, stable and suitable for use in hospital settings, which is rather important for wound-related pain management in cancer palliative care or burn patients

Lipidic profile among rats submitted to total splenectomy isolated or combined with splenic autotransplant Perfil lipídico em ratos submetidos a esplenectomia total isolada ou combinada com auto-implante esplênico

PURPOSE: To evaluate the alterations on plasmatic lipids levels among rats submitted to total splenectomy isolated or combined with splenic autotransplant receiving standard chow during the postoperative period. METHODS: Thirty Wistar rats were divided into three groups: control (C) - sham-operated, total splenectomy - isolated (TS) or combined with splenic autotransplantation (SA). Since the postoperative period, all animals received standard rat chow manipulated in accordance to the American Institute of Nutrition Rodents Diets (1993). The plasmatic levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and glucose (GLUC) were analyzed before the surgical procedure and after 6 and 12 weeks. RESULTS: All the animals presented significant increase of TG and VLDL levels. In relation to the other parameters there was no difference among the weeks 0 and 12 in the animals of group C. In TS group significant increase was observed in TC and GLUC levels during the experiment. In SA group TC, HDL, and GLUC levels remained unaffected while HDL levels increased. CONCLUSION: Our findings suggest that isolated total splenectomy alters lipids metabolism in rats fed with standard chow and splenic autotransplantation is effective in restoring its control.<br>OBJETIVO: Avaliar as alterações nos níveis de lipídios plasmáticos em ratos submetidos a esplenectomia total isolada ou combinada com auto-implante esplênico, recebendo dieta padrão no período pós-operatório. MÉTODOS: Trinta ratos Wistar foram distribuídos em três grupos: controle (C) - operação simulada, esplenectomia total isolada (ET) ou combinada com auto-implante esplênico (AE). A partir do período pós-operatório, todos os animais receberam ração padrão, manipulada segundo o American Institute of Nutrition (1993). Os níveis plasmáticos de colesterol total (CT), triglicerídeos (TG), lipoproteína de alta densidade (HDL), lipoproteína de baixa densidade (LDL), lipoproteína de muito baixa densidade (VLDL) e glicose (GLIC) foram analisados antes do procedimento e após 6 e 12 semanas. RESULTADOS: Todos os animais apresentaram aumento de TG e VLDL. Em relação aos demais parâmetros, não ocorreu diferença entre as semanas 0 e 12 nos animais do grupo C. No grupo ET, observou-se aumento de CT e GLIC durante o experimento. No grupo AE, os níveis de CT, HDL e GLIC permaneceram inalterados enquanto os níveis de HDL se elevaram. CONCLUSÃO: Nossos achados sugerem que a esplenectomia total isolada altera o metabolismo lipídico em ratos alimentados com ração padrão e que o auto-implante esplênico é eficaz na restauração do seu controle

Cellular and Molecular Immunology Approaches for the Development of Immunotherapies against the New Coronavirus (SARS-CoV-2): Challenges to Near-Future Breakthroughs

The severe acute respiratory syndrome caused by the new coronavirus (SARS-CoV-2), termed COVID-19, has been highlighted as the most important infectious disease of our time, without a vaccine and treatment available until this moment, with a big impact on health systems worldwide, and with high mortality rates associated with respiratory viral disease. The medical and scientific communities have also been confronted by an urgent need to better understand the mechanism of host-virus interaction aimed at developing therapies and vaccines. Since this viral disease can trigger a strong innate immune response, causing severe damage to the pulmonary tract, immunotherapies have also been explored as a means to verify the immunomodulatory effect and improve clinical outcomes, whilst the comprehensive COVID-19 immunology still remains under investigation. In this review, both cellular and molecular immunopathology as well as hemostatic disorders induced by SARS-CoV-2 are summarized. The immunotherapeutic approaches based on the most recent clinical and nonclinical studies, emphasizing their effects for the treatment of COVID-19, are also addressed. The information presented elucidates helpful insights aiming at filling the knowledge gaps around promising immunotherapies that attempt to control the dysfunction of host factors during the course of this infectious viral disease