Immunomodulation by tramadol combined with acetaminophen or dexketoprofen: In vivo animal study.

Among other functions, macrophages remove foreign particles, including medications, from the circulation, making them an important target for immunomodulatory molecules. Currently, growing evidence suggests that analgesics affect the activity of immune cells not directly related to pain, and thus may induce unwanted immunosuppression in patients at risk. However, the immunomodulatory effects resulting from macrophage targeting by these drugs are understudied. Therefore, the current study investigated the immune effects induced in healthy mice by repeated administration of tramadol alone or in combination with acetaminophen or dexketoprofen. We observed that drug administration decreased the percentage of infiltrating macrophages in favor of resident macrophages in peritoneal exudates. While all drugs reduced the number of infiltrating macrophages that phagocytosed sheep red blood cells (SRBC), their administration increased the effectiveness of phagocytosis, and treatment with acetaminophen with or without tramadol elevated the expression of MHC class II by Mac3+ macrophages. Interestingly, SRBC-pulsed macrophages from mice treated with tramadol combined with acetaminophen potently activated SRBC-specific B cells in humoral response, and administration of these drugs to recipients of contact hypersensitivity effector cells augmented the resulting cellular immune response. In addition, tramadol administered alone or with dexketoprofen enhanced the spontaneous release of pro-inflammatory cytokines by macrophages. Our current research findings demonstrate that tramadol therapy in combination with acetaminophen or dexketoprofen has a relatively low risk of causing immunosuppressive side effect because the drugs slightly reduce the inflammatory reaction of macrophages but do not impair their ability to activate the adaptive immune responses.

Factors connected with anxiety and other neuropsychiatric symptoms in advanced gastric cancer.

OBJECTIVE: The aim of study was to determine factors connected with neuropsychiatric symptoms and anxiety in patients with terminal stomach cancer. METHODS: We analysed retrospectively 134 terminal stomach cancer patients admitted to Palliative Care Unit. RESULTS: Patients with anxiety had a greater chance for emergency admission, higher Numerical Rating Scale result, occurrence of cachexia and neuropsychiatric symptoms, longer duration of treatment, higher albumin concentration and lower glucose concentration.Patients with neuropsychiatric symptoms had greater chance for emergency admission, higher Performance Status scale note, occurrence of dyselectrolytemia, lower albumin concentration. Patients with those symptoms had more than 7 times greater chance for death. CONCLUSION: It is important to know factors connected with neuropsychiatric symptoms and anxiety because thanks to that we could avoid those dangerous clinical symptoms.

Mortality Following Clostridioides difficile Infection in Europe: A Retrospective Multicenter Case-Control Study.

We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were ß-lactams; previous exposure to fluoroquinolones was significantly (p = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome.

Prognostic factors, symptoms and consequences of dehydration and dyselectrolytemia in patients with terminal stomach cancer.

BACKGROUND: Dyselectrolytaemia and dehydration are common symptoms in people with terminal stomach cancer. AIMS: To determine factors related to dyselectrolytemia and dehydration in patients with terminal stomach cancer. METHODS: An analysis of 134 patients with terminal stomach cancer admitted to the palliative care unit was conducted, through an audit of the patients' medical records. The average age of women was 63.1 years and that of men was 64.9 years. FINDINGS: Dehydrated patients were more likely to: have dyselectrolytaemia; have a higher PS scale score; be taking opioids as an analgesic; have a high sodium concentration; experience dyspnoea, constipation, nausea and vomiting during hospitalisation; and require glucocorticoids administration both during and before hospitalisation. Patients with dyselectrolytaemia were more likely to: be admitted to the palliative care unit from the emergency department; experience cachexia and dehydration during hospitalisation and constipation at discharge; have a lower albumin level; and have a higher glucose level. Patients with dyselectrolytaemia also had a shorter duration of treatment and a 2.48 greater chance for death compared with those who did not have it. CONCLUSIONS: Knowledge of the adverse factors connected with dehydration and dyselectrolytaemia will allow health professionals to avoid dangerous clinical symptoms and prolong the life of those with terminal stomach cancer, as they might be able to foresee the occurrence of these conditions based on the medication the patient has been taking and symptoms they have been experiencing. Nurses will have a greater understanding of the importance of fluid therapy to resolve ionic disturbances and the need to address dehydration and dyselectrolytemia as a means to prolong and improve quality of life.

Analgesic adjuvants modulate morphine-induced immune effects in mice.

BACKGROUND: Macrophages, involved in the pathogenesis of pain, express a variety of receptors enabling responsiveness to certain medications, including adjuvant analgesics (AAs), that are effective in neuropathic pain and include drugs not primarily indicated for pain treatment, such as anticonvulsants or antidepressants. Their analgesic effects are likely associated with immunomodulatory activity, that remain undefined. Thus, current research aimed at examining the impact of AAs on morphine-induced effects exerted on mouse immunity. METHODS: Macrophages from mice treated with morphine with or without gabapentin, amitriptyline or venlafaxine, were either subjected to phagocytosis assay, cultured to evaluate the generation of cytokines, or were pulsed with either corpuscular antigen or hapten and transferred to naive recipients to induce humoral or cellular response, respectively. Active contact hypersensitivity was also elicited in drug-treated mice. RESULTS: We observed that repeatedly administered morphine and AAs reduced antigen phagocytosis by macrophages. Further, amitriptyline with morphine enhanced basal secretion of cytokines by macrophages, and all drugs tended to decrease LPS-stimulated release of pro-inflammatory cytokines. Morphine and AAs impacted the expression of phagocytosis and antigen-presentation markers on macrophages, which led to the reduced ability of morphine-affected macrophages to induce B-cell secretion of specific antibodies, and the addition of AAs strengthened this effect. Finally, gabapentin and venlafaxine suppressed the contact hypersensitivity reaction, while amitriptyline seemed to have the opposite effect. CONCLUSIONS: Our study demonstrated a significant anti-inflammatory activity of AAs across a broad spectrum of macrophage immune functions, which is likely critical to their analgesic activity supporting the beneficial effect of morphine.

Pharmacotherapy of pain in cancer patients - recommendations of the Polish Association for the Study of Pain, Polish Society of Palliative Medicine, Polish Society of Oncology, Polish Society of Family Medicine, Polish Society of Anaesthesiology and Intensive Therapy and Association of Polish Surgeons.

Guidelines for the pharmacotherapy of pain in cancer patients were developed by a group of 21 experts of the Polish Association for the Study of Pain, Polish Society of Palliative Medicine, Polish Society of Oncology, Polish Society of Family Medicine, Polish Society of Anaesthesiology and Intensive Therapy and Association of Polish Surgeons. During a series of meetings, the experts carried out an overview of the available literature on the treatment of pain in cancer patients, paying particular attention to systematic reviews and more recent randomized studies not included in the reviews. The search was performed in the EMBASE, MEDLINE, and Cochrane Central Register of Controlled Trials databases using such keywords as "pain", "cancer", "pharmacotherapy", "analgesics", and similar. The overviewed articles included studies of pathomechanisms of pain in cancer patients, methods for the assessment of pain in cancer patients, and drugs used in the pharmacotherapy of pain in cancer patients, including non-opioid analgesics (paracetamol, metamizole, non-steroidal anti-inflammatory drugs), opioids (strong and weak), coanalgesics (glucocorticosteroids, α2-adrenergic receptor agonists, NMDA receptor antagonists, antidepressants, anticonvulsants, topical medications) as well as drugs used to reduce the adverse effects of the analgesic treatment and symptoms other than pain in patients subjected to opioid treatment. The principles of opioid rotation and the management of patients with opioidophobia were discussed and recommendations for the management of opioid-induced hyperalgesia were presented. Drugs used in different types of pain experienced by cancer patients, including neuropathic pain, visceral pain, bone pain, and breakthrough pain, were included in the overview. Most common interactions of drugs used in the pharmacotherapy of pain in cancer patients as well as the principles for the management of crisis situations. In the final part of the recommendations, the issues of pain and care in dying patients are discussed. Recommendations are addressed to physicians of different specialties involved in the diagnostics and treatment of cancer in their daily practice. It is the hope of the experts who took part in the development of these recommendations that the recommendations would become helpful in everyday medical practice and thus contribute to the improvement in the quality of care and the efficacy of pain treatment in this group of patients.

Data supporting the understanding of modulatory function of opioid analgesics in mouse macrophage activity.

The data presented herein expand the current understanding of the modulatory function of opioid drugs in mouse macrophage activity described in our relevant research article (Filipczak-Bryniarska et al., 2017) [1], in which we characterize the influence of morphine, buprenorphine and oxycodone on humoral and cell-mediated immune response in mice. Among other things, we have shown the effects of treatment with assayed analgesics on macrophage ability to induce antigen-specific B-cell response to sheep red blood cells as well as to generate reactive oxygen intermediates and nitric oxide. The current data demonstrate the effects of morphine, buprenorphine or oxycodone administration on phagocytosis of sheep red blood cells and zymosan by mouse macrophages, supplementing the data on immune modulatory capacities of assayed drugs, recently reported by us (Filipczak-Bryniarska et al., 2017; Kozlowski et al., 2017) [1,2].

In contrast to morphine, buprenorphine enhances macrophage-induced humoral immunity and, as oxycodone, slightly suppresses the effector phase of cell-mediated immune response in mice.

BACKGROUND: Opioid receptors are commonly expressed on various immune cells, macrophages especially. Thus, these cells are prone to stimulation with opioids, which seems to be responsible for opioid-induced immunomodulatory effects. While morphine, fentanyl and methadone influence on mouse immune response was recently studied, little is known about the potential immunomodulatory impact of buprenorphine and oxycodone. AIM: The current research aimed to investigate the influence of buprenorphine and oxycodone on immune responses in mice under homeostatic conditions. METHODS AND RESULTS: Repeated administration of morphine led to intensification of CHS response in actively sensitized mice, while buprenorphine or oxycodone administration exerted the opposite effect. Further, hapten-conjugated macrophages from mice treated with morphine, when transferred into naive recipients, induced more potent CHS response. The enhanced generation of reactive oxygen intermediates and nitric oxide by macrophages from mice treated with buprenorphine, oxycodone or morphine was also shown, along with increased release of IL-6, TNFα and TGFß. Treatment with opioids altered expression of antigen phagocytosis and presentation markers. Finally, the inhibitory effect of morphine treatment on induction of humoral immunity by macrophages was demonstrated, while oxycodone failed to influence humoral immune response and buprenorphine actually enhanced B-cell activation. CONCLUSIONS: Current observations confirm that macrophages greatly contribute to immunomodulatory effects of opioids. Studies on immunomodulation by opioids have great importance related to the evaluation of its beneficial and adverse effects on patient condition. Our research showed that oxycodone exerts the weakest immunomodulatory properties, allowing us to assume this drug as safer than morphine during prolonged therapy.

Evaluation of prognostic factors, symptoms and consequences of dehydration in patients with cancer based on retrospective data analysis of 102 patients treated in the Department of Palliative Medicine at the University Hospital in Cracow - preliminary report.

INTRODUCTION: Dehydration is a common problem in patients with terminal cancer patients. It worsens the quality of life and increases the amount of complications. Factors associated with dehydration need further exploration. The aim of our study was to determine the predictors of dehydration. PATIENTS AND METHODS: 102 terminal cancer patients admitted to Palliative Care Unit were retrospectively analyzed. Detailed physical examination, medical history including history taken from family and care givers was taken upon admission. Laboratory parameters including morphology, sodium, potassium, total and ionized calcium, LDH were taken on admission. We used univariate and multivariate logistic regression analysis to determine factors associated with dehydration. RESULTS: On admission 39% of patients were diagnosed with dehydration. Multivariate logistic regression analysis after adjustment for possible confounders reviled that lack of family care (p = 0.006; OR = 0.147; CI 95% = 0.038-0.577), higher level of PS (p = 0.0426; OR = 1.65; CI 95% = 1.017-2.667), lack of prior opioid use (p = 0.0233; OR = 0.386; CI 95% = 0.17-0.897), occurrence of nausea and vomiting at admission (p = 0.0077; OR = 3.297; CI 95% = 1.372-7.922), occurrence of dyselectrolytemia (p = 0.0012; OR = 4.462; CI 95% = 1.81-10.997), lack of prior GKS use (p = 0.0362; OR = 0.339; CI 95% = 0.123-0.933); lack of prior NSAID use (p = 0.0255; OR = 0.265; CI 95% = 0.082-0.849) remained independently associated with dehydration. CONCLUSIONS: Lack of family care, lack of prior opioid use, higher level of PS, occurrence of nausea and vomiting at admission, occurrence of dyselectrolytemia, lack of prior GKS use and lack of prior NSAID use in patients with terminal cancer are factors associated with dehydration.

The impact of advanced opioid drugs and analgesic adjuvants on murine macrophage oxygen burst.

Macrophages (Mf) are a versatile group of phagocytic cells responsible for fulfilling a variety of immune functions, most notably for mounting the initial anti-microbial response and for the clearance of cellular debris and apoptotic bodies. The key processes for fulfilling these functions include the production of reactive oxygen intermediates (ROIs) and nitric oxide (NO). Mf also express a variety of receptors, including opioid, serotonin, and norepinephrine receptors, and thus can react to various substances. Our study aimed to examine the effects of oxycodone and buprenorphine on the production ROIs and NO by Mf from intraperitoneally-treated mice, as compared to the previously studied morphine, fentanyl, and methadone, as well as the effects of the analgesic adjuvants gabapentin, amitriptyline, and venlafaxine. ROIs was estimated via luminol and lucigenin dependent chemiluminescence assay, and NO secretion was estimated via a colorimetric method utilizing a modified Griess reaction. We observed an overall decrease in both ROIs and NO production by Mf from adjuvant-treated mice, especially with amitriptyline. Opioids, however, resulted in enhanced ROIs production and mixed NO secretion, with oxycodone and buprenorphine have the least immunomodulatory effects. As ROIs and NO are potent mediators of Mf activity during the innate immune response, our current results express great translational potential. Our results suggest that OPs administration may boost Mf anti-microbial response. On the other hand, during sterile in ammation, enhanced generation of ROIs by Mf influenced by opioids may increase the risk of tissue damage, but co-administration of adjuvants could abolish this adverse effect.

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m2. Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

The role of macrophages in anti-inflammatory activity of antidepressant drugs.

Depression is a common disease influencing patients' quality of life, whose etiology involves complex interactions of environmental, genetic and immunological factors. The latter factors include proinflammatory activation of monocytes and macrophages and increased serum levels of proinflammatory cytokines, altogether formulated as the "macrophage theory of depression". Our current review summarizes the impact of the most commonly used antidepressant drugs on the immune response with special emphasis on the role of macrophages in the clinically observed effects. The anti-inflammatory action of antidepressants mainly results from their direct interaction with immune cells and from changes in the concentration and the relations of neurotransmitters sensed by these cells. The summarized data revealed that Mφs are one of the leading cell populations involved in drug-mediated immune effects that can be observed both in subjects with depression as well as in individuals not suffering from depression. Thus, currently reviewed immunomodulatory effects of the experimental use of different antidepressant drugs suggest the possibility of utilizing them in complex therapeutic strategies dedicated to various inflammatory and immune-mediated diseases. It is worth noting that an excessive inflammatory reaction is also associated with the pathogenesis of various cardiovascular, metabolic and neuro-endocrine diseases. Thus, the inclusion of antidepressants in the complex therapy of these disorders may have beneficial effects through the enhancement of the mood of the patient and alleviation of chronic inflammation. On the other hand, presented data suggest that the influence of chronically used antidepressants on anti-microbial and anti-tumor immunity could also be taken into consideration.

Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages.

Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive inflammation.

[The role of medicaments, exosomes and miRNA molecules in modulation of macrophage immune activity]. / Rola leków, egzosomów i czasteczek miRNA w modulacji aktywnosci immunologicznej makrofagów.

Macrophages play an important role in innate immunity, in induction and orchestration of acquired immune response as well as in the maintenance of tissue homeostasis. Macrophages as antigen presenting cells induce or inhibit the development of immune response and as effector cells play an important role in innate immunity to infectious agents and in delayed--type hypersensitivity as well. Thus, either up- or down-regulation of their activity leads to the impairment of different biological processes. This often results in the development of immunological diseases or inflammatory response associated with metabolic, cardiovascular or neuroendocrine disorders. Therefore, the possibility of modulation of macrophage function should allow for elaboration of new effective therapeutic strategies. Noteworthy, interaction of medicaments with macrophages may directly mediate their therapeutic activity or is an additional beneficial effect increasing efficacy of treatment. Further, macrophage differentiation is regulated by miRNA-223, while expression of miRNA-146 and miRNA-155 may modulate and/or be a result of the current cell phenotype. Present review is focused on the current knowledge about the action of medicaments, microRNA molecules, exosomes and related vesicles on macrophages leading to modulation of their biological activity.

The influence of opioids on the humoral and cell-mediated immune responses in mice. The role of macrophages.

BACKGROUND: Our experiments were aimed to test the influence of treatment with different opioids (morphine, fentanyl, methadone) on the humoral and cell-mediated immune responses. METHODS: Mice were treated intraperitoneally (ip) with opioids for several days and next either immunized with sheep red blood cells (SRBC) to test the antibody production or skin-sensitized with hapten picryl chloride (PCL) to induce contact hypersensitivity (CHS). In addition, the effects of opioids on the production of reactive oxygen intermediates (ROIs) and cytokines by peritoneal macrophages (Mf) and on the expression of surface markers on these cells and blood leukocytes were estimated. RESULTS: Opioids caused an enhancement of ROIs and cytokines production when macrophages were stimulated with zymosan or lipopolysaccharide (LPS) and reduced the expression of antigen presentation markers on Mf. Numbers of anti-SRBC plaque forming cells (PFC) and antibodies titres were lower in mice treated with all tested opioids. Depending on the use of particular opioid and the phase of allergic reaction, effects of the treatment on CHS were diverse. While morphine decreased the early and late phases of induction of CHS responses, methadone increased both reactions. In case of the effector phase of CHS, morphine and fentanyl increased both its early and late stages, while methadone decreased the late reaction. Treatment of recipients with opioids had diverse influence on the passive transfer of CHS in these animals. CONCLUSIONS: Our experiments show that the action of opioids on the immune system is a complex phenomenon dependent on such variables as type of opioid, character of response (humoral versus cellular) and types of cells involved. Here Mf seem to play a significant role.

[Experimental methods in the treatment of multiple sclerosis--new possibilities and hopes]. / Eksperymentalne metody leczenia stwardnienia rozsianego--nowe nadzieje, ogromne mozliwosci.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelinization. Although our knowledge on the pathomechanism of MS has evolved dramatically in recent years; however there is still no effective cure for MS. So far, non-specific immune suppressive agents are used to slow down the disease. Recently, there are many efforts to find a new method that would allow to control specifically unwanted immune response. It might be achieved by affecting antigen recognition or induction of "immune deviation".