Journal: Naunyn-Schmiedeberg's archives of pharmacology
Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.
Vitamin D is an immunomodulator hormone with an anti-inflammatory and antimicrobial effect with a high safety profile. A lot of COVID-19 infected patients develop acute respiratory distress syndrome (ARDS), which may lead to multiple organ damage. These symptoms are associated with a cytokine storm syndrome. The aim of this letter is to note the 5 crucial points that vitamin D could have protective and therapeutic effects against COVID-19. For that reason, COVID-19 infection-induced multiple organ damage might be prevented by vitamin D.
Anethole [1-methoxy-4-(1-propenyl)benzene] occurs naturally as a major component of the essential oil of star anise (Illicium verum Hook.f., family Illiciaceae), comprising more than 90 % of its volatile components. Studies showed that this substance has antioxidant, antibacterial, antifungal, and anesthetic properties. In this study, the anti-inflammatory properties of anethole in animal models of nonimmune acute inflammation such as croton oil-induced ear edema and carrageenan-induced pleurisy were investigated. The investigated parameters were edema formation, leukocyte migration, and inflammatory mediators involved. Oral administration of anethole at a dose of 250 and 500 mg/kg reduced both the volume of pleural exudates and the number of migrated leukocytes. Levels of nitric oxide (NO) and prostaglandins (PGE(2)) in the inflammatory exudate were reduced by treatment with anethole, but levels of tumor necrosis factor-α and interleukin-1β were not significantly altered. In ear edema, the oral treatment with anethole inhibited the formation of exudate and the activity of myeloperoxidase, but not after topical administration. These results suggest that the anethole may be effective in controlling some nonimmune acute inflammation-related disease, probably by an inhibitory action on production and/or release of PGE(2) and NO.
The serotonin (5-hydroxtryptamine, 5-HT) system plays a role in analgesia and emesis. The aim of this study was to test whether opioids or ketamine inhibit the human 5-HT transporter and whether this increases free plasma 5-HT concentrations. HEK293 cells, stably transfected with the human 5-HT transporter cDNA, were incubated with morphine, hydromorphone, fentanyl, alfentanil, pethidine (meperidine), tramadol, ketamine, and the reference substance citalopram (specific 5-HT transporter inhibitor). The uptake of [(3)H]5-HT was measured by liquid scintillation counting. In a second series of experiments, study drugs were incubated with plasma of ten healthy blood donors and change of 5-HT plasma-concentrations were measured (ELISA). The end point was the inhibition of the 5-HT transporter by different analgesics either in HEK293 cells or in human platelets ex vivo. Tramadol, pethidine, and ketamine suppressed [(3)H]5-HT uptake dose-dependently with an IC50 of 1, 20.9, and 230 μM, respectively. These drugs also prevented 5-HT uptake in platelets with an increase in free plasma 5-HT. Free 5-HT concentrations in human plasma were increased by citalopram 1 μM, tramadol 20 μM, pethidine 30 μM, and ketamine 100 μM to 280 [248/312]%, 269 [188/349]%, and 149 [122/174]%, respectively, compared to controls without any co-incubation (means [95 % CI]; all p < 0.005). No change in both experimental settings was observed for the other opioids. Tramadol and pethidine inhibited the 5-HT transporter in HEK293 cells and platelets. This inhibition may contribute to serotonergic effects when these opioids are given in combination, e.g., with monoamine oxidase inhibitors or selective serotonin reuptake inhibitors.
Our goal was to establish a model for the evaluation of the effects of uricosuric agents and to clarify the underlying mechanism(s). The effects of a uricosuric agent co-treated with pyrazinamide, an anti-tubercular agent, on urate handling were examined in rats. Furthermore, the effects of uricosuric agents on urate uptake were evaluated using the vesicles of rat renal brush-border membrane. Treatment with probenecid, at a dose of 100 mg/kg, significantly increased the urinary urate to creatinine ratio (UUA/UCRE) in pyrazinamide-treated rats although the same treatment did not produce any uricosuric effects in intact rats. In this model, the urinary excretion of pyrazinecarboxylic acid (PZA), an active metabolite of pyrazinamide, was decreased by probenecid and indicated an inverse correlation between urinary excretion of urate and PZA. Furthermore, in the examination using FYU-981, a potent uricosuric agent, a more than 10-fold leftward shift of the dose-response relationship of the uricosuric effect was observed in pyrazinamide-treated rats when compared with intact rats. In the in vitro study, the treatment of the vesicles of rat renal brush-border membrane with PZA produced an increased urate uptake, which was inhibited by uricosuric agents. The pyrazinamide-treated model used in the present study seems to be valuable for the evaluation of uricosurics because of its higher sensitivity to these drugs when compared to intact rats, and this is probably due to the enhanced urate reabsorption accompanied with trans-stimulated PZA transport at the renal brush-border membrane.
Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.
Hydroxychloroquine (HCQ) has been implicated in antiviral activity in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still controversy about whether HCQ should be used for coronavirus disease 2019 (COVID-19) patients due to the conflicting results in different clinical trials. To systematically assess the benefits and harms of HCQ for the treatment of COVID-19. Data sources were systematically searched from Pubmed, Biorxiv, ChiCTR, Clinicalrials.gov , and the Cochrane library of RCTs for studies published from inception to June 1, 2020, to obtain any possible inclusion. This meta-analysis of inclusion criteria was directed on the basis of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P). Pooled studies by the title and abstract were screened and removed in the light of meta-analysis by two reviewers. Seven studies involving 851 participants with COVID-19 were eligible for analysis. There was no significant difference in RT-PCR negative conversion between HCQ group and standard treatment (ST) group (RR = 1.11, 95% CI = 0.77-1.59, P = 0.591). The rate of exacerbated pneumonia on chest CT in HCQ group was lower than that in ST group (RR = 0.44, 95% CI = 0.20-0.94, P = 0.035). There was no statistical difference in progressed illness between the HCQ group and the ST group (RR = 0.66, 95% CI = 0.18-2.43, P = 0.530). Death (RR = 1.92, 95% CI = 1.26-2.93, P = 0.003) was distinctly different in HCQ group compared with ST group in the treatment of COVID-19. Our meta-analysis demonstrated that there was no robust evidence to support prescribing HCQ as a treatment for COVID-19.
As a new human immunodeficiency virus type 1 (HIV-1) vaccine approach, the live-attenuated measles virus (MV) Schwarz vaccine strain was genetically engineered to express the F4 antigen (MV1-F4). F4 is a fusion protein comprising HIV-1 antigens p17 and p24, reverse transcriptase and Nef. This study assessed the toxicity, biodistribution and shedding profiles of MV1-F4. Cynomolgus macaques were intramuscularly immunized one or three times with the highest dose of MV1-F4 intended for clinical use, the reference (Schwarz) measles vaccine or saline, and monitored clinically for 11 or 85 days. Toxicological parameters included local and systemic clinical signs, organ weights, haematology, clinical and gross pathology and histopathology. Both vaccines were well tolerated, with no morbidity, clinical signs or gross pathological findings observed. Mean spleen weights were increased after three doses of either vaccine, which corresponded with increased numbers and/or sizes of germinal centers. This was likely a result of the immune response to the vaccines. Either vaccine virus replicated preferentially in secondary lymphoid organs and to a lesser extent in epithelium-rich tissues (e.g., intestine, urinary bladder and trachea) and the liver. At the expected peak of viremia, viral RNA was detected in some biological fluid samples from few animals immunized with either vaccine, but none of these samples contained infectious virus. In conclusion, no shedding of infectious viral particles was identified in cynomolgus monkeys after injection of MV1-F4 or Schwarz measles vaccines. Furthermore, no toxic effect in relation to the MV vaccination was found with these vaccines in this study.
Voriconazole has been associated with cutaneous squamous cell carcinoma (cSCC) in transplant patients but less is known about the risk in less severely immunosuppressed patients. Our aim was to estimate the incidence of cSCC after voriconazole exposure in patients with chronic pulmonary aspergillosis on a background of chronic lung disease. The notes of patients seen at a tertiary referral centre from 2009 to 2019 with chronic pulmonary aspergillosis were reviewed for the diagnosis of cSCC and voriconazole use documented. Among 1111 patients, 668 (60.1%) received voriconazole for longer than 28 days. Twelve patients received a diagnosis of cSCC; nine had used voriconazole. Mean duration of voriconazole use was 36.7 months. The crude incidence rate was 4.88 in 1000 person/years in those who had voriconazole and 2.79 in 1000 patient/years in those who did not receive voriconazole for longer than 28 days. On Cox regression, age (HR 1.09, 95% CI 1.02-1.16, p = 0.01) and male gender (HR 3.97, 95% CI 0.84-18.90, p = 0.082) were associated with cSCC. Voriconazole use was associated with a slightly increased risk, which was not significant (HR 1.35, 95% CI 0.35-5.20, p = 0.659). Voriconazole use beyond 28 days did not lead to a significantly increased risk of cSCC in a large cohort of patients with chronic pulmonary aspergillosis.
Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in part in the pharmacokinetic phase.