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Antioxidant and anti-inflammatory effects of lixisenatide (LX) and ticagrelor (TC) have been previously identified in type 2 diabetes mellitus (T2DM). Diabetic nephropathy is one of the major complications of T2DM. In the current study, we examined the potential protective effects of LX and TC on experimentally induced diabetic nephropathy in T2DM rats and their possible molecular mechanisms. To examine this possibility, rats were fed a high-fat diet (HFD) for 12 weeks, followed by a single injection of 35 mg/kg streptozotocin (STZ) to induce T2DM. 10 μg/kg LX and 25 mg/kg TC were given alone or in combination to T2DM rats for 4 weeks. The kidney examination of T2DM rats showed clear deterioration. T2DM rats exhibited significantly higher body weight, blood glucose, hemostatic model assessment for insulin resistance (HOMA-IR), blood urea nitrogen (BUN), serum creatinine, kidney reactive oxygen species (ROS), nuclear factor-κ B (NF-κ B), and transforming growth factor-β (TGF-β ), and significantly lower serum insulin, urine creatinine, creatinine clearance (CRCL), kidney superoxide dismutase (SOD), glutathione reduced (GSH), nuclear factor erythroid 2 (NrF₂ ), heme oxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS) when compared to control rats. Single treatment with LX or TC showed obvious ameliorative effects on kidney complications in T2DM rats, with more ameliorative effects with the combined administration of both drugs. Conclusion: Our investigation found that both LX and TC could significantly ameliorate the development of diabetic nephropathy via stimulating NrF₂ /HO-1 antioxidant pathway in addition to increasing eNOS and decreasing NF-κ B renal tissue concentrations, and these effects were markedly augmented by their combined administration.

Background: Of all adverse drug reactions, 35-45% are due to medication errors and would therefore be preventable. Thus, it is essential to implement effective strategies to prevent medication errors. However, it remains unclear whether medication reviews provide an additional benefit compared to medication reconciliation regarding medication safety. Aim: The present study aimed to evaluate whether medication reconciliation and medication reviews affect the incidence of preventable adverse drug reactions in elderly patients. Method: Non-elective patients 65 years and above admitted to the hospital, taking at least one high-risk drug, were eligible for participation in a three-armed randomized controlled trial. One group went through the medication reconciliation process, a second group received a comprehensive medication review, including medication reconciliation, and the third group did not receive any pharmaceutical intervention (control group). The incidence of preventable adverse drug reactions during hospitalization was set as the primary endpoint. The severity of the preventable adverse drug reactions and the number and clinical relevance of drug-related problems and discrepancies were defined as secondary endpoints. Results: In 207 patients, 74 preventable adverse drug reactions were detected. Neither medication reconciliation nor medication reviews showed a significant impact on the incidence of preventable adverse drug reactions compared to the control group. However, medication reviews significantly reduced the severity of preventable adverse drug reactions (p=0.017). Conclusion: The current study results suggest that medication reviews may have an impact on a clinically relevant outcome by reducing the severity of preventable adverse drug reactions. A significant impact of medication reconciliation on clinically relevant outcomes could not be demonstrated. Based on the results of this study, when deciding on a pharmaceutical intervention comprehensive medication reviews should be preferred over sole medication reconciliation whenever possible.

Purpose: To investigate the potential impact of drugs for the treatment of attention deficit hyperactivity disorder (ADHD) on body weight and height in children and adolescents from the LIFE ('Leipzig Research Centre for Civilization Diseases', Leipzig, Germany) Child cohort. Methods: We included 2,115 participants aged ≥6 to <18.25 years who attended the LIFE study center between 2011 and 2020 in our analysis, of whom 48 used ADHD drugs. Anthropometric and medication data from baseline to the third follow-up visit were available for 659 participants. Body height and body weight measurements were subsequently converted to z-scores. A repeated measures analysis of variance (ANOVA) was performed on the z-scores of both ADHD drug users and non-users to determine potential trends in body weight and body height from baseline to the 3 rd annual follow-up. Results: At the last visit with ADHD drug use of the 48 ADHD drug users, 40% (19/48) of the children and adolescents were below the 25 th reference percentile for weight. Z-scores for body height declined from baseline to the 3^rd annual follow-up in individuals who used ADHD drugs (n=10; Difference_means =-0.310; p=0.002) compared to non-users (n=649; Difference_means =0.102; p<0.001). Body weight also decreased from baseline to 3^rd follow-up in the ADHD drug group (n=10; Difference_means =-0.473; p<0.001) compared to the non-user group (n=649; Difference_means =0.015; p=0.161). Conclusion: We observed a potential tendency towards lower Z-scores for body height and body weight in individuals taking ADHD medication for an extended period compared to the corresponding age- and sex-matched populations.

The present work reports on the preparation of the hitherto unknown title compounds 5, with various synthetic routes described. The initially pursued concept of S-N exchange with varioius 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazines 4 by using nitrogen nucleophiles was only marginally successful. The reactions proceeded slowly and the yields were low, mainly because of the pronounced formation of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2- a ]pyridazin-1-imines 7 by oxidation of the heterocyclic amines 5 initially formed. The integration of the synthesis of 3-acylsulfanyl analogues with the more reactive leaving groups also failed. On the other hand, the cyclization of the hydrohalides of hexahydropyridazine-1-carboximidamide with aromatic aldehydes and some low molecular weight ketones gives significantly better results in the synthesis of the title compounds 5. The use of the hydrochloride 6b proved to be advantageous in comparison to the hydroiodide 6a because the yields were significantly better and the imines 7 formed at the same time only to a small extent. In addition, the starting compound 6b can be prepared in a single-step synthesis in very good yield from hexahydropyridazine hydrochloride 1 and cyanamide. The cyclization of N' -phenylhexahydropyridazine-1-carboximidamide hydrochloride 6c with substituted benzaldehydes gives the 3-aryl-substituted 2-phenyl-2,3,5,6,7,8-hexahydro -1H -[1,2,4]triazolo[1,2- a ] pyridazin-1-imines 8. In the context with the study of the reaction of hexahydropyridazine-1-carboximidamide hydroiodide 6a with cyclohexanone, the hexahydropyridazine-1-carboxamide 9 was specifically synthesized. This can be reacted with aromatic aldehydes to give the 5,6,7,8-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazin-1-ones 10 in very good yields. The results of the biological testing of representatives of the synthesized 5,6,7,8-tetrahydro-[1,2,4] triazolo[1,2-a]pyridazine-1-amines 5 show, in comparison to the already examined thions 3 and 3-methylsulfanyl derivatives 4, significantly less inducible nitric oxide synthase (iNOS) inhibitory activity.

The principal aim of this study was to optimize analytical methodology based on mass spectrometry for the evaluation of the quality of recombinant human insulin and its analogs. In this study ESI-MS was used to assess the quality of human insulin, short acting insulin analogs, insulin lispro, insulin aspart and insulin glulisine and long acting analogs including insulin glargine, insulin degludec, and insulin detemir, in respective pharmaceutical formulations. In this study, with the aimed to optimize analytical conditions, different factors influencing the analytical performance such as pH, ionic strength, sample dilution, organic solvent addition were addressed. The study results demonstrated that MS is a suitable technique for the analysis of biotechnological compounds like insulin and its analogs. Although the obtained results provide an important information regarding this methodology, further studies are needed to validate this analytical approach and check for its suitability to be used in the regulatory environment.

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

Background: Gabapentinoid anticonvulsants are standard treatment for neuropathic pain and are often combined with opioids for treating cancer. It is assumed that this combination may heighten somnolence and respiratory depression due to the inhibitory effects of opioids on the central nervous system. Although pregabalin, a gabapentinoid, is known to increase somnolence frequency during opioid therapy, whether mirogabalin exerts similar effects on somnolence frequency under opioid therapy remains unknown. This study examined the signals of somnolence and respiratory depression in response to pregabalin and mirogabalin use by utilizing data from the Japanese Adverse Drug Event Report database and assessed their interaction with strong opioid analgesics. Methods: Information was obtained from the JADER database from April 2004 to August 2023 via the Pharmaceuticals and Medical Devices Agency website. The study focused on neuropathic pain medications, specifically "pregabalin" and "mirogabalin besilate." Adverse events were defined using preferred terms (PTs) from the Medical Dictionary for Regulatory Activities version 26.1. The PTs considered were "Somnolence (10041349)" and "Respiratory depression (10038678)." To investigate the effect of the combination of strong opioid analgesics with pregabalin and mirogabalin on the occurrence of somnolence, a multivariable logistic regression analysis was conducted. Results: Signals for somnolence were detected with the use of both drugs (pregabalin: information component (IC) [95% confidence intervals (CIs)]: 2.89 [2.70 to 3.08]; mirogabalin: IC [95% CIs] 2.50 [1.85 to 3.16]). When evaluating respiratory depression, a typical and serious adverse event of opioid analgesic use, a signal was detected with pregabalin use but not with mirogabalin use (pregabalin: (IC [95% CIs] 1.28 [0.83 to 1.73]; mirogabalin: IC [95% CIs] -0.15 [-2.20 to 1.89]). Multivariable analysis indicated that the use of strong opioid analgesics increased the occurrence of somnolence when combined with pregabalin but not when combined with mirogabalin (p = 0.004). Conclusion: While the safety of concomitant administation of mirogabalin with opioids remains controversial, caution should be exercised when using pregabalin, especially in combination with opioids for neuropathic pain, compared to that for mirogabalin.

Renal function significantly influences the appropriate warfarin dosage. However, studies investigating the impact of genetic factors on warfarin dosage, considering renal function, are limited. This study aimed to assess the role of genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, CYP4F2, GGCX, and APOE in warfarin dosage adjustment considering renal function. A total of 108 outpatients receiving warfarin treatment with controlled prothrombin time-targeted international normalized ratio (1.5-3.0) were included. Patient data, warfarin dosage, and laboratory results were collected from electronic medical records. Each SNP [VKORC1 rs9923231, CYP2C9 rs1057910, CYP4F2 rs2108622, CYP2C19^* 2 (rs4244285) and^* 3 (rs4986893), GGCX rs699664 and rs12714145, and APOE rs7421] was analyzed. Multiple regression analysis revealed estimated glomerular filtration rate as the most significant factor influencing warfarin dose (p <0.001) (^β = -0.445). VKORC1 rs9923231 AA, CYP4F2 rs2108622 CT/TT, GGCX rs12714145 CT/TT, and CYP2C9 rs1057910 AC carriers were associated with warfarin dose (p <0.001, 0.015, 0.020, 0.038 and β = -0.317, 0.191, -0.188, -0.162, respectively); however, other genes showed no significant association. In conclusion, after adjusting for renal function, genetic factors of VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs12714145, and CYP2C9 rs1057910 were found to contribute to warfarin dosage, having impact in that order. In contrast, the contribution of other genes to warfarin dosage was absent or negligible.

Substances metabolised by the intestinal microbiota can be used as colon markers and are gaining importance. The flavonoid glycoside baicalin has been described in the literature to be metabolised by the intestinal microbiota. The aim of this work was to investigate how the biotransformation of baicalin to baicalein is related to the intestinal microbiota. For this purpose, stool samples from healthy volunteers with different dietary habits were used. From the pre-cultured stool samples, different standard microbiota were obtained which were used for the subsequent metabolism studies in the in vitro model MimiCol. MimiCol represents the ascending section of the colon, the colon ascendens, in terms of available volume, pH-value, redox potential and bacterial abundance. While during the experiments with added standard microbiota a metabolism of baicalin to baicalein could be detected, this was not the case in a series of experiments without added microbiota. This confirmed the hypothesis that the metabolism of baicalin relies on the bacterial species that are present in the colon. The data collected in the MimiCol therefore support the use of baicalin as a potential marker for the determination of the colon arrival. This can be explained by the fact that baicalin in its native form is poorly absorbed from the gastrointestinal tract. Enzymes of the colonic microbiota, namely β-glucuronidases, hydrolyze baicalin to the aglycone baicalein. The resulting aglycone can be absorbed through the intestinal mucosa and detected in blood plasma. This potentially enables the use of baicalin as a marker to determine the time of arrival in the colon.

Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.