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Midazolam is a short-acting benzodiazepine widely used for sedation; however, its duration of action can be prolonged by various factors including hypoalbuminemia. Previous behavioral studies in rats with low albumin levels reported reduced muscle strength and spontaneous locomotion, but the relationship between hypoalbuminemia and midazolam pharmacokinetics remains unclear. This study investigated whether prolonged midazolam sedation in hypoalbuminemia correlates with unbound and brain midazolam concentrations. Low-albumin rats were generated using protein-controlled diets for 30 days. Midazolam (5 mg/kg, i. p.) was administered and total blood and brain concentrations were determined by high-performance liquid chromatography 10 and 60 minutes after administration. Compared to controls, low albumin rats showed significantly higher total blood concentrations at 60 minutes (0.27 ± 0.02 vs 0.12 ± 0.02 μg/mL) and brain concentrations (0.21 ± 0.02 vs 0.10 ± 0.03 μg/mL). Unbound concentrations remained below quantification limits due to ultrafiltration adsorption. Pharmacokinetic analysis revealed prolonged half-life and decreased clearance in low-albumin rats. These findings suggest that hypoalbuminemia prolonged midazolam actions through sustained blood and brain concentrations, likely due to increased initial unbound drug levels that rapidly distribute to the brain before accumulating in peripheral tissues. Clinicians should exercise caution when administering midazolam to patients with hypoalbuminemia.

Cinchona bark and its main medicinal derivative - quinine - are known antimalarials. Until the 20^th century, medicines with Cinchona bark or quinine were the only effective treatment for malaria used on a large-scale. However, Cinchona bark and quinine were also used in other diseases. Regarding psychiatric uses, in Britain, Cinchona bark was recommended in mania (17 th century) and nervous diseases (18 th century). Nevertheless, the full scope of Cinchona bark and quinine's proposed activity in psychiatric disorders has not been assessed. We aimed to investigate references to Cinchona bark and quinine's use and recommendation in psychiatric diseases and symptoms in Portugal, published in the 18^th and 19^th centuries. For this purpose, we reviewed Portuguese medical and pharmaceutical literature from this period. Our sources included books (namely pharmacopoeias) and periodical publications. We found 27 Cinchona bark or quinine medicines recommended in the treatment of psychiatric diseases and symptoms in Portugal. Those diseases included hysteria, hypochondria, and nervous diseases. Cinchona bark and quinine medicines were also advised in psychiatric symptoms such as anxiety-induced palpitations, melancholia, or hypochondriac or hysterical symptoms. For most of these medicines - 17 out of 27 - the authors mention their efficacy in clinical practice. Consequently, our research suggests that, in 18^th and 19^th -century Portugal, Cinchona bark and quinine medicines were a therapeutic option in various psychiatric conditions. Therefore, it is possible that Cinchona bark and quinine had additional therapeutic indications that remain unknown.

The prevention of nutrition-related diseases holds paramount significance for human well-being. Sweet basil (Ocimum basilicum L., Lamiaceae) emerges as a noteworthy candidate due to its robust antioxidant properties attributed to a high concentration of phenolic and flavonoid compounds, promising potential health benefits for humans. Notably, bile acids and their derivatives exert influence on the metabolic effects of both conventional and herbal drugs. The aim of this study was to examine the effects of administering an aqueous basil extract for seven days on glycemia and in vivo antioxidant activity in both healthy and diabetic animals, either alone or in combination with a bile acid derivative. The experimental design involved normoglycemic and diabetic Wistar rats subjected to a seven-day regimen of saline and basil water extract. Hyperglycemia was induced using alloxan. Following the treatment period, animals were euthanized by cardiopuncture, and serum analyses were conducted to assess fasting blood glucose levels and biochemical parameters. Additional assessments included oral glucose tolerance tests and antioxidative stress enzyme assays. The findings showed a significant hypoglycemic effect of the aqueous basil extract in both normoglycemic and diabetic animals. The extract also decreased lipid peroxidation and increased the activity of antioxidant enzymes. Basil extract treatment displayed protective effects on glycemia in both normoglycemic and diabetic animals, indicating considerable antioxidant potential. These effects were evident through increased antioxidant enzyme activity and decreased lipid peroxidation, affirming the beneficial impact of aqueous basil extract on health parameters.

Sports supplements containing a combination of creatine and taurine have seen a dramatic rise in popularity. However, adequate analytical techniques for the quantification of these metabolites in tissue samples and supplements are essential. Liquid chromatography mass spectrometry offers a selective and sensitive alternative but to date, no method has been reported for the quantification of both compounds in combination. The main objective was to develop and validate a fast analytical method using LC-MS/MS and to test its suitability on seven commercial sports supplements. An isocratic method with a run time of 2.5 min using a hydrophilic interaction liquid chromatography column and multiple reaction monitoring transitions was developed and validated for linearity, precision, LOD and LOQ, ruggedness and recovery. Spiking experiments on seven commercial samples were conducted to test for possible ion enhancement/suppression. All validation parameters fell well within acceptable limits and the spiking recoveries of the commercial samples all fell between 81-116%. The seven products revealed large discrepancies between the measured values by as much as +99.66% for creatine and as low as -83.81% for taurine as compared to the label claims. These discrepancies highlight the importance of quality control, as inaccurate labelling could lead to unintentional overdosing, which may cause gastric issues and, in severe cases, kidney problems.

Transmembrane 16A (TMEM16A) is highly expressed in interstitial cells of Cajal (ICC) and participates in ICC-mediated rhythmic contractile activity of intestinal smooth muscle. TMEM16A is also expressed in epithelium of intestine with a minor contributor to transepithelial fluid secretion, while other unidentified Ca²⁺ -activated Cl - channels (unCaCCs) are mainly responsible for this physiological process. TMEM16A/CaCCs dysfunction can lead to disorders of intestinal motility and transepithelial fluid secretion. TMEM16A/CaCCs regulators are important tools to identify unCaCCs and study the physiopathological functions related to TMEM16A/CaCCs. In the present study, coumarins were identified as TMEM16A inhibitors in a concentration- and time-dependent manner in TMEM16A-expressed Fischer rat thyroid (FRT) epithelial cells. Coumarins attenuated intestinal motility by inhibiting TMEM16A in vivo and ex vivo. Coumarins inhibited CaCCs-mediated Cl^- currents induced by ATP in T84 and HT-29 cells or by carbachol (CCh) in mouse colonic mucosa with reduction of ATP-induced increase of cytoplasmic Ca²⁺ concentration in HT-29 cells. Coumarins inhibited basolateral Ca²⁺ -activated K⁺ channels without affecting Na + /K + -ATPase activity in mouse colonic mucosa. Coumarins did not show inhibition of cystic fibrosis transmembrane conductance regulator (CFTR), but mild activation of CFTR-mediated Cl - currents under the low concentration forskolin (FSK) in CFTR-expressed FRT cells, while coumarins did not activate CFTR-mediated Cl- currents in mouse colonic mucosa. This study was the first to demonstrate that coumarins attenuate intestinal motility by inhibiting TMEM16A, which may provide a strategy for clinical drug intervention aimed at reducing secretory diarrhea.

Antimicrobial resistance (AMR) has emerged to be a big threat to both human and animal health. Along the tighter control on antibiotic use, developing novel therapeutic agents and approaches is crucial for combating AMR. We recently designed and synthesized several antibiotic-phytochemical conjugates which exhibited potent antimicrobial activities. To understand their pharmacological behavior and obtain a guideline for further drug development, we undertook a pharmacokinetic study on sulfamethoxazole-gallate and sulfamethoxazole-caffeate. C_max was determined to be 842 ± 544 ng/mL at dose of 1500 mg/kg and 733 ± 477 ng/mL at dose of 2000 mg/kg for sulfamethoxazole-gallate and 211 ± 100 at a dose of 150 mg/kg and 755 ± 705 ng/mL at dose of 300 mg/kg for sulfamethoxazole-caffeate. T_max was 1 h for sulfamethoxazole-gallate under both doses and 0.5 h for sulfamethoxazole-caffeate under both doses. Since C_max was significantly lower than the in vitro MIC for both conjugates, more formulations and administration routes such as IV injection will be investigated in our future studies.

This study was conducted to examine the disproportionality, times to onset, incidence rates, and outcomes of sorafenib-associated cardiac AEs, using the Japanese Adverse Drug Event Report database. We analyzed data for the period between April 2004 and May 2023. Data on cardiac AEs were extracted and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs). We analyzed 2,230,863 reports and identified 8,374 reports of AEs associated with sorafenib, including 318 cardiac AEs. Signals were detected for seven cardiac AEs: hypertension, cardiac failure congestive, myocardial infarction, acute myocardial infarction, angina pectoris, myocardial ischaemia, and angina unstable. Among these, fatal outcomes were observed for cardiac failure congestive, myocardial infarction, acute myocardial infarction, and myocardial ischaemia. Histograms of median times to onset for the seven detected cardiac AE signals showed that AEs occurred at a median of 9-159 days after sorafenib administration. Weibull distributions showed that the incidence of all these AEs occurred constantly throughout the exposure period (random failure type). In conclusion, we focused on cardiac AEs associated with sorafenib as post-marketing AEs. Some cases could experience serious outcomes after sorafenib administration. Patients should be monitored for signs of onset for these AEs not only at the start of administration, but also over an extended period.

Background/Objectives: Combined oral contraceptives (COC) represent an effective form of fertility control, with numerous potential side effects. The aim was to monitor the difference in hematological and hemostatic parameters in users and nonusers of oral contraceptives. Methods: A descriptive study included 121 subjects, classified as 72 oral contraceptive users and 49 nonusers. Participants were recruited by randomization from the Institute for Student Health Care in Novi Sad. Results: There was no difference in age and body mass index between the groups. The frequency of smoking was higher in the nonusers compared to users (36% vs. 19%; χ ²=0.039). No significant difference in hematological parameters when comparing the groups was noted. Activated partial thromboplastin time (aPTT) and prothrombin time (PT) were significantly shorter in the users compared to nonusers (24.69 ± 1.83 s vs. 25.78 ± 2.85 s; p = 0.011 and 9.72 ± 2.16 s vs. 10.50 ± 1.93 s vs. p = 0.045, respectively). Significant differences in area under the curve (AUC) for endogenous thrombin potential (ETP) and the time required to reach the maximum thrombin level (ETP-_tmax) were noticed when comparing oral contraceptive users and the control group (111.40 ± 28.14 % vs. 93.32 ± 17.03 %; p = 0.02, and 69.85 ± 11.15 vs. 80.78 ± 14.87 s, p = 0.02, respectively). There was no difference in fibrinogen and D-dimer concentrations, while antithrombin and von Willebrand factor were lower in the control group, without statistical significance. Conclusion: The use of oral contraceptives of the third and fourth generation leads to changes in the hemostasis functionality in terms of the shortening of aPTT and PT, and an increase in ETP, thus potentially enabling the identification of women with the increased venous thrombosis risk.

Histamine H1 receptor (H1R) antagonists are widely used to treat allergic reactions; however, their effects on the central nervous system can impair motor functions. This study investigated the impact of first-generation (diphenhydramine and d -chlorpheniramine) and second-generation (epinastine, ketotifen, bepotastine, and levocetirizine) H1R antagonists on motor functions in mice using activity wheel, balance beam, inclined screen, and rotarod tests. First-generation H1R antagonists significantly impaired motor functions, with diphenhydramine exerting stronger effects than those of d -chlorpheniramine. Among the second-generation agents, bepotastine and levocetirizine had minimal effects on all motor functions, whereas epinastine and ketotifen suppressed spontaneous movement, similar to first-generation H1R antagonists but had little effects on balance, postural stability, and coordinated movement. These findings provide valuable insights into the differential effects of first- and second-generation H1R antagonists on motor functions. These results highlight the importance of understanding individual profiles of H1R antagonists to minimize adverse effects, ensure patient safety, and improve quality of life.

The history of the Croatian pharmaceutical company PLIVA from the very beginning to the status of a recognisable European and global player is described. Special attention is paid to PLIVA's cooperation with the Croatian Nobel laureate Vladimir Prelog and the invention of the proprietary antibiotic azithromycin. The antibiotic was commercialised in cooperation with the US-based company Pfizer. PLIVA's predecessor was Kaštel, Factory for Chemico-Pharmaceutical Products Joint-Stock Company. It was founded in 1920 in Karlovac, Croatia to continue operation in Zagreb in 1928. Eventually it was incorporated into the State Institute for the Production of Medicines and Vaccines bearing the acronym PLIVA (1942). In 1952, thanks to the collaboration with the organic chemist and 1975 Nobel Prize laureate Vladimir Prelog, the PLIVA Research Institute was founded. Thirty years later the research conducted by a team of scientists led to the invention of azithromycin, a new antibiotic, first member of azalides, a new class of macrolides. The core team working on azithromycin synthesis, development and patent protection (priority patent applications submitted in 1979 and 1981) included Dr Slobodan Đokić, Gabrijela Kobrehel, MSc, Dr Gorjana Lazarevski, and Dr Zrinka Tamburašev. Azithromycin was marketed globally under the trademarks of Sumamed® (PLIVA, 1988) and Zithromax® (Pfizer, 1991). It has become and still is one of the most successful and best-selling antibiotics in the world. The story of PLIVA and azithromycin shows that blockbusters can be invented based on dedication, knowledge and long-time experience despite possibly unfavourable conditions.