Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor Mpro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the WT glutamine at the P1 position with isoleucine retains Mpro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter assay suitable for compound library screening and evaluation in HEK293T cells. This assay can detect both overall Mpro inhibition and the fraction of uncleaved precursor form of Mpro through separable fluorescent signals. We observed that inhibitory compounds preferentially block mature Mpro. Bofutrelvir and a novel compound designed in-house showed the lowest selectivity between precursor and mature Mpro, indicating that inhibition of both forms may be possible. Additionally, we observed positive modulation of precursor activity at low concentrations of inhibitors. Our findings help expand understanding of the SARS-CoV-2 viral life cycle and may facilitate development of strategies to target precursor form of Mpro for inhibition or premature activation of Mpro.
- MeSH
- Antiviral Agents * pharmacology chemistry MeSH
- COVID-19 Drug Treatment MeSH
- HEK293 Cells MeSH
- Protease Inhibitors pharmacology chemistry MeSH
- Coronavirus 3C Proteases * metabolism antagonists & inhibitors chemistry genetics MeSH
- Humans MeSH
- Mutation MeSH
- Drug Discovery * methods MeSH
- Proteolysis MeSH
- SARS-CoV-2 * enzymology drug effects metabolism genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: The safety profile of venom immunotherapy (VIT) is a relevant issue, and considerable differences have been reported in the safety and efficacy of this treatment modality. The primary aim of this study was to evaluate the safety of angiotensin-converting enzyme inhibitors and ß-blockers during VIT. In a second analysis, we evaluated data on premedication and venom preparations and their association with systemic adverse events (AEs) during the up-dosing phase and the first year of the maintenance phase, as well as the outcome of field stings and sting challenges. METHODS: Ours was an open, prospective, observational, multicenter study that recruited 1425 patients, of whom 1342 underwent VIT. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during up-dosing and 19.7% of patients during the maintenance phase. Antihistamines had no effect on the frequency of systemic AEs (P=.11), although large local reactions (LLRs) were less frequent (OR, 0.74; 95%CI, 0.58-0.96; P=.02). Aqueous preparations were preferred for up-dosing (73.0%), and depot preparations were used for the maintenance phase (64.5%). The type of venom preparation had no influence on the frequency of systemic AEs or on the effectiveness of VIT (P=.26 and P=.80, respectively), while LLRs were less frequent with depot preparations (P<.001). CONCLUSIONS: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLRs but not systemic AEs. All venom preparations were equally effective and did not differ in terms of the frequency of systemic AEs.
- MeSH
- Allergens immunology administration & dosage MeSH
- Histamine Antagonists therapeutic use MeSH
- Adrenergic beta-Antagonists therapeutic use MeSH
- Desensitization, Immunologic * methods adverse effects MeSH
- Child MeSH
- Adult MeSH
- Angiotensin-Converting Enzyme Inhibitors therapeutic use adverse effects MeSH
- Insect Bites and Stings immunology MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Prospective Studies MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Venoms immunology adverse effects therapeutic use MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
BACKGROUND: The medication used to treat benign prostate hyperplasia (BPH), a common condition in men over 50 years of age, can alter the levels of biomarkers used in prostate cancer detection. Commonly used medications for BPH include alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), and muscarinic antagonists. We studied the impact of these drugs on total prostate-specific antigen (tPSA), free PSA (fPSA), [-2]proPSA, fPSA/tPSA ratio, and the Prostate Health Index (PHI), as well as novel potential biomarkers in the form of glycan composition of fPSA. PATIENTS AND METHODS: Serum samples were collected from 564 males with BPH, with a mean age of 68.5 years. The samples were used to measure levels of tPSA, fPSA, and [-2]proPSA. The fPSA/tPSA and PHI were then calculated. The glycan composition of fPSA was analyzed using lectin-based glycoprofiling. Pharmacotherapy data was collected from the patients' medical records. RESULTS: Alpha-blocker monotherapy was associated with higher fPSA and fPSA/tPSA ratio, and decreased PHI. Levels of tPSA were not impacted. Alpha-blocker and 5-ARI dual therapy was associated with reduced levels of fPSA, [-2]proPSA, and PHI. Therapy combining alpha-blockers and antimuscarinic agents did not significantly influence biomarker levels apart from an increase in a Maackia amurensis lectin-recognized glycan originating in fPSA. CONCLUSION: BPH pharmacotherapy notably affects prostate cancer biomarkers. Recognizing the impact of pharmacotherapy is crucial for achieving an accurate diagnosis of prostate cancer and for planning treatment.
- MeSH
- Adrenergic alpha-Antagonists therapeutic use MeSH
- Muscarinic Antagonists * therapeutic use MeSH
- Glycosylation MeSH
- Prostatic Hyperplasia * blood drug therapy MeSH
- 5-alpha Reductase Inhibitors therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Prostatic Neoplasms blood drug therapy MeSH
- Prostate pathology metabolism MeSH
- Prostate-Specific Antigen * blood MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Adrenergic beta-3 Receptor Agonists pharmacology classification therapeutic use MeSH
- Antidepressive Agents, Tricyclic pharmacology classification therapeutic use MeSH
- Botulinum Toxins pharmacology therapeutic use MeSH
- Cholinergic Antagonists pharmacology classification therapeutic use MeSH
- Estrogen Replacement Therapy methods MeSH
- Urinary Bladder, Overactive * diagnosis drug therapy MeSH
- Phosphodiesterase 5 Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- Urinary Incontinence, Urge * diagnosis drug therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Patient Compliance MeSH
- Adrenergic beta-3 Receptor Agonists pharmacology therapeutic use MeSH
- Behavior Therapy methods MeSH
- Cholinergic Antagonists pharmacology therapeutic use MeSH
- Urinary Bladder, Overactive * diagnosis drug therapy psychology MeSH
- Quality of Life * MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Bisoprolol is a second-generation, highly selective beta-1 adrenergic receptor antagonist with various beneficial effects in patients with heart failure. Interindividual variability in response to bisoprolol is known, and finding the optimal dose for individual patients with heart failure is still challenging. This pilot study included patients treated with bisoprolol for chronic heart failure with reduced ejection fraction. Between November 2022 and November 2023, one to six blood samples were collected from these patients to determine the trough serum concentration of bisoprolol. At the same time, the values of selected clinical variables were recorded. Bisoprolol concentrations ranged from 1.1 to 65.0 μg/L and correlated with both the daily dose and the dose per kilogram of body weight. However, wide variability in measured serum concentrations of bisoprolol was observed at the same daily dose and in apparent weight-adjusted clearance. Patients classified as NYHA III-IV received a 33% higher dose per kilogram of body weight than patients in NYHA I-II but achieved 165% higher serum concentrations of bisoprolol. An inverse correlation was found between diastolic blood pressure and dose per kilogram of body weight, and a positive correlation between N-terminal pro-B-type natriuretic peptide and both dose per kilogram of body weight and serum bisoprolol concentration. A wide variability in patients' serum concentrations of bisoprolol achieved after taking the same dose has been observed. A significantly higher concentration-to-dose ratio and a significantly lower weight-adjusted apparent clearance were demonstrated in patients with reduced cardiac function, reduced renal function, and taking the combination with amiodarone. These patients may be more prone to overdose with bisoprolol.
- MeSH
- Adrenergic beta-1 Receptor Antagonists * blood administration & dosage pharmacokinetics therapeutic use MeSH
- Bisoprolol * blood administration & dosage pharmacokinetics therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Drug Monitoring MeSH
- Pilot Projects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Heart Failure * drug therapy blood physiopathology MeSH
- Stroke Volume drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND AND OBJECTIVES: N-acetyl-l-leucine (NALL) has been established to improve the neurologic manifestations of Niemann-Pick disease type C (NPC) after 12 weeks in a placebo-controlled trial. In the open-label extension phase (EP) follow-up, data were obtained after 12 and 18 months to evaluate the long-term effects of NALL for NPC. METHODS: This is an ongoing, multinational, multicenter EP. Patients with a genetic diagnosis of NPC aged 4 years or older who completed the placebo-controlled trial were eligible to continue in the EP and receive orally administered NALL 2-3 times per day in 3 tiers of weight-based dosing. The primary end point is the modified 5-domain NPC Clinical Severity Scale (NPC-CSS) (range 0-25 points; lower score representing better neurologic status); data from the EP cohort are compared with the expected annual trajectory of decline (i.e., disease progression) established in natural history studies. Analyses are also performed on exploratory end points, including the 15-domain and 4-domain NPC-CSSs and the Scale for Assessment and Rating of Ataxia (SARA). RESULTS: Fifty-three patients aged 5-67 years (45.3% female, 54.7% male) were enrolled in the EP. After 12 months, the mean (±SD) change from baseline on the 5-domain NPC-CSS was -0.27 (±2.42) with NALL vs +1.5 (±3.16) in the historical cohort (95% CI -3.05 to -0.48; p = 0.009), corresponding to a 118% reduction in annual disease progression. After 18 months, the mean (±SD) change was +0.05 (±2.95) with NALL vs +2.25 (±4.74) in the historical cohort (95% CI -4.06 to -0.35; p = 0.023). The 15-domain and 4-domain NPC-CSSs were consistent with the 5-domain NPC-CSS. The improvements in neurologic manifestations demonstrated in the placebo-controlled trial on the primary SARA end point were sustained over the long-term follow-up. NALL was well tolerated, and no treatment-related adverse events or serious reactions occurred. DISCUSSION: Treatment with NALL was associated with a significant reduction in NPC disease progression after 12 and 18 months, demonstrating a disease-modifying, neuroprotective effect. TRIAL REGISTRATION INFORMATION: The trial is registered with ClinicalTrials.gov (NCT05163288; registered December 6, 2021), EudraCT (2021-005356-10). The first patient was enrolled into the EP on March 8, 2023. The trial was funded by IntraBio Inc. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that NALL reduces disease progression in NPC.
- MeSH
- Child MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Leucine * analogs & derivatives therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Follow-Up Studies MeSH
- Neuroprotective Agents * therapeutic use MeSH
- Niemann-Pick Disease, Type C * drug therapy MeSH
- Child, Preschool MeSH
- Disease Progression MeSH
- Severity of Illness Index MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Dlouhodobé podávání betablokátorů pacientům po infarktu myokardu (IM) se zachovalou ejekční frakcí levé komory (EFLK) zůstává kontroverzní. Zatímco benefit betablokátorů je prokázán u pacientů se sníženou EFLK, pro nemocné s EFLK > 40 % chybí jednoznačná data z randomizovaných klinických studií. Dvě nedávno publikované studie (REDUCE-AMI a ABYSS) přinesly rozdílné výsledky ohledně bezpečnosti vysazení betablokátorů. REDUCE-AMI neprokázala přínos dlouhodobého podávání betablokátorů na mortalitu nebo nový IM, zatímco ABYSS ukázala vyšší riziko KV hospitalizací po vysazení, zejména u hypertoniků. Výsledky metaanalýz zůstávají rozporuplné. Fixní kombinace betablokátorů s jinými léky může zlepšit adherenci a kardiovaskulární prognózu, zejména u hypertenzních pacientů. Odpověď na otázku trvalé indikace betablokátorů by měly přinést tři probíhající studie (BETAMI, DANBLOCK, REBOOT).
The long-term use of beta-blockers in patients after myocardial infarction (MI) with preserved left ventricular ejection fraction (LVEF) remains controversial. While benefits of beta-blockers are well established in patients with reduced LVEF, there is a lack of randomized clinical trial data for patients with LVEF > 40 %. Two recent studies (REDUCE-AMI and ABYSS) yielded conflicting results regarding the safety of beta-blocker discontinuation. REDUCE-AMI showed no mortality or reinfarction benefit from long-term beta-blocker therapy, while ABYSS indicated increased cardiovascular hospitalizations, especially in hypertensive patients. Results of meta-analyses remain inconclusive. Fixed-dose combinations of beta-blockers with other cardiovascular medications may improve adherence and long-term outcomes, particularly in hypertensive patients. Ongoing randomized trials (BETAMI, DANBLOCK, REBOOT) may provide definitive answers.
- Keywords
- kardiovaskulární riziko,
- MeSH
- Adrenergic beta-Antagonists * pharmacology therapeutic use MeSH
- Heart Failure, Diastolic * drug therapy MeSH
- Myocardial Infarction drug therapy MeSH
- Cardiovascular Diseases etiology MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Treatment Interruption MeSH
- Check Tag
- Humans MeSH
The consumption of drugs used for the treatment of overactive bladder (OAB) in the Czech Republic has increased significantly over the past 10 years, and the number of potential drug interactions of these drugs is undoubtedly also increasing. This review article summarizes the current knowledge on this issue in order to provide treating physicians with the information necessary for optimal pharmacotherapy of OAB, which includes individual selection of drugs with regard to the patient‘s condition and drugs that are being used for other diseases.
- MeSH
- Acetanilides administration & dosage pharmacokinetics adverse effects MeSH
- Adrenergic beta-3 Receptor Agonists administration & dosage pharmacokinetics adverse effects MeSH
- Cholinergic Antagonists administration & dosage pharmacokinetics blood adverse effects MeSH
- Urinary Bladder, Overactive * drug therapy MeSH
- Cytochrome P-450 Enzyme Inhibitors adverse effects MeSH
- Cognitive Dysfunction chemically induced epidemiology MeSH
- Drug Interactions * MeSH
- Humans MeSH
- Risk MeSH
- Aged, 80 and over MeSH
- Solifenacin Succinate administration & dosage adverse effects MeSH
- Arrhythmias, Cardiac chemically induced MeSH
- Statistics as Topic MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Publication type
- Case Reports MeSH
- Review MeSH
