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Patient-reported outcomes such as the Patient Perception of Bladder Condition (PPBC) score are frequently used to characterize overactive bladder syndrome (OAB) patients and their treatment outcomes. However, little information is available on the relationship of such scores to OAB symptoms at the individual patient level.We have performed a post hoc analysis of two large noninterventional studies (n = 1345 and 745) in which patients received propiverine extended release (30 or 45 mg/day) for 12 weeks to determine the strength of nonparametric correlations between PPBC and OAB symptoms at baseline, after treatment and with treatment-associated changes thereof.PPBC was not correlated with age but with episode frequencies of urgency, incontinence, micturitions, and nocturia, but the strength of correlations was only moderate (Spearman rank correlation coefficient 0.2045-0.3553). Similarly moderate correlations were observed after treatment and when changes in PPBC were compared to those of OAB symptoms, although these correlations were somewhat stronger.PPBC is only moderately correlated to OAB symptoms indicating that it characterizes patients beyond what is captured by their symptoms.

Neuropeptide Y (NPY) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [158]) are activated by the endogenous peptides neuropeptide Y, neuropeptide Y-(3-36), peptide YY, PYY-(3-36) and pancreatic polypeptide (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [139]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene [84]. Three-dimensional structures have been determined for subtype active receptors Y1, Y2 and Y4 [211, 114] and inactive antagonist bound Y1 and Y2 receptors [240, 210]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y4 receptor than at the human receptor [62]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [125I]-PYY or [125I]-NPY can be used to label Y1, Y2, Y5 and y6 subtypes non-selectively, while [125I][cPP(1-7), NPY(19-23), Ala31, Aib32, Gln34]hPP may be used to label Y5 receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence).

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197].

ZusammenfassungAuch Jahrzehnte nach der Einführung der 5α-Reduktasehemmer und der α1-Adrenozeptor-Antagonisten ergeben sich praxisrelevante, neue Daten zu deren erwünschten und unerwünschten Wirkungen. Einige der neuen Befunde sind ihrer Natur nach ernst zu nehmen, aber bisher unzureichend abgesichert wie z.B. ein Zusammenhang mit Depressionen oder Demenz. Verschiedene Kombinationsbehandlungen wurden getestet. Dabei war die Kombination der Monotherapie häufig statistisch signifikant überlegen, aber der Unterschied bewegte sich meistens in der Größenordnung von 1 IPSS-Punkt, was Zweifel an der klinischen Relevanz der Beobachtungen im Gruppenmittel lässt. Die neuen Daten ermöglichen eine weiter individualisierte BPS-Behandlung, machen die individuelle Nutzen-Risiko-Abwägung aber komplizierter.

Fenoterol is a β2-adrenoceptor (AR)-selective agonist that is commonly used to investigate relaxation responses mediated by β2-AR in smooth muscle preparations. Some data have questioned this because fenoterol had low potency in the rat urinary bladder when a muscarinic agonist was used as a pre-contraction agent and because some investigators proposed that fenoterol may act in part via β3-AR. We designed the present study to investigate whether fenoterol is a proper pharmacological tool to study β2-AR-mediated relaxation responses in the rat urinary bladder. Firstly, we have compared the effect of pre-contraction agents on fenoterol potency and found that fenoterol potency was about 1.5 log units greater against KCl than carbachol (pEC50 7.19 ± 0.66 and 5.62 ± 1.09 of KCl and of carbachol, respectively). To test the selectivity of fenoterol, we have determined the effects of the β2-AR antagonist ICI 118,551 and the β3-AR antagonist L 748,337 on relaxation responses to fenoterol. While 300 nM L 748,337 had little effect on the potency of fenoterol (pEC50 6.56 ± 0.25 and 6.33 ± 0.61 in the absence and presence of L 748,337, respectively), the relaxation curve for fenoterol was right-shifted in the presence 300 nM ICI 118,551 (pEC50 5.03 ± 0.18). Thus, we conclude that fenoterol is a proper pharmacological tool to assess β2-AR-mediated responses in the rat urinary bladder and most likely in other smooth-muscle preparations containing multiple subtypes of the β-AR.

SamenvattingMuscarine-receptorantagonisten en de β3-agonist mirabegron vormen de basis van de medicamenteuze behandeling van het overactieveblaassyndroom (OAB). De effectiviteit van muscarine-receptorantagonisten en mirabegron is vergelijkbaar en de combinatie solifenacine en mirabegron is minimaal effectiever dan dezelfde middelen als monotherapie. De bijwerkingen van antimuscarinica zijn onder andere een droge mond en obstipatie en die van mirabegron zijn vergelijkbaar met placebo. Weinig patiënten gebruiken deze middelen langdurig vanwege een gebrek aan effectiviteit ervan en vanwege de bijwerkingen. Er lijken op dit moment geen middelen met een nieuw werkingsmechanisme in ontwikkeling te zijn en de kans is klein daar op korte termijn verandering in komt. Omdat OAB een symptoomcomplex is, met mogelijk verschillende onderliggende pathologieën en symptoomcombinaties, is het onwaarschijnlijk dat nieuwe middelen duidelijk effectiever zullen zijn. De belangrijkste prioriteiten voor de toekomst zijn niet alleen de ontdekking van nieuwe therapeutische targets, maar ook identificatie van subgroepen met dezelfde symptomatologie of onderliggende pathologie. Biomarkers zouden een rol kunnen spelen bij deze zoektocht.

Functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS), are frequently handled by self-management with over-the-counter (OTC) products such as hyoscine butylbromide (HBB), alone or in combination with paracetamol, and natural products such as peppermint oil. To obtain real-world information, we have performed an anonymous pharmacy-based patient survey among 1686 users of HBB, HBB + paracetamol, and peppermint oil. Based on the distinct but overlapping indications for the three OTC products, multiple logistic regression was applied to compare them in users reporting gastrointestinal cramps and pain, bloating, flatulence, or IBS as cardinal symptoms. All three treatments reduced symptoms and associated impairments of work/daily chores, leisure activities, and sleep by approximately 50%. Based on the four cardinal symptoms and the four dependent continuous variables of interest (change in intensity of symptoms and of the three impairment domains) a total of 16 logistic regression models were applied. HBB, HBB + paracetamol, and peppermint oil had similar reported overall effectiveness in those models. Gender, age, baseline symptom severity, and impairment in one of three domains had small and inconsistent effects on perceived treatment success. We provide evidence that HBB, HBB + paracetamol, and peppermint oil have comparable effectiveness in their approved indications under real-world conditions in an OTC setting.

βTwo out of four studies have reported that the 64Arg allele was found more frequently in subjects with OAB than in healthy controls. A large study in a highly selective population (men undergoing prostatectomy for cancer treatment) did not confirm this. On the other hand, studies examining symptom severity typically found little difference between 64Arg and 64Trp carriers. In vitro studies with endogenously expressed βThe overall evidence points to carriers of the 64Arg genotype expressing fewer and/or hypofunctional β

Aim To describe the trend in the prevalence of statistical inference in three influential clinical pharmacology journals METHODS: We applied a computer-based algorithm to abstracts of three clinical pharmacology journals published in 1976 to 2016 to identify statistical inference and its subtypes. Furthermore, we manually reviewed a random sample of 300 articles to access algorithm's performance in finding statistical inference in abstracts and as a screening tool for presence and absence of statistical inference in full text. Result The algorithm identified 59% (13,375/22,516 [mid p 95% CI, 59%-60%]) article abstracts with statistical inference. The percentage of abstracts with statistical inference was similar in 1976 and 2016, 48% (179/377 [mid p 95%CI, 42%-52%]) versus 49% (386/791 [mid p 95%CI, 45%-52%]). Statistical reporting pattern varied among journals. Among abstracts containing any statistical inference in the publications from 1976 to 2016 null-hypothesis significance testing was the most prevalent reported statistical inference. The algorithm had high sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for finding statistical inferences in abstract. While PPV for predicting the statistical inference in full text (including abstract, text, tables and figures) was high, NPV was low. Conclusion Despite journal's editorials and statistical associations' guidelines, most authors focused on testing rather than estimation. In future, a better statistical reporting might be ensured by improving the statistical knowledge of authors and an addition of statistical guides to journals' instruction to authors to the extent that editors would like their statistical inference preferences to be incorporated into submitted manuscripts.

Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) improve outcomes in heart failure patients and animal models thereof. Therefore, we have investigated the effects of EMPA on in vivo cardiac function (pressure-volume loop analysis) and β-AR-mediated contractile responses (papillary strips) in streptozotocin (STZ; 40 mg/kg, i.p.)-induced diabes in male Sprague Dawley rats (control, EMPA-treated control, diabetic, EMPA-treated diabetic) in a design reflecting late-onset treatment. 13-16 weeks after STZ injection treatment with a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contration and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some but not all parameters. Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes is manifest. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.

While the COVID-19 pandemic also affected the work of regulatory authorities, the US Food and Drug Administration approved a total of 53 new drugs in 2020, one of the highest numbers in the past decades. Most newly approved drugs related to oncology (34%) and neurology (15%). We discuss these new drugs by level of innovation they provide, i.e., first to treat a condition, first using a novel mechanisms of action, and “others.” Six drugs were first in indication, 15 first using a novel mechanism of action, and 32 other. This includes many drugs for the treatment of orphan indications and some for the treatment of tropical diseases previously neglected for commercial reasons. Small molecules continue to dominate new drug approvals, followed by antibodies. Of note, newly approved drugs also included small-interfering RNAs and antisense oligonucleotides. These data show that the trend for declines in drug discovery and development has clearly been broken.

Aims Combination therapy of 5α‐reductase inhibitor and α‐blocker is a guideline‐endorsed therapeutic approach for patients with moderate‐to‐severe lower urinary tract symptoms or benign prostatic hyperplasia (LUTS/BPH) who are at risk of disease progression. We aimed to disentangle the contribution of clinical and demographic baseline characteristics affecting the risk of acute urinary retention or BPH‐related surgery (AUR/S) from the effect of treatment with drugs showing symptomatic and disease‐modifying properties. Methods A time‐to‐event model was developed using pooled data from patients (n = 10 238) enrolled into six clinical studies receiving placebo, tamsulosin, dutasteride or tamsulosin‐dutasteride combination therapy. A parametric hazard function was used to describe the time to first AUR/S. Covariate model building included the assessment of relevant clinical and demographic factors on baseline hazard. Predictive performance was evaluated by graphical and statistical methods. Results An exponential hazard model best described the time to first AUR/S in this group of patients. Baseline International Prostate Symptom Score, prostate‐specific antigen, prostate volume and maximum urine flow were identified as covariates with hazard ratio estimates of 1.04, 1.08, 1.01 and 0.91, respectively. Dutasteride monotherapy and tamsulosin‐dutasteride combination therapy resulted in a significant reduction in the baseline hazard (56.8% and 66.4%, respectively). By contrast, the effect of tamsulosin did not differ from placebo. Conclusions Our analysis showed the implications of disease‐modifying properties of dutasteride and tamsulosin‐dutasteride combination therapy for the risk of AUR/S. It also elucidated the contribution of different baseline characteristics to the risk of these events. The use of tamsulosin monotherapy (symptomatic treatment) has no impact on individual long‐term risk., Visual predictive checks. The line shows observed survival over time, whereas the shaded area describes the model predicted 95% CI for the survival. The different slopes of the survival curves for dutasteride monotherapy and combination therapy (relative to placebo) reflect the disease‐modifying properties of the intervention.

Purpose To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. Methods Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1–24 months). AUR/S incidence was described by Kaplan–Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. Results Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p Conclusions Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.

Dysfunction of the lower urinary tract (LUT) including urinary bladder and urethra (and prostate in men) is one of the most frequent complications of diabetes and can manifest as overactive bladder, underactive bladder, urinary incontinence, and as aggravated symptoms of benign prostate hyperplasia. We have performed a selective literature search to review existing evidence on efficacy of classic medications for the treatment of LUT dysfunction in diabetic patients and animals, i.e., α

Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting.Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution.The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials.These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.Unmet expectations are a major reason why patients with overactive bladder syndrome discontinue treatment. To enable evidence-based counselling of patients on realistic expectations, we have determined the chance that patients with overactive bladder become free of urgency, incontinence, voiding frequency, and nocturia. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. The probability of becoming symptom-free was largest for incontinence and voiding frequency (about 50%), but lesser for urgency and nocturia (about 20%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.

Der multimorbide altere Mann ist in Praxis und klinischem Alltag eine Herausforderung, weil haufig von Beschwerden des unteren Harntraktes („lower urinary tract symptoms“, LUTS) und dem altersassoziierten benignen Prostatasyndrom (BPS) betroffen. Um mogliche Risiken bei Diagnostik, Therapie und Beratung fruhzeitig zu erkennen, ist ein Screening auf Funktionsdefizite oder Risikofaktoren mit standardisierten Verfahren hilfreich. Ein Eingangsscreening mit nachfolgendem Assessment der Alltagsfahigkeiten durch Barthel-Index, „Timed up and go“-Test und einem kognitiven Test sind anzuraten. Ein „Frailty“-Syndrom ist als geriatrisches Syndrom bei zeitnaher Diagnose im pra-, peri- und postoperativen Management entsprechend zu Berucksichtigung, da es auf eine erhohte Morbiditat und Mortalitat hinweisen kann. Bei der medikamentosen Therapie sind Begleitmedikation und deren Wechselwirkung insbesondere im Cytochromsystem, eine bestehende Multimorbiditat und die Therapieadharenz zu berucksichtigen. Kombinationstherapien erganzen sich moglicherweise und helfen bei der Zeit bis zu einer operativen Intervention. Nicht-invasive Verfahren zur Reduktion des Prostatavolumens ohne Narkose konnen bei individueller Planung und Berucksichtigung der Risikofaktoren auch bei alteren multimorbiden Patienten eine Therapieoption darstellen und bis zu 70 % Symptomfreiheit erreichen. Jedoch gibt es derzeit keinen Goldstandard fur diese vulnerable Patientengruppe. Anzahl der Medikamente und Begleiterkrankungen und hoherer Hilfebedarf stellen per se Risikofaktoren fur ein unbefriedigendes Ergebnis nach transurethraler Resektion der Prostata (TURP) oder Laservaporisation dar. Minimal-invasive Methoden, die ohne Allgemeinnarkose durchgefuhrt werden konnen, bieten sich fur geriatrische Patienten zunehmend an, v. a. fur jene mit rezidivierenden Retentionen. Studien mit dem Rezūm®-System (NxThera Inc., Maple Grove, MN, USA) und UroLift® (NeoTract Inc., Pleasanton, CA, USA) zeigen, dass etwa 70 % der Patienten von einem Dauerkatheter befreit werden konnen.

Introduction Ambroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period. Methods An open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18–45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1–5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0–24) and maximum plasma level (Cmax SS). Results Twenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0–24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h). Conclusions ER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions. ClinicalTrials.gov identifier NCT02036775. Electronic supplementary material The online version of this article (10.1007/s41030-020-00116-7) contains supplementary material, which is available to authorized users., Plain Language Summary Ambroxol is used to relieve the symptoms of respiratory conditions in which abnormal mucus secretion is a problem, including the common cold, acute and chronic bronchitis, and chronic obstructive pulmonary disease. Different formulations of ambroxol are available, including tablets and effervescent tablets that release the drug as soon as they are digested, but need to be taken twice a day, or extended release (retard) capsules that release the drug slowly over 24 h and can be taken once a day. This randomized, three-period, six-sequence crossover study in 24 healthy volunteers compared the pharmacokinetics of three formulations of ambroxol: tablets, effervescent tablets, and retard capsules. The amount of drug in the bloodstream over 24 h was similar with all three formulations, but (as expected) the time to reach peak plasma concentration was longer with the retard capsules than both forms of tablet. These results show that people who take ambroxol for respiratory conditions will receive the same amount of ambroxol whether they take retard capsules, standard tablets, or effervescent tablets. Electronic supplementary material The online version of this article (10.1007/s41030-020-00116-7) contains supplementary material, which is available to authorized users.

Dysfunction of the lower urinary tract (LUT) including urinary bladder and urethra (and prostate in men) is one of the most frequent complications of diabetes and can manifest as overactive bladder, underactive bladder, urinary incontinence, and as aggravated symptoms of benign prostate hyperplasia. We have performed a selective literature search to review existing evidence on efficacy of classic medications for the treatment of LUT dysfunction in diabetic patients and animals, i.e., α1-adrenoceptor and muscarinic receptor antagonists, β3-adrenoceptor agonists, and phosphodiesterase type 5 inhibitors. Generally, these agents appear to have comparable efficacy in patients and/or animals with and without diabetes. We also review effects of antidiabetic medications on LUT function. Such studies have largely been performed in animal models. In the streptozotocin-induced models of type 1 diabetes, insulin can prevent and reverse alterations of morphology, function, and gene expression patterns in bladder and prostate. Typical medications for the treatment of type 2 diabetes have been studied less often, and the reported findings are not yet sufficient to derive robust conclusions. Thereafter, we review animal studies with emerging medications perhaps targeting diabetes-associated LUT dysfunction. Data with myoinositol, daidzein, and with compounds that target oxidative stress, inflammation, Rac1, nerve growth factor, angiotensin II receptor, serotonin receptor, adenosine receptor, and soluble guanylyl cyclase are not conclusive yet, but some hold promise as potential treatments. Finally, we review nonpharmacological interventions in diabetic bladder dysfunction. These approaches are relatively new and give promising results in preclinical studies. In conclusion, the insulin data in rodent models of type 1 diabetes suggest that diabetes-associated LUT function can be mostly or partially reversed. However, we propose that considerable additional experimental and clinical studies are needed to target diabetes itself or pathophysiological changes induced by chronic hyperglycemia for the treatment of diabetic uropathy.

La nivel mondial, migrena este una dintre principalele cauze ale limitărilor vieții de zi cu zi și/sau incapacității de a munci. 50% dintre cei care suferă de aceasta nu au consultat niciodată un medic, apelând în schimb la automedicație. O opinie consensuală a experților recent publicată a investigat mai în detaliu acest fenomen și l-a asociat unui concept științific denumit „migrena secolului 21”.

El dolor de cabeza es una de las principales causas de limitación en la vida cotidiana y/o de incapacidad laboral en todo el mundo. El 50% de los afectados nunca acuden a un médico, sino que recurren a la automedicación. Un consenso de expertos publicado recientemente ha investigado este fenómeno con más detalle y lo ha asociado a un concepto científico denominado «dolor de cabeza del siglo XXI».