BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

• Klíčová slova
• macitentan, pulmonary arterial hypertension, randomized controlled trial, single-tablet (fixed-dose) combination therapy, tadalafil,
• MeSH
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• plicní arteriální hypertenze * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH

The aim of this study was to investigate the molecular structures of tadalafil solid dispersions prepared by different techniques and further to relate them to surface free energy information indicating the final amorphousness of the product. Thus, we tried to complement the existing knowledge of solid dispersion formation. Poorly water-soluble tadalafil was combined with different polymers, i.e. Kollidon® 12 PF, Kollidon® VA 64 and Soluplus®, to form model systems. To assess the extent of drug-polymer miscibility, we studied model solid dispersion surface energy using inverse gas chromatography and phase micro-structure using confocal Raman microscopy. The selection of the preparation method was found to play a crucial role in the molecular arrangement of the incorporated drug and the polymer in resulting solid dispersion. Our results showed that a lower surface free energy indicated the formation of a more homogeneous solid dispersion. Conversely, a higher surface free energy corresponded to the heterogeneous systems containing tadalafil amorphous clusters that were captured by Raman mapping. Thus, we successfully introduced a novel evaluation approach of the drug molecular arrangement in solid dispersions that is especially useful for examining the miscibility of the components when the conventional characterizing techniques are inconclusive or yield variable results.

• Klíčová slova
• Drug-polymer interaction, Inverse gas chromatography, Molecular dispersion, Raman mapping, Structure of solid dispersions, Surface free energy,
• MeSH
• chromatografie plynová MeSH
• polymery * chemie   MeSH
• povidon * chemie   MeSH
• rozpustnost MeSH
• tadalafil chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• polymery * MeSH
• povidon * MeSH
• tadalafil MeSH

AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects. METHODS: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. CONCLUSION: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.

• Klíčová slova
• bioequivalence, fixed-dose combination, macitentan, pulmonary arterial hypertension, tadalafil,
• MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• hypoglykemika * farmakologie   MeSH
• klinické křížové studie MeSH
• léky s prodlouženým účinkem MeSH
• lidé středního věku MeSH
• lidé MeSH
• metformin * MeSH
• mladiství MeSH
• mladý dospělý MeSH
• plocha pod křivkou MeSH
• pyrimidiny * farmakologie   MeSH
• sulfonamidy * farmakologie   MeSH
• tablety MeSH
• tadalafil * farmakologie   MeSH
• terapeutická ekvivalence MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fixní kombinace léků MeSH
• hypoglykemika * MeSH
• léky s prodlouženým účinkem MeSH
• macitentan MeSH Prohlížeč
• metformin * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil * MeSH

OBJECTIVE: Tadalafil (Cialis) is an inhibitor of phosphodiesterase type 5, which mediates relaxation of vascular smooth muscle in the corpus cavernosum thus facilitating erection. The purpose of this multicentre, randomized, double-blind, parallel group, placebo-controlled study was to evaluate efficacy and treatment satisfaction of on-demand Cialis in men with mild-to-severe erectile dysfunction (ED). METHODS: Following a 4-week treatment-free run in period, patients stratified into three severity groups by the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score were randomized to receive either placebo or Cialis 20 mg taken on demand over a 12-week period. Efficacy endpoints were change from baseline in IIEF EF domain scores, responses to Sexual Encounter Profile diary (SEP) questions, and responses to the Global Assessment Questions (GAQ). Treatment satisfaction was evaluated using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire in two of seven participating countries where validated translations were available. RESULTS: Of the 443 men who entered the trial, 409 (mean age, 52 years) formed the intent-to-treat population. Mean baseline demographics and ED severity measures were balanced between treatment groups except for a higher percentage of patients naïve to sildenafil in the tadalafil group compared to placebo (50% versus 36%). The percentage of patients in each IIEF EF severity class (mild, moderate and severe) was 47%, 30% and 23% for placebo patients and 48%, 29% and 23% for tadalafil patients, respectively. Tadalafil was significantly superior to placebo on all primary efficacy measures (IIEF EF domain scores, SEP15, GAQ1; p < 0.001); notably 64% of tadalafil patients achieved a normal IIEF EF domain score at endpoint compared to 16% of placebo patients (p < 0.001). Of the 185 patients completing the EDITS questionnaire (137 receiving Cialis and 48 receiving placebo), tadalafil-treated patients had a median EDITS score of 84 (95%CI 80, 86), which was significantly higher than the median score for placebo-treated patients of 41 (95%CI 32, 59; p < 0.001; Wilcoxon test). The proportion of patients satisfied with treatment (defined as final EDITS score greater than 50) was 87% for the tadalafil-treated group and 46% for the placebo-treated group (p < 0.001; exact test). Adverse events were significantly more common with tadalafil than placebo (p < 0.01) and included primarily headache (7.2% versus 1.9%) and flushing (4.6% versus 0%). One patient discontinued tadalafil treatment due to back pain. CONCLUSION: In men with mild-to-severe ED, tadalafil 20 mg significantly improves erectile function, demonstrates superior treatment satisfaction relative to placebo, and is well tolerated. This is the first study to yield efficacy data on tadalafil in an Eastern European population of men with erectile dysfunction, and the first to measure satisfaction with the EDITS questionnaire in any study population of men with this condition using tadalafil.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• erektilní dysfunkce farmakoterapie   MeSH
• karboliny terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spokojenost pacientů MeSH
• stupeň závažnosti nemoci MeSH
• tadalafil MeSH
• vazodilatancia terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• karboliny MeSH
• tadalafil MeSH
• vazodilatancia MeSH

The aims of this study were to investigate how the release of tadalafil is influenced by two grades of polyvinylpyrrolidone (Kollidon® 12 PF and Kollidon® VA 64) and various methods of preparing solid dispersions (solvent evaporation, spray drying and hot-melt extrusion). Tadalafil is poorly water-soluble and its high melting point makes it very sensitive to the solid dispersion preparation method. Therefore, the objectives were to make a comparative evaluation among different solid dispersions and to assess the effect of the physicochemical nature of solid dispersions on the drug release profile with respect to the erosion-diffusion mechanism. The solid dispersions were evaluated for dissolution profiles, XRD, SEM, FT-IR, DSC, and solubility or stability studies. It was found that tadalafil release was influenced by polymer molecular weight. Therefore, solid dispersions containing Kollidon® 12 PF showed a faster dissolution rate compared to Kollidon® VA 64. Tadalafil was released from solid dispersions containing Kollidon® 12 PF because of the combination of erosion and diffusion mechanisms. The diffusion mechanisms were predominant in the initial phase of the experiment and the slow erosion was dissolution-controlling at the second stage of the dissolution. On the contrary, the tadalafil release rate from solid dispersions containing Kollidon® VA 64 was controlled solely by the erosion mechanism.

• Klíčová slova
• Weibull dissolution model, Wood’s apparatus, dissolution rate, intrinsic dissolution rate, solid dispersion, tadalafil,
• Publikační typ
• časopisecké články MeSH

The production and distribution of counterfeit pharmaceuticals present a serious problem worldwide. This is true especially in case of phosphodiesterase type 5 inhibitors for treating erectile dysfunction, where consumers often prefer buying them anonymously from unverified sources. In this study, genuine and counterfeit Cialis® 20 mg tablets were analyzed by electronic circular dichroism, vibrational circular dichroism, and infrared spectroscopy. The characteristic spectral patterns were identified by comparison with the spectra of tadalafil standard as an active pharmaceutical ingredient, and its presence was confirmed in all samples. The amount of tadalafil, however, was markedly lower in the case of counterfeit tablet as the observed band intensities were considerably lower. No other significant differences between the genuine and counterfeit tablets were revealed. Ab initio density functional theory calculations provided a detailed description of the stable conformers of tadalafil in a solution and enabled thorough interpretation of the experimental spectra.

• Klíčová slova
• Cialis®, ab initio calculations, circular dichroism, conformation, structure,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The dubious online market in phosphodiesterase type 5 inhibitors is growing on a global scale. Counterfeit medical products can represent health issues for the user and cause medical mistrust. Within this work, genuine Cialis containing the active pharmaceutical ingredient (API) tadalafil, its generics available in the Czech Republic and the Cialis tablets from questionable online pharmacies were analysed. The methods of infra-red and Raman spectroscopy were used for the identification of the counterfeit tablets and for the verification of their API and excipients. All 9 tablets from online pharmacies were counterfeit with 2 of them even containing a different API (sildenafil, vardenafil). In addition, Raman mapping was used to determine the API and excipients' distribution and, in combination with multivariate data analysis, to separate similar tablets in clusters and to identify the outliers. Scanning electron microscopy of the samples revealed that the process of a wet granulation of micronized API was used during the formulation of the tablets. This comprehensive approach of analysis can be used for advanced exploration of the dubious samples of various medical products.

• Klíčová slova
• Cialis, Counterfeit medical products, Raman spectroscopy, Tadalafil, Vibrational spectroscopy,
• MeSH
• důvěra * MeSH
• padělané léky * MeSH
• Ramanova spektroskopie MeSH
• tablety MeSH
• tadalafil MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• padělané léky * MeSH
• tablety MeSH
• tadalafil MeSH

Although the fragmentation of the active pharmaceutical ingredient (API) is a phenomenon that is mentioned in many literature sources, no well-suited analytical tools for its investigation are currently known. We used the hot-stage microscopy method, already presented in our previous work, and studied the real fragmentation of the tadalafil particles in model tablets which were prepared under different compaction pressures. The morphology, spectral imaging and evaluation of plastic and elastic energies were also analyzed to support the hot-stage method. The prepared blend of tadalafil and excipients was compacted under a several forces from 5 to 35 kN to reveal the trend of fragmentation. The exact fragmentation of tadalafil with increased compaction pressure was revealed by the hot-stage microscopic method and it was in good agreement with plastic and elastic energies. Conversely, spectral imaging, which is being used for this analysis, was considered to be inaccurate methodology as mainly agglomerates, not individual particles, were measured. The availability of the hot-stage microscopic method equips pharmaceutical scientists with an in vitro assessment technique that will more reliably determine the fragmentation of the API in finished tablets and the behavior of the particles when compacted.

• Klíčová slova
• API, fragmentation, hot-stage microscopy, particle size, spectral imaging,
• MeSH
• farmaceutická technologie metody   MeSH
• mikroskopie elektronová rastrovací metody   MeSH
• tablety MeSH
• tadalafil analýza   chemie   MeSH
• velikost částic MeSH
• vysoká teplota * MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• tablety MeSH
• tadalafil MeSH

UNLABELLED: The authors present results of a clinical study examining therapeutic effects of PDE5 inhibitors in the management of male erectile dysfunction following spinal cord injuries. The study was prospective, non-invasive, observational. AIM: The aim of the study was to determine efficacy and safety of tadalafil in the treatment of male erectile dysfunction following spinal cord injuries and to assess one-year treatment results. MATERIAL AND METHODS: 16 males, the mean age of 33 years, participated in a four-week assessment of tadalafil efficacy and safety. A paraplegic couple received 8 tablets of tadalafil 20 mg and recommendation of sexual intercourse twice a week. The males recorded the tablet intake in a "Diary". The following questionnaire scores were used in the assessment prior and after the four-week treatment period: IIEF-5 (International Index of Erectile Function), GAO (Global Assessment Question), SEP 2 a 3 (Sexual Encountner Profile, questions 2,3). A non-parametric test was used for statistical evaluation. RESULTS: In 94% of the males, the treatment resulted in improved erection quality (GAQ) and there was statistically significant improvement in ability for penis emission to vagina (SEP 2, p = 0.005). In 69% of the young disabled males, tadalafil-mediated erection was sufficient to perform a satisfactory intercourse (SEP3, p = 0.001). Based on the IIEF-5 questionnaire data, the erectile function score improvement was statistically significant, compared to that prior to therapy (p = 0.001). 75% of the paralyzed used the benefit of the long-acting PDE5 inhibitor and repeated the sexual intercourse within 36 hours of its intake. Undesirable effects were reported in 3 out of the 16 subjects and a single patient discontinued the treatment due to the side effects. 8 out of the 16 males (50%) continued the tadalafil treatment after one year of medication. The authors conclude that tadalafil treatment of male erectile dysfunction following spinal cord injuries is safe and effective and is well tolerated for over a year.

• MeSH
• dospělí MeSH
• erektilní dysfunkce farmakoterapie   etiologie   MeSH
• inhibitory fosfodiesteras terapeutické užití   MeSH
• karboliny terapeutické užití   MeSH
• koitus MeSH
• lidé středního věku MeSH
• lidé MeSH
• poranění míchy komplikace   MeSH
• tadalafil MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• inhibitory fosfodiesteras MeSH
• karboliny MeSH
• tadalafil MeSH

UV-induced fingerprint spectroscopy (UV-IFS), a new tool in a toolbox of analytical methods, is a powerful technique registering molecule-specific changes of fluorescence induced by UV irradiation. Analysis of fluorescence spectra of a sample prior and after UV irradiation enables an identification of a sample of a drug or pharmaceutics based on a comparison with signals of known standards. Moreover, UV-IFS uncovers the presence of undesired contaminations or intentional changes of the composition. Herein, we employ UV-IFS for qualitative as well as quantitative analysis of common medicines including analgesic/antipyretic (Acetaminophen), antihistamines (Loratadine and Desloratadine), and phosphodiesterase type 5 inhibitors (Tadalafil and Sildenafil citrate). UV irradiation (λem = 254 nm) for 2 - 10 min induced significant changes of fluorescence of the studied samples and according to the unique patterns, the quality and quantity were evaluated. Limits of detection for individual active ingredients were calculated as follows: Acetaminophen = 0.1 µg·mL-1, Loratadine = 0.1 μg·mL-1, Desloratadine = 0.01 µg·mL-1, Tadalafil = 0.04 µg·mL-1 and Sildenafil = 0.2 µg·mL-1. Moreover, genuine and fake CIALIS, VIAGRA and KAMAGRA tablets were reliably identified.

• Klíčová slova
• Counterfeiting, Fingerprint, Irradiation, Medicines, Photochemistry,
• MeSH
• loratadin * MeSH
• paracetamol * MeSH
• sildenafil citrát MeSH
• spektrální analýza MeSH
• tablety MeSH
• tadalafil MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• desloratadine MeSH Prohlížeč
• loratadin * MeSH
• paracetamol * MeSH
• sildenafil citrát MeSH
• tablety MeSH
• tadalafil MeSH