Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6-10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.
- Publikační typ
- časopisecké články MeSH
This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed drug. Three comparative bioavailability studies conducted in healthy subjects provided data from flurbiprofen 8.75 mg formulations, including spray solution, spray gel, lozenges, and granules. A parallel interstudy comparison was made of PK parameters, including partial AUCs (pAUCs), using an ANOVA model with the calculation of 90% confidence intervals (CI) for the differences between least squares (LS) means for each of the test groups versus the respective reference groups. All three studies showed bioequivalence for the respective product comparisons. The interstudy comparison showed a slower rate of absorption for granules compared to spray solution (reference) based on Tmax, Cmax, and pAUCs for 1 h and 2 h. When AUC0.25h and AUC0.5h were considered, slower rates of absorption were also seen for lozenges and spray gel. The differences correlated with the reported time of onset of action, which is faster for the spray solution (20 min) compared to lozenges (26 min) and granules (30 min). These pAUCs provide useful data that allow for the discrimination between formulations. Moreover, the pAUC values represent <5% of the total AUC, suggesting that the early onset of pain relief is a response to immediate local absorption at the site of action rather than a systemic effect.
- Publikační typ
- časopisecké články MeSH
2',3,4'-trihydroxychalcone is a newly synthesized substance with antioxidant properties. The aim of this pilot study was to monitor its effect during heart perfusion in the laboratory rat. The study included two groups of animals of the same number (n = 10). The 1st group was pretreated with chalcone in a dose of 10 mg/kg p.o. during 15 days. The 2nd group was a placebo one. After i.p. administration of a heparin injection of 500 IU dose, the hearts were excised and perfused (a modified Langendorf's method). Working schedule: stabilization/ischaemia/reperfusion proceed at intervals of 20/30/60 min. Monitored parameters in the isolated heart: left ventricle pressure (LVP), end-diastolic pressure (LVEDP), contractility (+dP/dtmax). The treated hearts showed improved postischemic recovery, reaching LVP values of 101 ± 4% at the end of reperfusion, the placebo ones only 42 ± 6%. In the placebo hearts LVEDP increased from 10.0 ± 0.5 mm Hg to 32 ±5 mm Hg after, in treated animals only about 10.5 ± 2 mm Hg. The treated hearts improved +dP/dtmax recovery during reperfusion to 92 ± 7 %. These values were significantly greater than those obtained from the placebo hearts. We conclude that the administration of 2',3,4'-?-trihydroxychalcone in laboratory rats has a cardioprotective potential against ischemia-reperfusion induced injury.
2',3,4'-trihydroxychalcone is a newly synthesized substance with antioxidant properties. The aim of this pilot study was to monitor its effect during heart perfusion in the laboratory rat. The study included two groups of animals of the same number (n = 10). The 1st group was pretreated with chalcone in a dose of 10 mg/kg p.o. during 15 days. The 2nd group was a placebo one. After i.p. administration of a heparin injection of 500 IU dose, the hearts were excised and perfused (a modified Langendorf's method). Working schedule: stabilization/ischaemia/reperfusion proceed at intervals of 20/30/60 min. Monitored parameters in the isolated heart: left ventricle pressure (LVP), end-diastolic pressure (LVEDP), contractility (+dP/dtmax). The treated hearts showed improved postischemic recovery, reaching LVP values of 101 ± 4% at the end of reperfusion, the placebo ones only 42 ± 6%. In the placebo hearts LVEDP increased from 10.0 ± 0.5 mm Hg to 32 ±5 mm Hg after, in treated animals only about 10.5 ± 2 mm Hg. The treated hearts improved +dP/dtmax recovery during reperfusion to 92 ± 7 %. These values were significantly greater than those obtained from the placebo hearts. We conclude that the administration of 2',3,4'-?-trihydroxychalcone in laboratory rats has a cardioprotective potential against ischemia-reperfusion induced injury.
Chřipkový virus A je známý svojí schopností genetických změn, způsobených genetickým driftem nebo posunem. Ve 20. století tak vznikly tři drtivé pandemie, v roce 1918, 1957 a 1968, způsobené H1N1 (španělská chřipka), H2N2 (asijská chřipka) a H3N2 (Hong Kong chřipka). Od března 2009, kdy došlo k propuknutí infekce novým kmenem chřipky A (H1N1) u lidí, nastal zvýšený zájem a obavy ze vzniku pandemie. Nový typ chřipky je vnímavý na neuraminidazové inhibitory oseltamivir a zanamivir, je ale rezistentní vůči amantadinu a rimantadinu. Oseltamivir je perorálně podávané antivirotikum, dosahující vysokých systémových hladin. Zanamivir je určen pro inhalační terapii.
Influenza A virus is well known for its capability for genetic changes either through antigen drift or antigen shift. In the 20th century alone, there were three overwhelming pandemics, in 1918, 1957 and 1968, caused by H1N1 (Spanish flu), H2N2 (Asian flu) and H3N2 (Hong Kong flu), respectively. Since March 2009, the outbreak of a new strain of influenza A (H1N1) virus infection in humans has raised increasing concerns of the risk of a global flu epidemic. The new influenza A (H1N1) viruses are currently susceptible to the neuraminidase inhibitors (NAIs) oseltamivir and zanamivir but resistant to amantadine or rimantadine (adamantane or M2 inhibitor drugs). Oseltamivir is administered orally and gives higher systemic level. Zanamivir is delivered by oral inhalation with low systemic absorption.
- Klíčová slova
- Tamiflu, Relenza,
- MeSH
- amantadin farmakologie škodlivé účinky terapeutické užití MeSH
- antibakteriální látky terapeutické užití MeSH
- antivirové látky aplikace a dávkování farmakologie klasifikace MeSH
- chřipka lidská diagnóza etiologie farmakoterapie MeSH
- epidemický výskyt choroby prevence a kontrola MeSH
- epidemiologické studie MeSH
- hodnocení rizik MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- Illicium MeSH
- lidé MeSH
- oseltamivir aplikace a dávkování farmakologie terapeutické užití MeSH
- oxygenoterapie metody využití MeSH
- primární prevence metody normy zákonodárství a právo MeSH
- rimantadin aplikace a dávkování farmakologie terapeutické užití MeSH
- vakcíny proti chřipce aplikace a dávkování terapeutické užití MeSH
- virus chřipky A, podtyp H1N1 imunologie patogenita účinky léků MeSH
- zanamivir aplikace a dávkování farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- Alendros,
- MeSH
- alendronát MeSH
- Evropská unie MeSH
- hodnocení léčiv MeSH
- schvalování léčiv MeSH
- zákonodárství lékové MeSH
