Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications.
A phase I, open-label, single-dose, pharmacokinetic study.
London, Ontario, Canada.
Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68).
Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice.
Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0 - 8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice.
Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.

Calcium channel blockers may ameliorate the decline in renal function caused by calcineurin inhibitors in lung transplantation (LTX) recipients. We hypothesized that pre-operative and 12-week post-operative treatment with the calcium channel blocker felodipine would reduce the decline in glomerular filtration rate (GFR).
In this prospective, randomized, double-blind trial, 39 LTX recipients were transplanted and received placebo (n = 19; GFR, 102 ml/min/1.73 m2 [range, 91-113 ml/min/1.73 m2]) or felodipine (n = 20, GFR, 96 ml/min/1.73 m2 [range, 88-104 ml/min/1.73 m2]). Pre-operative treatment was titrated post-operatively to 10 mg or the maximum tolerable dose. The primary end-point was the change in GFR using Cr-51-labeled EDTA from LTX to 12 weeks thereafter, and follow-up was 52 weeks.
The treatment group showed an absolute mean decline in GFR of 31 ml/min/1.73 m2 (95% CI: -40 to 22 ml/min/1.73 m2), whereas that of the placebo group was 48 ml/min/1.73 m2 (95% confidence interval [CI]: -56 to 40 ml/min/1.73 m2). Thus, the difference between groups at 12 weeks was 17 ml/min/1.73 m2 (95% CI: 4-29 ml/min/1.73 m2; p = 0.01). Half of the patients were unable to complete the 3-month primary follow-up, and the analysis includes these patients by intention-to-treat. After 52 weeks (40 weeks after termination of treatment), the treatment effect was maintained at 12 ml/min/1.73 m2 (95% CI: 0-24 ml/min/1.73 m2, p = 0.05). The number of days with registered hypotension was significantly higher in the felodipine group than in the placebo group (39 days vs 13 days, rate ratio: 2.9 [95% CI: 1.5-5.3]).
Use of felodipine in select patients was associated with greater preservation in renal function early (90 days) after LTX. The observed benefits were attenuated by 1 year, although trends in better renal function were noted.

Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution-digestion-permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis. The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.

OBJECTIVE: The aim of present study was to develop a simple, rapid, selective, sensitive and robust reverse phase high performance liquid chromatographic method for quantification of felodipine in rabbit plasma at the wavelength of 360nm.
METHODS: Protein was precipitated from rabbit plasma sample by addition of acetonitrile as a vehicle. An isocratic elution of samples was performed on capcell pak C8 DD S5 column (4.6mm×250mm particle size 5μm) column with mobile phase consisting 5mM Phosphate Buffer (pH 4.8 adjusted with dilute ortho-phosphoric acid solution): acetonitrile (25:75:v/v) delivered at flow rate 1.0mLmin-1.
RESULTS: A good linear response was achieved over the range of 0.25-20.00μgmL-1. LODs and LOQs for felodipine were found to be 0.055 and 0.201μgmL-1, respectively. The method was quantitatively evaluated in terms of linearity, precision, accuracy (recovery), selectivity robustness and stability study as per standard guidelines. The validated RP-HPLC method was successfully applied for the bioavailability studies of felodipine. The pharmacokinetic parameters were calculated for all the investigated drugs in rabbit after single-dose administrations of pure drug and formulation of felodipine. Finally, the obtained results for the application of the proposed RP-HPLC method proved its efficiency to be applied to the therapeutic drug monitoring (TDM) and bioequivalence (BE) studies.
CONCLUSIONS: Thus, developed method is simple, convenient and suitable for the analysis of felodipine in bulk and pharmaceutical formulations.

In this study, a new cocrystal of felodipine (Fel) and glutaric acid (Glu) with a high dissolution rate was developed using the solvent ultrasonic method. The prepared cocrystal was characterized using X-ray powder diffraction, differential scanning calorimetry, thermogravimetric (TG) analysis, and infrared (IR) spectroscopy. To provide basic information about the optimization of pharmaceutical preparations of Fel-based cocrystals, this work investigated the thermal decomposition kinetics of the Fel-Glu cocrystal through non-isothermal thermogravimetry. Density functional theory (DFT) simulations were also performed on the Fel monomer and the trimolecular cocrystal compound for exploring the mechanisms underlying hydrogen bonding formation and thermal decomposition. Combined results of IR spectroscopy and DFT simulation verified that the Fel-Glu cocrystal formed via the NH⋯OC and CO⋯HO hydrogen bonds between Fel and Glu at the ratio of 1:2. The TG/derivative TG curves indicated that the thermal decomposition of the Fel-Glu cocrystal underwent a two-step process. The apparent activation energy (Ea) and pre-exponential factor (A) of the thermal decomposition for the first stage were 84.90 kJ mol-1 and 7.03 × 107 min-1, respectively. The mechanism underlying thermal decomposition possibly involved nucleation and growth, with the integral mechanism function G(α) of α3/2. DFT calculation revealed that the hydrogen bonding between Fel and Glu weakened the terminal methoxyl, methyl, and ethyl groups in the Fel molecule. As a result, these groups were lost along with the Glu molecule in the first thermal decomposition. In conclusion, the formed cocrystal exhibited different thermal decomposition kinetics and showed different Ea, A, and shelf life from the intact active pharmaceutical ingredient.

In order to overcome deficiencies for simultaneously determining felodipine (FDP) and metoprolol (MPL) with low recovery and low sensitivity, a new online SPE coupled with the liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method for the simultaneous quantitative determination of FDP and MPL in beagle dog plasma was established. The SPE extraction of FDP and MPL was performed on a Retain PEP Javelin column (10 × 2.1 mm, 5 μm), while the chromatographic separation was achieved on a ZORBAX SB-C18 (50 × 2.1 mm, 3.5 μm) analytical column. Multiple reaction monitoring operated in the positive ion mode was adopted in MS detection, and the precursors to the product ion transition values of m/z 384/338.1, 268/74.2 and 436.2/207.1 were used to measure FDP, MPL and the internal standard (valsartan). The high throughput, accurate and sensitive method for FDP and MPL was validated and applied to the bioavailability research of FDP and MPL in beagle dogs.

Calcium channel blockers (CCBs) have been proved to have beneficial effects on cardiovascular (CV) outcomes, especially in stroke. Lercanidipine, a highly lipophilic CCB, lacks data regarding long-term outcomes including: CV, stroke, renal and all-cause mortality. This retrospective cohort study aims to clarify this.
A total of 144,630 newly diagnosed hypertension (HTN) patients (age: 18-65 years) in 2005 from the Taiwan\'s National Health Insurance Research Database were enrolled in this observational study. A pure hypertension population was fetched by excluding all chronic diseases in the Charlson Comorbidities Index. Patients were stratified into the lercanidipine group (n = 1303) and the propensity-score-matched comparative group (nifedipine, amlodipine or felodipine, n = 15,301).
Compared to other CCBs, lercanidipine didn\'t have a significant difference on the study endpoints. In individual head-to-head comparisons, lercanidipine was shown to be superior to nifedipine in incident stroke with an adjusted HR with 95% CI of 0.526 (0.347-0.797) (p = .0025). The key limitations were that personal variables, such as smoking habits, alcohol intake, body mass index and physical activity and blood pressure profiles were not available in the nationwide registry database.
In newly diagnosed patients with hypertension, lercanidipine was superior to nifedipine in the six-year period when the analyzed endpoint was stroke.

To prepare felodipine/copovidone solid dispersions, which were made based on different preparation technologies. Insoluble felodipine was selected as the model drug in this research. This drug belonged to Biopharmaceutics Classification System II (BCSII) with insoluble property and good permeability across intestinal mucosa simultaneously. A comparative study was carried out for further investigating their corresponding pharmaceutical properties.
Felodipine/copovidone solid dispersions were achieved by four methods including spray-drying method, microwave-induced fusion quench cooling method, freeze-drying method and co-precipitation method. These solid dispersions were produced based on corresponding processes that corresponded to these methods. Internal properties of co-povidone solid dispersions were analyzed by various approaches including scanning electron microscope (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The improvement on insoluble properties of felodipine by solid dispersions produced by different technologies was characterized by dissolution experiments based on dissolution instrument. Crystallization inhibition effect of polymers against drugs was studied by supersaturated experiments through determining the concentration value at different time points.
The internal drug was dispersed in amorphous form in solid dispersions produced by spray-drying, microwave method, microwave/quench-cooling method and co-precipitation method. Freeze-drying method resulted in a form of crystal in felodipine/copovidone solid dispersions. Compared with other technologies, microwave-induced quench cooling method could significantly improve the dissolution of insoluble drug felodipine (P<0.05). The dissolution concentration reached approximately 4.65 mg/L at 60 min time point. Copovidone could inhibit or retard the crystallization of felodipine in a supersaturated state. In the solution pre-dissolved with maximum copoyidone polymer, the minimum crystallization rate of supersaturated felodipine was observed at 240 min time point. The value of crystallization rate was 0.19 mg/(L×min).
The study is helpful to understand and clarify the internal properties of solid dispersions obtained by different technologies. The research also provides beneficial consultation for the choice of technology in practical production of drug-polymer solid dispersions.

A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine.
A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects.
Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee.
Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.