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C Reppas

Publications and source records attributed to C Reppas.

At least 19 recordsLinked to original sources
PubMed2006

Optimization and validation of a high-performance liquid chromatographic method with UV detection for the determination of ketoconazole in canine plasma.

An isocratic high-performance liquid chromatographic method with detection at 240 nm was developed, optimized and validated for the determination of ketoconazole in canine plasma. 9-Acetylanthracene was used as internal standard. A Hypersil BDS RP-C18 column (250 mm x 4.6 mm, 5 microm particle size), was equilibrated with a mobile phase composed of methanol, water and diethylamine 74:26:0.1 (v/v/v). Its flow rate was 1 ml/min. The elution time for ketoconazole and 9-acetylanthracene was approximately 9 and 8 min, respectively. Calibration curves of ketoconazole in plasma were linear in the concentration range of 0.015-10 microg/ml. Limits of detection and quantification in plasma were 5 and 15 ng/ml, respectively. Recovery was greater than 95%. Intra- and inter-day relative standard deviation for ketoconazole in plasma was less than 3.1 and 4.7%, respectively. This method was applied to the determination of ketoconazole plasma levels after administration of a commercially available tablet to dogs.

Administration, Oral↗
PubMed2006

Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.

Acetaminophen↗
PubMed2005

Optimized determination of lycopene in canine plasma using reversed-phase high-performance liquid chromatography.

An isocratic high-performance liquid chromatographic method with detection at 472 nm was developed, optimized and validated for the determination of lycopene in canine plasma. Ethyl-beta-apo-8'-carotenoate was used as internal standard. A Hypersil BDS RP-C18 column (150 mm x 4.6 mm), 5 microm particle size, was equilibrated with a mobile phase composed of acetonitrile and methanol (50:50, v/v). Its flow rate was 1.5 ml/min. The elution time for lycopene and ethyl-beta-apo-8'-carotenoate was approximately 11 and 5 min, respectively. Calibration curves of lycopene were linear in the concentration range of 3-200 ng/ml in plasma. Limits of detection and quantification in plasma were 1 and 4 ng/ml, respectively. Recovery was greater than 97%. Intra- and inter-day relative standard deviation for lycopene in plasma was less than 1.8 and 3.1%, respectively. This method was applied to the determination of lycopene plasma levels after single dose administration to dogs.

Animals↗
PubMed2001

Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration.

PURPOSE: To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. METHODS: Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f1. RESULTS: No model consistently provided the best fit to the in vitro data, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 < or = f1 < or = 34.2) in seven out of eleven cases. CONCLUSIONS: Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.

Adamantane↗
PubMed2000

In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs.

Although several routes of administration can be considered for new drug entities, the most popular remains the oral route. To predict the in vivo performance of a drug after oral administration from in vivo data, it is essential that the limiting factor to absorption can be modelled in vitro. In the case of BCS class II drugs dissolution is rate-limiting to absorption, so the use of biorelevant dissolution tests can be used to predict differences in bioavailability among different formulations and dosing conditions. To achieve an a priori correlation, the composition, volume and hydrodynamics of the contents in the gastrointestinal lumen following administration of the dosage form must be accurately simulated. Four media have been chosen/developed to model composition of the gastric and intestinal contents before and after meal intake. These are SGF, milk, FASSIF and FeSSIF, which model fasted and fed state conditions in the stomach and small intestine respectively. Using these media, excellent correlations have been obtained with the following poorly soluble drugs: danazol, ketoconazole, atovaquone and troglitazone. In all cases, fed vs. fasted state effects can be predicted from dissolution data and, where several formulations were available for testing, dissolution tests could also be used to determine which would have the best in vivo performance.

Administration, Oral↗
PubMed1999

Longitudinal versus radial effects of hydroxypropylmethylcellulose on gastrointestinal glucose absorption in dogs.

Many water soluble fibers have been shown to favorably affect the postprandial glucose profile in humans. Hydroxypropylmethylcellulose (HPMC), a fiber which has been shown to increase glucose tolerance in dogs and noninsulin dependent diabetics, was chosen to study the luminal interactions which mediate this effect. The ability of HPMC to influence upper gastrointestinal (GI) viscosity, transit, and water flux of 5% and 20% glucose solutions was studied in five female dogs fistulated at the proximal duodenum and/or midjejunum. HPMC elevated intraluminal viscosity, with a linear relationship existing between input and luminal viscosity. The ability to modify intraluminal viscosity was greater for isoosmotic (5%) glucose solutions than for hyperosmotic (20%) glucose solutions. HPMC also modified the transit profile of isoosmotic (5%) glucose solutions at midgut by both increasing the lag times before the onset of chyme recovery from 5.5+/-3.1 min to 9-55 min (depending on the viscosity of the administered solution) and decreasing the first-order transit rate constants from 0.115+/-0.07 min-1 to 0.014-0.035 min-1. By contrast, the transit profile of hyperosmotic (20%) glucose solutions was not significantly affected. Net cumulative water flux across the gut wall was not significantly affected in either case by the presence of HPMC. These results, in combination with the amount of glucose recovered from midgut fistula, suggest that following the administration of glucose solutions, HPMC effects on blood glucose levels are mediated by mechanisms which relate to the increased intraluminal viscosity but vary according to the input glucose load. For isoosmotic glucose loads, both the decreased upper GI transit rate and hindered radial movement play a role. Although HPMC modifies glucose absorption from hyperosmotic solutions, this study shows that luminal effects occurring before midgut are modest.

Animals↗
PubMed1999

Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data.

PURPOSE: To assess the usefulness of biorelevant dissolution tests in predicting food and formulation effects on the absorption of four poorly soluble, lipophilic drugs. METHODS. Dissolution was studied with USP Apparatus II in water, milk, SIFsp, FaSSIF, and FeSSIF. The in vitro dissolution data were compared on a rank order basis with existing in vivo data for the tested products under fasted and fed state conditions. RESULTS: All drugs/formulations showed more complete dissolution in bile salt/lecithin containing media and in milk than in water and SIFsp (USP 23). Comparisons of the in vitro dissolution data in biorelevant media with in vivo data showed that in all cases it was possible to forecast food effects and differences in absorption between products of the same drug with the physiologically relevant media (FaSSIF, FeSSIF and milk). Differences between products (both in vitro or in vivo) were less pronounced than differences due to media composition (in vitro) or dosing conditions (in vivo). CONCLUSIONS: Although biorelevant dissolution tests still have issues which will require further refinement, they offer a promising in vitro tool for forecasting the in vivo performance of poorly soluble drugs.

Adamantane↗
PubMed1998

The effect of HPMC--a cholesterol-lowering agent--on oral drug absorption in dogs.

The objective of this study was to evaluate the effects which hydroxypropylmethylcellulose (HPMC) may exert on oral drug absorption, in cases where this soluble fiber is administered to regulate blood lipid levels. Studies were conducted in vitro and in healthy female mongrel dogs using two different grades of HPMC, i.e. K8515 HPMC and ultra high molecular weight (UHMW) HPMC. The maximum plasma concentration, Cmax, of paracetamol and both the Cmax and the area under the concentration-time curve, AUC, of cimetidine were significantly decreased by the coadministration of 10 g of K8515 HPMC or 7.5 g of UHMW HPMC dissolved in 500 mL normal saline under fasting conditions. No statistically significant effects were observed on hydrochlorothiazide or mefenamic acid absorption. Based on in vitro data and previous studies it appears that reductions in gastric emptying and dissolution rate of paracetamol account for the effect observed in vivo. For cimetidine, a drug which can be absorbed from both the small and the large intestine, the indigestibility of HPMC in the colon in addition to the great reduction of dissolution rate led to reductions of both the Cmax and AUC values. The long Tmax values, even in the absence of HPMCs and the more modest reduction of the dissolution rate of hydrochlorothiazide by the HPMCs are thought to have precluded the observation of any significant alterations in the in vivo absorption profile. Owing to its erratic absorption, no statistically based conclusion could be drawn about the effects of coadministered HPMC on the oral absorption of the poorly soluble mefenamic acid. It is concluded that the effects of HPMCs on drug absorption in dogs are most pronounced for compounds with absorption profiles that are dependent on gastric emptying, i.e. compounds that are highly water soluble and that exhibit short Tmax values. Compounds with long absorption profiles appear to be less susceptible to changes in absorption behavior due to coadministration of HPMCs.

Animals↗
PubMed1998

Effect of elevated viscosity in the upper gastrointestinal tract on drug absorption in dogs.

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drugs and, second, to identify the key processes influencing drug absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel dogs under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drugs, and results from a combination of a decrease in dissolution rate and gastric emptying rate.

Acetaminophen↗
PubMed1998

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PURPOSE: In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. METHODS: Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. RESULTS: Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. CONCLUSIONS: As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Acetaminophen↗
PubMed1998

Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms.

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.

Administration, Oral↗
PubMed1997

Prevalence of asthma and asthma-like symptoms in Athens, Greece.

Asthma is a common chronic condition and there is evidence that its prevalence may be rising. The European Respiratory Health Survey (ECRHS) was planned to produce comparable data on asthma epidemiology in Europe. In Greece, in particular, a similar study has not been conducted previously and no epidemiological data are available on adult asthma prevalence. Furthermore, the role of air pollution in the pathogenesis of asthma is currently an issue of debate. Athens is a city with high air pollution, and a study of asthma epidemiology in this city may confirm or refute a possible link with the expression of asthma. A questionnaire developed by the ECRHS was sent to a random sample of 3533 households in Peristeri, an industrialized borough of Athens. Responses were received from 2774 households (response rate 78%). Of all the data on individual subjects, only those from 3325 adults aged 20-44 years were considered, according to the study protocol. The self-reported current prevalence of asthmatic attacks and asthma-like symptoms were as follows: asthma attack 2.4%, use of asthma medication 2.1%, awakening by shortness of breath 5.6%, awakening by cough 17.8%, wheezing 15.8% and nasal allergies 18.4%. It is concluded that the prevalence of asthma and related symptoms in this region of Athens is rather low, despite the high air-pollution levels in the city.

Adult↗
PubMed1995

Evaluation of different metrics as indirect measures of rate of drug absorption from extended release dosage forms at steady-state.

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.

Absorption↗
PubMed1994

The cutoff time point of the partial area method for assessment of rate of absorption in bioequivalence studies.

The partial area method has been suggested for the assessment of the absorption rate in bioequivalence studies. This paper provides a theoretical basis for the estimation of the optimal cutoff time point of the partial areas for drugs with one compartment model disposition. The analysis is performed by using the appropriate equations which relate the normalized (in terms of the extent of absorption) partial areas with time expressed in terms of multiples of half-life. Provided that the quality of experimental data ensures precise estimation of the parameters, the tmax of the formulation with the faster absorption characteristics is generally the most practical cutoff time point for calculation of the normalized partial areas, when a drug follows one compartment model disposition with linear absorption.

Half-Life↗