Bioequivalence study of a fixed dose combination of nitazoxanide and ofloxacin in Indian healthy volunteers.

OBJECTIVE: The pharmacokinetics of nitazoxanide (CAS 55981-09-4) and ofloxacin (CAS 82419-36-1) has been extensively evaluated in adult human volunteers individually after oral administration of tablet formulation. However, no published data is available regarding the combined pharmacokinetics and bioavailability of this particular fixed dose combination. In light of the above, a clinical study was designed to evaluate the bioequivalence of two fixed dose combination (FDC) products of two manufacturers containing nitazoxanide 500 mg and ofloxacin 200 mg in healthy Indian male volunteers. METHODS: 24 healthy male volunteers (age 25 +/- 4.6 years; weight 74.5 +/- 7.87 kg) were enrolled in this study. Each subject received a Test fixed dose combination and a Reference fixed dose combination formulation in a randomized, single dose, fasting state, two period, crossover study design with a 1-week washout period between the doses. Extraction of the drugs from the plasma was carried out by precipitation method. Analysis of tizoxanide (active metabolite of nitazoxanide) and ofloxacin from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC(0-t), AUC(0-infinity). using general linear model (GLM) procedures in which sources of variation were subject, formulation, period. RESULTS: The results of this investigation indicated that there were no statistically significant differences between the two products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90 % confidence limits for the log-transformed data of Cmax, AUC(0-t), AUC(0-infinity) were within the acceptable range of 0.80-1.25. CONCLUSION: Thus, these findings clearly indicate that the two products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions seen throughout the study.

Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study.

A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometry (LC-MS-MS) method is described for the determination of duloxetine in human plasma. Duloxetine was extracted from plasma using methanol and separated on a C18 column. The mobile phase consisting of a mixture of acetonitrile and 5mM ammonium acetate (45:55, v/v, pH 3.5) was delivered at a flow rate of 0.3 ml/min. Atmospheric pressure ionization (API) source was operated in positive ion mode. Multiple reaction monitoring (MRM) mode using the transitions of m/z 298.1-->m/z 44.0 and m/z 376.2-->m/z 123.2 were used to quantify duloxetine and internal standard (I.S.), respectively. The linearity was obtained over the concentration range of 0.1-50.0 ng/ml and the lower limit of quantitation (LLOQ) was 0.1 ng/ml. This method was successfully applied to pharmacokinetic study of a duloxetine formulation product after oral administration to healthy human subjects.

Simultaneous determination of fixed dose combination of nebivolol and valsartan in human plasma by liquid chromatographic-tandem mass spectrometry and its application to pharmacokinetic study.

A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometry method is described for the simultaneous determination of nebivolol and valsartan in human plasma. Nebivolol and valsartan were extracted from plasma using acetonitrile and separated on a C18 column. The mobile phase consisting of a mixture of acetonitrile and 0.05 mM formic acid (50:50 v/v, pH 3.5) was delivered at a flow rate of 0.25 ml/min. Atmospheric pressure ionization (API) source was operated in both positive and negative ion mode for nebivolol and valsartan, respectively. Selected reaction monitoring mode (SRM) using the transitions of m/z 406.1-->m/z 150.9; m/z 434.2-->m/z 179.0 and m/z 409.4-->m/z 228.1 were used to quantify nebivolol, valsartan and internal standard (IS), respectively. The linearity was obtained over the concentration range of 0.01-50.0 ng/ml and 1.0-2000.0 ng/ml and the lower limits of quantitation were 0.01 ng/ml and 1.0 ng/ml for nebivolol and valsartan, respectively. This method was successfully applied to the pharmacokinetic study of fixed dose combination (FDC) of nebivolol and valsartan formulation product after an oral administration to healthy human subjects.

Liquid chromatography tandem mass spectrometry method for simultaneous determination of metoprolol tartrate and ramipril in human plasma.

A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of metoprolol tartrate (MT) and ramipril, in human plasma. Both the drugs were extracted by liquid-liquid extraction with diethyl ether-dichloromethane (70:30, v/v). The chromatographic separation was performed on a reversed-phase C8 column with a mobile phase of 10 mM ammonium formate-methanol (3:97, v/v). The protonated analyte was quantitated in positive ionization by multiple reaction monitoring with a mass spectrometer. The method was validated over the concentration range of 5-500 ng/ml for metoprolol and ramipril in human plasma. The precursor to product ion transitions of m/z 268.0-103.10 and m/z 417.20-117.20 were used to measure metoprolol and ramipril, respectively.

Evaluation of bioequivalence of two formulations containing 100 milligrams of aceclofenac.

The bioequivalence of two oral formulations containing aceclofenac 100 mg was determined in 24 healthy Indian male volunteers. The study was designed as a single dose, fasting, two-period two-sequence crossover study with a washout period of 1 week. The content of aceclofenac in plasma was determined by a validated HPLC method with UV detection. The preparations were compared using the parameters area under the plasma concentration-time curve (AUC0-t), area under the plasma concentration-time curve from zero to infinity (AUC0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). No statistically significant difference was observed between the logarithmic transformed AUC0-infinity and Cmax values of the two preparations. The 90% confidence interval for the ratio of the logarithmic transformed AUC0-t, AUC0-infinity, and Cmax were within the bioequivalence limit of 0.80-1.25.

Having our cake and eating it too: how the GALEN Intermediate Representation reconciles internal complexity with users' requirements for appropriateness and simplicity.

Clinical terminologies are complex objects, getting more complex as the requirements on them grow, and as more complex technologies are used in their construction. But to the clinical end-user, functionality and utility is important, not inherent complexity--the simpler a clinical terminology can be for the end-user, the better. To reconcile these contradictory requirements, the GALEN Programme has developed an Intermediate Representation that allows the OpenGALEN Clinical Terminology to retain a high degree of internal complexity, whilst allowing it to be efficiently maintained, and easily used. This paper describes the elements of the Intermediate Representation, how it works, and some experience of its use.

A reference terminology for drugs.

GALEN technology for re-usable terminologies using formal classification is being applied to the creation and maintenance of a reference terminology for drugs. GALEN's techniques are being used to address specific deficiencies of existing drug classifications that make it difficult to create and maintain guidelines to support prescribing in the care of patients with chronic diseases. The reference terminology is in two parts; firstly, a re-usable and automatically-classified 'ontology' is built with GALEN technology; this describes generic drugs, their composition in terms of chemicals and chemical classes, their actions, indications and interactions. Secondly, a 'dictionary' of prescribable proprietary products is integrated with this ontology. The result is a drug resource designed to support both the traditional uses of a drug knowledge base (e.g. prescribing and messaging), and the specialized demands of guideline authoring and execution.

Validating clinical terminology structures: integration and cross-validation of Read Thesaurus and GALEN.

A European pre-standard and an intermediate representation facilitated exchange of two independently authored compositional knowledge bases: one formal and automatically classified, the other manually classified. The exchange highlights different strengths and weaknesses in each approach, and offers a mechanism for partial, mutual quality assurance.

Reconciling users' needs and formal requirements: issues in developing a reusable ontology for medicine.

A common language, or terminology, for representing what clinicians have said and done is an important requirement for individual clinical systems, and it is a pre-requisite for integrating disparate applications in a distributed telematic healthcare environment. Formal representations based on description logics or closely related formalisms are increasingly used for representing medical terminologies. GALEN's experience in using one such formalism raises two major issues, as follows: how to make ontologies based on description logics easy to use and understand for both clinicians and applications developers; what features are required of the ontology and description logic if they are to achieve their aims. Based on our experience we put forward four contentions: two relating to each of these two issues, as follows: that natural language generation is essential to make a description logic based ontology accessible to users; that the description logic based ontology should be treated as an "assembly language" and accessed via "intermediate representations" oriented to users and "perspectives" adapting it to specific applications; that independence and reuse are best supported by partitioning the subsumption hierarchy of elementary concepts into orthogonal taxonomies, each of which forms a pure tree in which the branches at each level are disjoint but nonexhaustive subconcepts of the parent concept; that the expressivity of the description logic must include support for transitive relations despite the computational cost, and that this computational cost is acceptable in practice. The authors argue that these features will be necessary, though by no means sufficient, for the development of any large reusable ontology for medicine.

The GRAIL concept modelling language for medical terminology.

The GALEN representation and integration language (GRAIL) has been developed to support effective clinical user interfaces and extensible re-usable models of medical terminology. It has been used successfully to develop the prototype GALEN common reference (CORE) model for medical terminology and for a series of projects in clinical user interfaces within the GALEN and PEN&PAD projects. GRAIL is a description logic or frame language with novel features to support part-whole and other transitive relations and to support the GALEN modelling style aimed at re-use and application independence. GRAIL began as an experimental language. However, it has clarified many requirements for an effective knowledge representation language for clinical concepts. It still has numerous limitations despite its practical successes. The GRAIL experience is expected to form the basis for future languages which meet the same requirements but have greater expressiveness and more soundly based semantics. This paper provides a description and motivation for the GRAIL language and gives examples of the modelling paradigm which it supports.

Rubrics to dissections to GRAIL to classifications.

This paper summarises the process in the GALEN-IN-USE project by which rubrics from traditional medical coding schemes are analysed into an intermediate, relatively informal conceptual representation which is then automatically translated into the GRAIL formalism and its Common Reference Model.

Using the GRAIL language for classification management.

This paper describes a novel approach in classification management where a formal model of medical semantics is being used for manipulations on existing classification systems. The paper addresses the issue of semi-automatically making specialist classifications that are compatible with the source classification. The examples in this paper are from a limited domain. At the time of the presentation results will be shown of the present modelling work within the GALEN-In-Use project. The model will then contain several thousands of medical procedures from four different classification centres.

A Terminology Server for medical language and medical information systems.

GALEN is developing a Terminology Server to support the development and integration of clinical systems through a range of key terminological services, built around a language-independent, re-usable, shared system of concepts--the CORE model. The focus is on supporting applications for medical records, clinical user interfaces and clinical information systems, but also includes systems for natural language understanding, clinical decision support, management of coding and classification schemes, and bibliographic retrieval. The Terminology Server integrates three modules: the Concept Module which implements the GRAIL formalism and manages the internal representation of concept entities, the Multilingual Module which manages the mapping of concept entities to natural language, and the Code Conversion Module which manages the mapping of concept entities to and from existing coding and classification schemes. The Terminology Server also provides external referencing to concept entities, coercion between data types, and makes its services available through a uniform applications programming interface. Taken together these services represent a new approach to the development of clinical systems and the sharing of medical knowledge.

Multilingual natural language generation as part of a medical terminology server.

Re-usable and sharable, and therefore language-independent concept models are of increasing importance in the medical domain. The GALEN project (Generalized Architecture for Languages Encyclopedias and Nomenclatures in Medicine) aims at developing language-independent concept representation systems as the foundations for the next generation of multilingual coding systems. For use within clinical applications, the content of the model has to be mapped to natural language. A so-called Multilingual Information Module (MM) establishes the link between the language-independent concept model and different natural languages. This text generation software must be versatile enough to cope at the same time with different languages and with different parts of a compositional model. It has to meet, on the one hand, the properties of the language as used in the medical domain and, on the other hand, the specific characteristics of the underlying model and its representation formalism. We propose a semantic-oriented approach to natural language generation that is based on linguistic annotations to a concept model. This approach is realized as an integral part of a Terminology Server, built around the concept model and offering different terminological services for clinical applications.

Constructing clinical applications: the GALEN approach.

A common problem for developers of clinical applications is coping with the diversity of medical language. Medical language as it is used all over the world varies widely, while the referents for these words stay essentially the same. Software developers must reconcile this diversity with the practical necessity of producing applications that are usable in a variety of hospitals, while ensuring that information can be shared between applications. Existing approaches center around coding and classification schemes, but these approaches must be supplemented by a range of sophisticated terminological services in order for the language barriers to be overcome. To address this, the GALEN project is developing an application called the Terminology Server to provide such a range of terminological services (e.g., conceptual and multilingual services). The software is built upon a re-usable core model of medical terminology. This paper reports on the development of a clinical application called the SCUI (Structured Clinical User Interface) which draws on these GALEN technologies and illustrates an innovative approach to the construction of future clinical applications. The SCUI was specifically developed and tested in the context of infectious diseases to satisfy the demands made by the medical intensive care unit on the Geneva Hospital's microbiology laboratory.

From terminology to terminology services.

Terminologies have traditionally been considered as static datasets held in books or databases. The GALEN Terminology Server presents a prototype for a new view of terminologies delivered as a set of functions and services provided to other applications. This facilitates their development and integration as part of a strategy for sharing and re-using information and knowledge. The essential features of the Terminology server are the functions which it can perform; questions which it can answer and statements which it can be told. The GALEN Terminology Server supports these operations through a modular architecture and uniform applications programming interface which allows client applications to ignore the internal structure and simply use the Server for terminological, coding, and linguistic functions.