Thesis (doctoral)--Groningen, 1980.

No description available.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Letters to editor

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves 145-176).

Carbamazepine is a drug which is now widely used for the treatment of both generalised epilepsy (tonic-clonic seizures) and partial epilepsy (with simple or complex symptomatology). This study was undertaken in an attempt to assess the role of the metabolites of carbamazepine, viz. 10, 11-epoxy-carbamazepine and 10, 11-dihydro-10,11-dihydroxy-carbamazepine, with regard to their therapeutic efficacy and the occurrence of side effects of the parent drug. It was also designed to seek a possible explanation as to why certain patients with optimal levels of carbamazepine in plasma fail to respond to therapy. A total of 23 epileptic patients (11 females and 12 males) suffering from either generalised (tonic-clonic) seizures or partial complex seizures took part in the study. The patients were divided into two groups according to their seizure frequency: Responders - those patients who had no seizures in the month prior to entry into the study (12 patients). Non-Responders - those patients who had a minimum of one seizure a week in the month prior to entry into the study (11 patients). Carbamazepine and its metabolites were monitored between 8 a.m. and 6 p.m. by taking blood samples at two hourly intervals. Cerebrospinal fluid (CSF) was also obtained from seven patients in the non-responder group. The drug and its metabolites were assayed simultaneously by the thin-layer chromatographic (TLC) method of Hundt and Clark (1975). Six of the 23 epileptic patients complained of side effects: nausea and headaches were the most frequently mentioned complaint. Statistical analysis showed, however, that there was no significant difference in the peak levels of carbamazepine and metabolites in patients both with or without side effects. Therefore, it was not possible to define a threshold level of the drug above which side effects were likely to occur. Also, no definite conclusion could be reached as to whether the metabolites play a role in the manifestation of side effects. The area under the curve (AUC) is a measure of the overall plasma concentration of carbamazepine and metabolites (present between 8 a.m. and 6 p.m.) in the individual patients of the two groups. There was no significant difference in the AUC of carbamazepine between responders and non-responders. However, the AUC of the dihydroxy and epoxy metabolites was significantly higher in the non-responders (P<-0.002 and P < 0.02 respectively). Moreover, in the CSF samples of the non-responders, the mean (±SD) ratio of the dihydroxy metabolite to the parent drug was as high as 1.17 (±0,36). The results show a clear association between high levels of metabolites and poor response to carbamazepine therapy. Furthermore, it would seem that either both metabolites are inactive or that if the epoxy metabolite is active as in the rat (Frigerio and Morselli 1975), any likely therapeutic effect is counter-acted by the relatively large concentration of inactive dihydroxy metabolite (Schmutz et al 1979). Moreover, it may follow that non-response to carbamazepine - despite optimal levels of the drug in plasma - may be due to competition by inactive dihydroxy metabolite for the site (s) of action of the parent drug in the brain. Research strategies which might be used to test this hypothesis have been proposed.

Pharmaceuticals are emerging surface water contaminants, and are manufactured, used, and released into environment in considerable amounts. Concerns have been raised due to the inherent potency and bioactivity of these molecules, which makes effects at low concentrations more likely. The ubiquitous presence and stability of pharmaceuticals brings up concerns about the frequency and length of exposures. However, the distribution and fate of these compounds in surface water bodies is not clear. There is limited information about the potential effects in non-target, especially aquatic, species vulnerable to cumulative or lifelong exposures. Carbamazepine (CBZ) and gemfibrozil (GEM) are two of the most frequently detected pharmaceuticals in surface water. This thesis examined sub-lethal adverse reproductive effects of chronic direct exposure of CBZ and GEM to F0 zebrafish and several generations of unexposed offspring; the effects of exposure on testicular steroidogenesis were also examined. Chronic exposure of zebrafish to CBZ and GEM reduced ex vivo production of 11KT in testes. In vivo, CBZ decreased reproductive output, 11-ketotestosterone (11KT), male courtship and aggression behaviours, and sperm morphology in F0 parents. The F1, F2 and F3 offspring of CBZ exposed males had lower reproductive output, altered courtship, aggression, sperm morphology and lower 11KT compared to fish from the unexposed lineage. The adverse effects persisted into the F3 generation which suggested transgenerational paternal effects. GEM decreased reproductive output in F0 parents and a reduction in 11KT, altered male courtship, aggression and sperm morphology. Unexposed F1 male offspring, but not other generations, had sub-lethal toxic effects from parental exposure. We therefore suggest that CBZ and GEM act as endocrine disruptors in fish and that chronic exposure may reduce male reproductive fitness. / Dissertation / Doctor of Philosophy (PhD) / Human pharmaceuticals reach aquatic environments through municipal wastewater. The bioactivity of pharmaceuticals at low concentrations has raised concerns about undesired effects in aquatic species like fish, which can experience chronic exposures. This thesis examined adverse reproductive effects of direct chronic exposure of carbamazepine and gemfibrozil to parental zebrafish and their un-exposed offspring for multiple generations. Exposure to both compounds reduced androgens and reproduction and altered behaviour, and sperm quality in males. Effects persisted in the unexposed offspring. Parental carbamazepine exposure impacted multiple generations. We suggest that carbamazepine and gemfibrozil may reduce male reproductive fitness by reducing male sex steroids.

No / Mechanistic understanding of competitive destabilization of carbamazepine:nicotinamide and carbamazepine:saccharin cocrystals under solvent free conditions has been investigated. The crystal phase transformations were monitored using hot stage microscopy, variable-temperature powder X-ray diffraction, and sublimation experiments. The destabilization of the two cocrystals occurs via two distinct mechanisms: vapor and eutectic phase formations. Vapor pressure measurements and thermodynamic calculations using fusion and sublimation enthalpies were in good agreement with experimental findings. The mechanistic understanding is important to maintain the stability of cocrystals during solvent free green manufacturing. / EPSRC (EP/J003360/1, EP/ L027011/1). MHD. Bashir would like to thank CARA for providing doctoral degree scholarship.

The aim of this study is to investigate the effects of coformers and polymers on the phase transformation and release profiles of cocrystals. Pharmaceutical cocrystals of Carbamazepine (CBZ) (namely 1:1 carbamazepine-nicotinamide (CBZ-NIC), 1:1 carbamazepine-saccharin (CBZ-SAC) and 1:1 carbamazepine-cinnamic acid (CBZ-CIN) cocrystals, were synthesized. A Quality by Design (QbD) approach was used to construct the formulation. Dissolution and solubility were studied using UV imaging and High Performance Liquid Chromatography (HPLC). The polymorphic transitions of cocrystals and crystalline properties were examined using Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction (XRPD), Raman spectroscopy (Raman) and Scanning Electron Microscopy (SEM). JMP 11 software was used to design the formulation. It has been found that Hydroxupropyl methylcellulose (HPMC) cannot inhibit the transformation of CBZ-NIC cocrystals to Carbamazepine Dihydrate (CBZ DH) in solution or in the gel layer of the matrix, as opposed to its ability to inhibit CBZ Form III (CBZ III) phase transition to CBZ DH. The selection of different coformers of SAC and CIN can affect the stability of CBZ in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of the CBZ-SAC cocrystal can only be shown for 20 minutes during dissolution because of the conversion to its dihydrate form (CBZ DH). In contrast, the improved CBZ dissolution rate of the CBZ-CIN cocrystal can be realised in both solution and formulation because of its stability. The polymer of Hypromellose Acetate Succinate (HPMCAS) seemed to best augment the extent of CBZ-SAC and CBZ-CIN cocrystal supersaturation in solution. At 2 mg/ml of HPMCAS concentration, the apparent CBZ solubility of CBZ-SAC and CBZ-CIN cocrystals can increase the solubility of CBZ III in pH 6.8 phosphate buffer solutions (PBS) by 3.0 and 2.7 times respectively. All pre-dissolved polymers in pH 6.8 PBS can increase the dissolution rates of CBZ cocrystals. In the presence of a 2 mg/ml HPMCAS in pH 6.8 PBS, the cocrystals of CBZ-NIC and CBZ-CIN can dissolve by about 80% within five minutes in comparison with 10% of CBZ III in the same dissolution period. Finally, CBZ-NIC cocrystal formulation was designed using the QbD principle. The potential risk factors were determined by fish-bone risk assessment in the initial design, after which Box-Behnken design was used to optimize and evaluate the main interaction effects on formulation quality. The results indicate that in the Design Space (DS), CBZ sustained release tablets meeting the required Quality Target Product Profile (QTPP) were produced. The tablets’ dissolution performance could also be predicted using the established mathematical model.

Polymorphism can influence every aspect of the properties of a solid including the shelf life, dissolution rate, solubility, formulation properties and processing properties of a solid drug. A deeper understanding of polymorphism and related solid state properties would ensure an improved quality of the materials used throughout drug preparation, dosage form formulation and clinical trials. Therefore, determination of the existence of polymorphs and pseudopolymorphs, characterization of different solid state forms and their respective properties, and controlling the existing form in the resulting formulation all form part of a rapidly growing field within pharmaceutical research and industry. Carbamazepine (CBZ) was the model drug used in this study. FT-Raman spectroscopy was chosen as a main investigative technique in this study to evaluate its potential in monitoring (pseudo)polymorphic conversions in aqueous suspensions in the absence or presence of various pharmaceutical excipients. Partial least squares analysis (PLS) was used for quantitative analysis of the spectral data. Earlier it has been found that CBZ converts rapidly to the dihydrate (DH) when exposed to humidity or water, and this has been reported to be the main reason for the sometimes observed greatly decreased bioavailability of marketed CBZ tablets. In this study, the conversion kinetics of CBZ (forms I, II and III) to DH in aqueous suspension were found to be first order kinetics with an unconverted portion (R� [greater than or equal to] 0.95), where the crystal morphology appeared to play a more important role in its conversion kinetics than the polymorphic form. The influence of pharmaceutical excipients on the conversion of CBZ in aqueous suspension was also explored. For excipients such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) which have both a low solubility parameter (< 27.0 MPa[1/2]) and strong hydrogen bonding groups, complete inhibition of the conversion of CBZ was possible even at a very low concentration (0.1 % w/v). Raman spectroscopy showed its high applicability in investigating CBZ conversion kinetics and screening of excipient effects in aqueous environment. It was demonstrated that Raman has a robust nature in quantitative analysis since problems such as different particle size, morphology, and spatial distribution of the two solid state forms of the drug seemed not to have significant influence on Raman scattering. This study has also clarified the relative importance of many contributing factors (type of crystalline form (CBZ or DH), crystal morphology, surface area, and excipient interactions with drug particles) influencing the in vitro dissolution of CBZ. The solid state characterization approach taken in this study will provide a deeper insight into the dissolution performance of drugs and should thus lead to a better understanding of in vitro/in vivo behavior of drugs.

Access to abstract restricted until 05/2015. / Access to thesis restricted until 05/2015. / Department of Biology