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Biomedical subjects

D J Saville

Publications and source records attributed to D J Saville.

12 recordsLinked to original sources
PubMed2006

Visualizing the conversion of carbamazepine in aqueous suspension with and without the presence of excipients: a single crystal study using SEM and Raman microscopy.

Visual observations of the hydration process of single carbamazepine (CBZ) crystals in water and in various excipient solutions [(1% w/v) - hydroxypropyl cellulose (HPC), poly(vinyl pyrrolidone) (PVP), sodium carboxymethylcellulose (CMC) at pH 7.5 and 3.0, and polyethylene glycol (PEG)] using scanning electron microscopy (SEM) are reported in this paper. Raman microscopy was used to confirm the chemical structures of the unconverted CBZ and the CBZ dihydrate (DH) needles. It was found that defect structures were a more important driving force than the nature of crystal faces for the initiation of the hydration, but face differences became obvious after 6 h immersion. The biggest crystal face grown from methanol, (100), was the slowest one to be covered with DH needles. A comparison of the molecular arrangements along the three crystal faces [(100), (010) and (001)] was carried out using crystal structure visualization software, and fewer polar groups exposed on the (100) face than on the (001) and (010) faces were found, explaining the comparatively weak interaction of the (100) face with water during hydration. Furthermore, investigation of the influence of excipients on the hydration of CBZ showed that both HPC and PVP strongly inhibited conversion, and no conversion of CBZ to DH was found after 18 h immersion in water. PEG and CMC (pH 7.5) were less potent inhibitors than HPC and PVP, and DH needles were observed on all the faces except the (100) face after 18 h immersion. No conversion was detected for the crystal immersed in CMC solution at pH 3.0. This is likely to be caused by the decreased polarity of CMC in water at pH 3.0 (pKa,cmc = 4.3), and thus a higher surface adsorption of CMC to the CBZ crystals in dispersion. The influence of excipients on the conversion of CBZ observed in this study agreed well with our previous quantitative studies using Raman spectroscopy. In this study, visual observation using electron microscopy has been demonstrated to be a unique and powerful tool to improve our understanding of polymorphic conversions of CBZ in aqueous suspension.

Carbamazepine↗
PubMed2005

Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy.

In an aqueous environment, polymorphic forms I-III of carbamazepine all convert to the dihydrate. This study investigated the conversion of each polymorphic form individually and of a mixture of forms III and I to the dihydrate. Two batches of form I with different crystal morphology were used. Samples were dispersed independently in water at 23+/-1 degrees C and recovered at various timepoints varying from 10 to 210 min. Scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy were used to characterize the initial polymorphic forms and the recovered samples after 210 min. Raman spectroscopy combined with partial least squares analysis was used to generate quantitative models of binary and ternary mixtures of the different polymorphic forms with the dihydrate. On the basis of these models the conversion kinetics of the polymorphic forms I-III were characterized. First-order kinetics with an unconverted portion were used to model the data (R2> or =0.95). The unconverted portions ranged from 16 to 51% after dispersion for 210 min. The conversion kinetics were similar between polymorphic forms with comparable crystal morphology, but differed significantly between batches of the same polymorph (form I) with different crystal morphology. Furthermore, the conversion of forms III and I in the aqueous suspension was not influenced by the presence of the other polymorph when dispersed together.

Anticonvulsants↗
PubMed2001

Influence of storage on in-vitro release of ibuprofen from sugar coated tablets.

Studies performed on ibuprofen tablets (one brand of 400 mg, two brands of 200 mg sugar coated and one brand of film coated tablets) are reported. Tablets were subjected to conditions of 23 degrees C, 30 degrees C and 40 degrees C; at 75% RH and 96% RH for periods of up to 4 weeks. Tablets were stored in different ways--unpacked, packed in air-tight/moisture proof containers, packed in tablet vials and packed in two unit dose packs. Dissolution was carried out in pH 7.2 phosphate buffer using USP or FDA conditions for ibuprofen (Basket-150 rpm or Paddle-50 rpm) with sampling and UV analysis up to 90 or 120 min. Serious reduction in dissolution was noted for the 400 mg sugar coated tablets exposed to moisture. Mean % released at 30 mm (USP conditions) was as low as 1% and, for these tablets, dissolution continued to proceed extremely slowly for the full dissolution period. The film coated tablets were not affected. The tablet vials and unit dose packs showed some protection. Investigation showed not only a change in the subcoat properties (which did not break down easily) but also in the tablet core, which became hard and non-disintegrating.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Content of CYP3A4 inhibitors, naringin, naringenin and bergapten in grapefruit and grapefruit juice products.

The flavonoids, naringin and naringenin and the furanocoumarin, bergapten (5-methoxypsoralen), were detected in some fresh grapefruit and commercial grapefruit juices but were not detected in other fruit juices tested (orange; orange with apple base; dark grape; orange and mango with apple base; orange, peach, passion fruit juice). The contents of these three grapefruit constituents in commercial juice and fresh grapefruit varied from brand to brand and also from lot to lot. Juice was prepared from the fresh fruit via different methods (by hand, squeezer or blender). The naringin content, after hand-squeeze, ranged from 115 to 384 mg/l. With hand-squeeze juice production, bergapten was not detected (less than 0.5 mg/l) in two varieties of grapefruit, and naringenin was usually not in detectable levels (less than 2 mg/l) in three varieties. All three constituents were present in New Zealand grapefruit preparations (including juice by hand-squeeze) and different lots showed variation in content (1.5-, 2.3- and 4.7-fold for naringin, naringenin and bergapten, respectively). Differences in the concentrations of these three constituents, which have potential for drug interaction, may contribute to the variability in pharmacokinetics of CYP3A4 drugs and some contradictory results of drug interaction studies with grapefruit juice.

5-Methoxypsoralen↗
PubMed2000

Stability of polymorphic forms of ranitidine hydrochloride.

Ranitidine-HCl can exist in two different polymorphic forms: form I (m.p. 134-140 degrees C) and form II (m.p. 140-144 degrees C). In the present study the stability of form I of ranitidine-HCl to a selection of powder pretreatments, to reflect conditions which might occur in manufacturing procedures, and also to a limited range of storage conditions was investigated. The original samples of form I and form II used were characterised by X-ray powder diffraction (XRPD), hot stage microscopy (HSM) and differential scanning calorimetry (DSC). A quantitative XRPD method for determining the fraction of form II in the presence of form I was used. XRPD data were analysed using regression techniques and artificial neural networks (ANN). The quantitative XRPD technique was then used to monitor the relative proportion of form II in each treated sample. Pretreatments of form I included (i) mixing with form II or with common excipients (ii) compression and grinding (iii) contact with solvents (followed by drying) before storage. Storage conditions involved three temperatures (20 degrees C, 30 degrees C, 42 degrees C) and three relative humidities (45% RH; 55% RH; 75% RH). Samples were stored for a period of 6 months. A limited factorial design was used. No increase in the form II:form I ratio was observed in the following pretreatment processes: introduction of form II nuclei into form I; introduction of excipients to form I; compression of form I powder at 5 and 15 tons; normal mixing and grinding processes; addition of isopropanol (IPA) or water/IPA mix followed by drying. In the pretreatment process where water was added to form I powder (with most or all of the powder dissolving), drying of the liquefied mass led to a mix of form I and form II. On storage at room temperature (20-30 degrees C), low relative humidity (45-55% RH), and in an air-tight container there was no increase in the form II:form I ratio. Storage of form I/form II mixes, particularly at high humidity, resulted in a preferential loss of form II (compared to form I). Loss was greater at 30 degrees C/75% RH than at 20 degrees C/75% RH. Form II was also preferentially lost under low humidity conditions created by a saturated solution of potassium carbonate (45% RH) at the elevated temperature of 42 degrees C. This environment was shown to be acidic.

Calorimetry, Differential Scanning↗
PubMed1999

In vitro hepatic metabolism of a CYP3A-mediated drug, quinine, in Adélie penguins.

Very little is known about Antarctic animals' ability to metabolise or detoxify xenobiotics. The activity of cytochromes P450 subfamily 3A (CYP3A) in Adélie penguin liver was studied by incubating penguin liver microsomes with a human CYP3A substrate, quinine, and results were compared with those from human liver microsomes. The mean maximum rate of metabolism (Vmax) for quinine in penguin livers was approximately five times less (160+/-72 versus 574+/-416 pmol/mg/min; P<0.01), and the mean Km (substrate affinity) for the formation of quinine's major metabolite (3-hydroxyquinine) was significantly greater than that observed in human livers (160+/-73 versus 83+/-19 microM; P<0.01). The mean intrinsic clearance (Vmax/Km) was 1.1+/-0.4 microl/min (penguin), i.e. sevenfold less than in human livers (7.4+/-5.9 microl/min, P<0.005), suggesting that penguins have much less ability than humans to eliminate xenobiotics having a similar metabolic nature to quinine (i.e. CYP3A substrates). 3-Hydroxyquinine formation in penguin liver was inhibited by specific CYP3A inhibitors, midazolam and troleandomycin, but not by other CYP inhibitors, indicating that quinine metabolism to 3-hydroxyquinine in Adélie penguin liver is likely to be catalysed by a CYP isoform resembling human CYP3A. Adélie penguin liver CYP isoforms could serve as biomarkers for the impact of environmental pollution.

Animals↗
PubMed1996

Tactical control of ovine Campylobacter abortion outbreaks with a bacterin.

Abortions due to Campylobacter fetus fetus (C. fetus fetus) were diagnosed in three Canterbury ewe flocks 6 weeks prior to lambing. In two of the flocks, two inoculations of a C. fetus fetus bacterin, 10 days apart, reduced the incidence of abortions in the treated ewes to about one third and one half respectively of the level in the control ewes in the same flock. The treatment had no effect in a third flock where an outbreak had been in progress for 2 weeks before investigations started. The results confirm earlier Scottish work where pregnant sheep were inoculated with a C. fetus fetus vaccine following artificial challenge with C. fetus fetus. This inoculation significantly reduced the number of C. fetus fetus abortions. The results also indicate that treatment must start very early in an outbreak.

Journal Article↗
PubMed1992

Increase in selenium status of Christchurch adults associated with deregulation of the wheat market.

AIMS: to determine whether there have been changes in the plasma selenium status of Christchurch adults between 1981 and 1992, and likely causes of any such changes. METHOD: selenium analyses were performed on plasma samples collected during the period. Changes in agricultural practices and importation policies were also examined. RESULTS: mean plasma selenium levels ranged between 46 and 54 micrograms/L (0.59-0.69 mumol/L) until 1987, after which there was a dramatic and sustained increase to between 66 and 70 micrograms/L (0.84-0.88 mumol/L) for 1988-91, with a 1992 mean of 80 micrograms/L (1.01 mumol/L). This increase closely follows the deregulation of the New Zealand wheat market and greater South Island consumption of wheat imported from Australia and the United States. Whereas flour was made from South Island wheat prior to 1988 and contained about 15 micrograms/kg selenium, flour manufactured by Christchurch mills in 1991 contained between 80 and 140 micrograms/kg. CONCLUSIONS: these results imply that as a result of current government policy, the population of Christchurch no longer has particularly low selenium levels. It follows that if there is an association between low selenium and any form of ill health, a declining incidence or severity in this population might be expected.

Adult↗
PubMedDate not supplied

Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds.

PURPOSE: To evaluate the inhibition of CYP3A4 activity in human liver microsomes by flavonoids, furanocoumarins and related compounds and investigate possibly more important and potential inhibitors of CYP3A4 in grapefruit juice. METHODS: The effects of various flavonoids and furanocoumarin derivatives on CYP3A4 activity in two human liver microsomal samples was determined using quinine as a substrate. All flavonoids and furanocoumarin derivatives were dissolved in DMSO. In all cases, inhibition activities were compared with activities in control incubations containing 0.2% (v/v) DMSO. RESULTS: The results showed that the inhibition of quinine 3-hydroxylation (CYP3A4 activity) by bergapten (67%), and quercetin (55%) was greater than naringenin (39%) and naringin (6%), at the same inhibitor concentration of 100 M. The results also demonstrated that the furan ring in the furanocoumarins enhanced the inhibitory effect on CYP3A4 activity. Flavonoids with more phenolic hydroxyl (-OH) groups produced stronger inhibition than those with less hydroxyl groups. Of all the chemicals studied, bergapten (5-methoxypsoralen) with the lowest IC50 value (19-36 microM) was the most potent CYP3A4 inhibitor. CONCLUSIONS: These results suggest that more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4. Bergapten appears to be a potent inhibitor of CYP3A4, and may therefore be primarily responsible for the effect of grapefruit juice on CYP3A4 activity.

Beverages↗