Evaluation of the wrist-worn ActiGraph wGT3x-BT for estimating activity energy expenditure in preschool children.

BACKGROUND/OBJECTIVES: Easy-to-use and accurate methods to assess free-living activity energy expenditure (AEE) in preschool children are required. The aims of this study in healthy preschool children were to (a) evaluate the ability of the wrist-worn ActiGraph wGT3x-BT to predict free-living AEE and (b) assess wear compliance using a 7-day, 24-h protocol. SUBJECTS/METHODS: Participants were 40 Swedish children (5.5±0.2 years) in the Mobile-based intervention intended to stop obesity in preschoolers (MINISTOP) obesity prevention trial. Total energy expenditure (TEE) was assessed using the doubly labeled water method during 14 days. AEE was calculated as (TEEx0.9) minus predicted basal metabolic rate. The ActiGraph accelerometer was worn on the wrist for 7 days and outputs used were mean of the daily and awake filtered vector magnitude (mean VM total and mean VM waking). RESULTS: The ActiGraph was worn for 7 (n=34, 85%), 6 (n=4, 10%), 5 (n=1, 2.5%) and 4 (n=1, 2.5%) days (a valid day was ⩾600 awake minutes). Alone, mean VM total and mean VM waking were able to explain 14% (P=0.009) and 24% (P=0.001) of the variation in AEE, respectively. By incorporating fat and fat-free mass in the models 58% (mean VM total) and 62% (mean VM waking) in the variation of AEE was explained (P<0.001). CONCLUSIONS: The wrist-worn ActiGraph wGT3x-BT in combination with body composition variables explained up to the 62% of the variation in AEE. Given the high wear compliance, the wrist-worn ActiGraph has the potential to provide useful information in studies where physical activity in preschool children is measured.

Parental body mass index and its association with body composition, physical fitness and lifestyle factors in their 4-year-old children: results from the MINISTOP trial.

BACKGROUND/OBJECTIVES: To examine the association between parental body mass index (BMI) and their offspring's body composition, physical fitness and lifestyle factors (that is, sedentary time, physical activity and diet). SUBJECTS/METHODS: A total of 307 preschoolers (4.5±0.1 years) and their parents (fathers: 38.1±5.1 years and mothers: 35.6±4.2 years) participated in this study. Parental BMI was calculated using self-reported weight and height. Preschoolers body composition was assessed using: BMI, fat mass percentage, fat mass index, fat-free mass index (measured via air-displacement plethysmography) and waist circumference. Physical fitness was assessed by the PREFIT fitness battery. Lifestyle factors were assessed using the ActiGraph wGT3x-BT (sedentary time and physical activity), and the mobile-phone based tool for energy balance in children (diet). RESULTS: Parental BMI were positively associated with their offspring's BMI (paternal BMI: standardised beta, ß=0.233, P<0.001; maternal BMI: ß=0.186, P=0.001), fat mass index (paternal BMI: ß=0.130, P=0.026; maternal BMI: ß=0.163, P=0.005), fat-free mass index (paternal BMI: ß=0.214, P<0.001; maternal BMI: ß=0.119, P=0.036) and waist circumference (paternal BMI: ß=0.178, P=0.001; maternal BMI: ß=0.179, P=0.001). A negative association was found between maternal BMI and their offspring's standing long jump test (ß=-0.132, P=0.022). Paternal BMI was associated with their offspring's sedentary time (ß=0.100, P=0.026), whereas parental BMI was not associated with neither physical activity nor diet (all P⩾0.104). CONCLUSIONS: Parental BMI was positively associated with their offspring's BMI, fat as well as fat-free mass index and waist circumference. Moreover, a higher paternal and maternal BMI were related to higher levels of sedentary time and a lower performance in the standing long jump test of their offspring, respectively.

Physical activity intensity, sedentary behavior, body composition and physical fitness in 4-year-old children: results from the ministop trial.

BACKGROUND: Existing knowledge on associations of physical activity (PA) and sedentary behavior (SB) with body composition and physical fitness in preschoolers is limited. OBJECTIVE: To examine associations of PA and SB with body composition and physical fitness in healthy Swedish 4-year-old children. METHODS: We utilized baseline data collected in 2014 for the population-based MINISTOP trial (n=307). Light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), moderate-to-vigorous PA (MVPA) and SB were measured using accelerometry (ActiGraph-wGT3x-BT). Body composition was measured using air-displacement plethysmography, and physical fitness (that is, cardiorespiratory fitness, lower and upper body muscular strength and motor fitness) was measured using the PREFIT fitness test battery. Multiple linear regression models adjusted for relevant confounders, and in addition, isotemporal substitution models were applied. RESULTS: Greater MVPA was associated with lower fat mass percent (%FM, P=0.015), and greater VPA and MVPA were associated with higher fat-free mass index (FFMI, P=0.002 and P=0.011). In addition, greater VPA and MVPA were associated with higher scores for all physical fitness tests (P=0.042 to P<0.001). The results for MVPA were primarily due to VPA. SB was associated with weaker handgrip strength (P=0.031) when PA was not adjusted, but after adjusting also for VPA, the significant association disappeared (P=0.25). Substituting 5 min per day of SB, LPA or MPA with 5 min per day of VPA was associated with higher FFMI and better scores for cardiorespiratory fitness and motor fitness. Correspondingly, substituting 5 min per day of VPA with SB or LPA was associated with weaker performance for lower muscular strength. CONCLUSIONS: Time spent on VPA was associated with higher FFMI and better physical fitness. The results suggest that promoting VPA may be important to improve childhood body composition and physical fitness already at an early age.

Prevalence of overweight/obesity and fitness level in preschool children from the north compared with the south of Europe: an exploration with two countries.

BACKGROUND: North-south differences in the prevalence of obesity and fitness levels have been found in European adolescents, yet it is unknown if such differences already exist in very young children. OBJECTIVES: This study aims to compare the prevalence of overweight/obesity and fitness levels in preschool children aged 4 years from Sweden (north of Europe) and Spain (south of Europe). METHODS: The sample consisted of 315 Swedish and 128 Spanish preschoolers. Anthropometry (weight, height, waist circumference) and fitness (strength, speed-agility, balance and cardiorespiratory fitness) were assessed. Analysis of covariance adjusted for age, sex and height/body mass index (BMI) was used. RESULTS: Preschool children from Sweden had lower prevalence of overweight/obesity than their peers from Spain (World Obesity Federation, mean difference, MD = -9%, P = 0.010; World Health Organization, MD = -11%, P = 0.011). Concerning fitness, preschoolers from Spain were more fit in terms of upper-muscular strength (MD = +0.4 kg, P = 0.010), speed-agility (MD = -1.9 s, P = 0.001), balance (MD = +4.0 s, P = 0.001) and cardiorespiratory fitness (MD = boys = +6.6 laps, girls = +2.3 laps; P < 0.001 for all), yet they had worse lower-muscular strength (MD = -7.1, P ≤ 0.001) than those from Sweden. Differences in upper-muscular strength were largely explained by differences in BMI, and differences in cardiorespiratory fitness should be interpreted cautiously due to some methodological deviations. CONCLUSIONS: These findings suggest that a higher prevalence of overweight/obesity in Spain compared with Sweden is present already at early childhood, while differences in physical fitness components showed mixed findings.

Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers.

OBJECTIVES: An oral dispersible microtablet formulation of levodopa/carbidopa 5/1.25 mg (LC-5) was developed for individualized repeated dosing. The aim was to compare pharmacokinetic profiles of LC-5 and levodopa/carbidopa/entacapone (LCE). MATERIALS AND METHODS: A randomized, crossover study was carried out in 11 healthy subjects. Plasma concentrations of levodopa, carbidopa and 3-O-methyldopa were determined after intake of 300 mg levodopa during the day, either as three intakes of 100/25/200 mg LCE or as a morning dose of 75/18.25 mg followed by five repeated doses of 45/11.25 mg LC-5. RESULTS: Repeated dosing (2.4-hourly) with LC-5 microtablets compared to LCE (6-hourly) avoided long periods with low plasma levodopa levels. Time to maximum plasma concentrations was significantly shorter for LC-5. LC-5 showed lower fluctuation index (FI) in plasma compared to LCE (ANOVA P = 0.0028). FI for dose 2-5 was on average 1.26 for levodopa in LC-5, and 2.23 for dose 1-2 of LCE. The ratio between the two mean FI:s is 0.565; that is, LC-5 gave nearly half the FI as compared to LCE. CONCLUSIONS: Fractionation of levodopa with LC-5 into small, frequent administrations as compared to standard administrations of LCE decreased the FI in plasma for both levodopa and carbidopa by nearly half.

Isolation and identification of Taylorella asinigenitalis from the genital tract of a stallion, first case of a natural infection.

Contagious equine metritis (CEM), caused by Taylorella equigenitalis, is a widely known highly contagious genital equine disease that is transmitted venereally. A new bacterium, Taylorella asinigenitalis resembling T. equigenitalis was recently isolated from three American donkey jacks, at routine testing for CEM. The purpose of this study was to identify and characterize a strain of Taylorella sp. from the genital tract of a stallion. Swab samples for culture of T. equigenitalis were taken from urethral fossa, urethra and penile sheath of a 3-year-old stallion of the Ardennes breed when it was routinely tested for CEM. A small Gram-negative rod was isolated, but the colony appearance, the slow growth rate and the results in the API ZYM test differed slightly from those of T. equigenitalis. Sequencing of the 16S rRNA gene was therefore performed and phylogenetic analysis demonstrated that the sequence of the strain Bd 3751/05 represents T. asinigenitalis and that the strain is identical with the Californian asinine strain UCD-1T (ATCC 700933T). The T. asinigenitalis strain had a low MIC of gentamicin (MIC16 microg/ml). Taylorella asinigenitalis has thus for the first time been isolated from the genital tract of a stallion with a natural infection. To determine the pathogenicity of T. asinigenitalis it will be important to conduct further experimental studies. Sequence analysis of 16S rRNA genes was shown to be a reliable tool for differentiation of T. asinigenitalis from T. equigenitalis as well as for identification of these species.

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.

AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

Activation of the glucocorticoid receptor or liver X receptors interferes with growth hormone-induced akr1b7 gene expression in rat hepatocytes.

The akr1b7 gene encodes an aldo-keto reductase involved in detoxification of isocaproaldehyde, the product from side chain cleavage of cholesterol, and of 4-hydroxynonenal (4-HNE) formed by lipid peroxidation and cleavage. Here we show that the expression of akr1b7 mRNA in rat liver is sexually differentiated, expressed in females but not in males, and regulated by the sexually dimorphic secretion pattern of GH. A GH dose-dependent induction of akr1b7 was demonstrated in cultured primary rat hepatocytes, which was sensitive to cycloheximide. Activation of the glucocorticoid receptor (GR) or liver X receptors (LXR) by dexamethasone (Dex) and T1317, respectively, attenuated the GH-induced expression of akr1b7 and CYP2C12, the prototypical rat hepatic gene dependent on the female-characteristic secretion pattern of GH. In contrast, neither Dex nor T1317 had any repressive effect on the GH induction of IGF-I mRNA. A common mechanism for LXR- and GR-mediated repressive actions on gene transcription is inhibition of nuclear factor (NF)-kappaB; however, EMSAs and pharmacological interference with NF-kappaB signaling provided no evidence for the involvement of NF-kappaB in the repressive action of Dex and T1317 on GH-induced akr1b7 expression.

The use of mercury porosimetry in assessing the effect of different binders on the pore structure and bonding properties of tablets.

This study investigated the effect of binders with different deformability characteristics on the pore structure of tablets composed of binary mixtures. The pore structure was evaluated using mercury porosimetry. The pore size distribution in tablets of both individual components and binary mixtures indicated that the pores in pure binder tablets appeared not to exist to the same degree in composed tablets and were therefore unlikely to substantially contribute to the pore structure. It is therefore suggested that, because the binder undergoes extensive deformation and shearing during compaction, it will exist as relatively small lumps or aggregates or even primary particles that are located between the compound particles. Most of the pores in the binary tablets studied were thus found between particles of the compound and the binder phase. The most deformable binder, polyethylene glycol 3000, had the greatest effect on pore structure, reflected in the greatest increase in tablet strength. An attempt was also made to use mercury porosimetry data to qualitatively assess the effect of a binder on the dominating bond types in a tablet. The results indicated that addition of a binder caused a decrease in the probability of forming solid bridges.

Assessing tablet bond types from structural features that affect tablet tensile strength.

PURPOSE: The aim of this article was to study the possibility of assessing the structural features affecting tablet tensile strength to obtain information on the dominating bond types, i.e. interparticulate attractions, in tablets. METHODS: The features of the internal tablet structure considered to be important for tablet tensile strength were assessed using a simple tablet model for tablets made from seven materials: potassium chloride, sodium chloride, sodium bicarbonate, lactose, sucrose, microcrystalline cellulose, and ascorbic acid. RESULTS: Tablet porosity and particle size (measured as external specific surface area by permeametry) were the structural features that best correlated with tablet tensile strength. These features were described by a "structural factor," which was combined with tablet tensile strength, as an "interaction factor," to reflect the dominating bond types in tablets. CONCLUSION: The qualitative results gave dominating bond types in the tablets studied that matched the results of earlier studies, thus supporting the applicability of the method.

Evaluation of critical binder properties affecting the compactibility of binary mixtures.

The aim of this study was to identify essential physical and mechanical properties of various binders and to investigate their influence on the tensile strength and porosity of tablets made from binary mixtures with sodium bicarbonate. The binders were characterized according to axial and radial tensile strength after compression into tablets, yield pressure and minimum porosity during compression, and elastic recovery after compression. The addition of a binder generally resulted in an increase in the tensile strength and a decrease in the porosity of the sodium bicarbonate tablets. The location of the binder in the voids between the sodium bicarbonate particles thus decreasing the porosity of the tablet seemed to be an important consideration. Consequently, the addition of binders with a low yield pressure value and a relatively small elastic recovery value (e.g., polyethylene glycol 3000 and polyvinylpyrrolidone) resulted in tablets of low porosity and high tensile strength, especially in the axial direction. The tensile strength of the pure binder also seemed to be important, especially for binders with a lower degree of deformability (e.g., microcrystalline cellulose and pregelatinised starch). The results also indicated the value of using both axial and radial tensile strength measurements in assessing the effect of a dry binder and showed that the importance of different binder properties varied according to the direction of the tablet strength measurements. The results demonstrated that the applied characteristics of the binders used in this study may serve as a useful tool in evaluating the effectiveness of binders.

The possibility of achieving an interactive mixture with high dose homogeneity containing an extremely low proportion of a micronised drug.

The homogeneity of binary mixtures containing coarse particulate mannitol and three different size fractions of sodium salicylate particles was investigated. The proportion of sodium salicylate (0.15% w/w and 0.015% w/w) and the sample size of the mixture were also varied. The homogeneity of these experimental mixtures was compared with the theoretical values that would be expected from ordered, adhesive interactive (pseudo-random) and random model mixtures. The results indicated that adhesive interactive forces were created between the drug and the carrier particles in most of the experimental mixtures, since their homogeneity tended to be higher than that of a theoretical randomised mixture. In fact, there was some resemblance to an ideal ordered state in mixtures containing the highest drug proportion (0.15%) and the smallest particles. However, the effect of sample size was not negligible and it was concluded that the number of drug particles interacting with individual carrier particles was not constant but was in fact related to a process of randomisation. The homogeneity of the mixture was predicted using two approaches: the ratio of the number of drug to carrier particles in the mixture and the absolute number of drug particles, estimated by weight, in the sample. It is suggested that calculating the relative numbers of particles by weight in the mixture could aid in predicting the feasibility of achieving an interactive powder mixture with a high dose-homogeneity.

Evaluation of strength-enhancing factors of a ductile binder in direct compression of sodium bicarbonate and calcium carbonate powders.

This study evaluated the effectiveness of a ductile binder in direct compression of sodium bicarbonate and calcium carbonate powders. Properties associated with both the binder and the compound were studied. The addition of binder materials, such as polyethylene glycols (PEGs) of differing molecular weights or microcrystalline cellulose, generally resulted in an increase in the axial tensile strength of the corresponding compacts. The increase in tablet strength was generally greater with the PEGs than with microcrystalline cellulose. The results indicate that the improvement in tablet strength caused by the binder is dependent on properties of both the binder and the compound. By utilising different methods it was established that the fracture during tablet strength testing mainly occurred around the compound particles. As a consequence of this, it appears that the ability of the binder to fill the voids between the compound particles is a determinative factor for increasing tablet strength. The binder appeared to have less effect when added to compounds that fragmented during compaction. Characteristics of the binder resulting in the greatest decrease in porosity, and thus the greatest increase in the tensile strength of the compound, included a high degree of plastic deformation with a limited elastic component and a small particle size. Obviously, the amount of binder added to the mixture also affected the results.

Porous cellulose matrices containing lipophilic release modifiers--a potential oral extended-release system.

A multiple-unit extended-release matrix preparation was prepared by the incorporation of a hydrophilic drug (paracetamol) and lipophilic release modifiers (cetyl alcohol and paraffin) into porous cellulose matrices. The incorporation was performed using a one-step melt method. The in vitro drug release could be extended up to at least 16 h. The release rate could be controlled by varying the ratio of cetyl alcohol to paraffin. The porosity of the matrix during release increased to a larger extent than explainable by dissolution of the drug substance. This increase in porosity appears to be caused by swelling of the cellulose in combination with some erosion of the matrix material.

Use of tablet tensile strength adjusted for surface area and mean interparticulate distance to evaluate dominating bonding mechanisms.

In this study, tablet tensile strength has been adjusted for tablet surface area and the average distance between particles in compacts of different materials. The aim of the study was to evaluate the feasibility of using this concept to assess the dominating interparticulate bonding mechanisms. Adjustment of the tensile strength for both tablet surface area and mean pore radius gave similar bonding strength values for materials bonding mainly by weak distance forces (crystalline lactose, sucrose, and microcrystalline cellulose) almost independently of compaction pressure. However, particle size and other factors may still affect the compensated strength values. The bond strength was much higher and more varied for materials bonding also with solid bridges (potassium chloride, sodium chloride, and possibly also sodium bicarbonate and amorphous lactose). For these materials, particle size and compaction pressure had a substantial effect on the bond strength. It is probably the formation of continuous bridges between adjacent particles that is important in these materials rather than the surface properties and the average distance between particles positioned at some distance from each other. Hence, adjusting the tensile strength of compacts does not necessarily reflect all the dominating factors responsible for interparticulate bonding. Nonetheless, adjustment for tablet surface area and mean pore radius allowed discrimination between different dominating interparticulate bonding mechanisms in these compacted materials.

A novel tablet-based 13C urea breath test for Helicobacter pylori with enhanced performance during acid suppression therapy.

BACKGROUND: The urea breath test (UBT) can still be improved in terms of user-friendliness and accuracy during acid-suppression therapy. This study was designed to evaluate a novel, rapidly disintegrating 13C UBT tablet, which was supplemented with citric acid to facilitate diagnosis of Helicobacter pylori in the hypochlorhydric stomach. METHODS: The efficacy of a fasting 13C tablet-based UBT (TUBT) was compared with that of a standard 13C UBT (SUBT) during 40 min after dosing, and optimal sampling points were determined. The single-point TUBT was validated against a 'gold standard' (GS) including a TUBT, culture, histology, and a CLO test in 134 dyspeptic patients, and its optimal cut-off point was determined by means of a biometric method. In addition, 20 SUBT-positive patients were randomized to perform either the TUBT or the SUBT after 7 days of omeprazole therapy (20 mg twice daily). RESULTS: Compared with a SUBT, the TUBT gave a quicker and wider separation between positive and negative results and an earlier optimal sampling point (10 versus 40 min). At 10 min the TUBT correctly classified 40 of 42 GS-positive subjects (sensitivity, 95%) and all of 92 GS-negative patients (specificity, 100%), and the optimal cut-off point was 1.8 delta per mil. Furthermore, when optimal sampling points were used, the TUBT (t = 10 min) proved to be more accurate than the SUBT (t = 40 min) during omeprazole treatment, correctly identifying all of 10 and 3 of 9 H. pylori-infected patients, respectively. CONCLUSIONS: By supplying 13C urea and citric acid as a rapid-release tablet, it is possible to shorten the duration of the 13C UBT to 10 min, omit the test meal, and still maintain excellent accuracy, even during acid suppression therapy.

The effects of disordered structure on the solubility and dissolution rates of some hydrophilic, sparingly soluble drugs.

The effects of experimental design on the apparent solubility of two sparingly soluble hydrophilic compounds (barium sulphate and calcium carbonate) were studied in this paper. The apparent solubility appeared to be primarily dependent on the amount of solute added to the solvent in each experiment, increasing with increased amounts. This effect seems to be due to the existence of a peripheral disordered layer. However physico-chemical methods used in the present study were not able to unambiguously verify the existence of any disorder in the solid state structure of the drugs. At higher proportions of solute to solvent, the solubility reached a plateau corresponding to the solubility of the disordered or amorphous molecular form of the material. Milling the powders caused the plateau to be reached at lower proportions of solute to solvent, since this further disordered the surface of the drug particles. It was also found that the apparent solubility of the drugs tested decreased after storage at high relative humidities. A model for describing the effects of a disordered surface layer of varying thickness and continuity on the solubility of a substance is presented. This model may be used as a method for detection of minute amount of disorder, where no other technique is capable of detecting the disordered structure. It is suggested that recrystallisation of the material occurs via slow solid-state transition at the surface of the drug particle; this would slowly reduce the apparent solubility of the substance at the plateau level to the thermodynamically stable value. A biphasic dissolution rate profile was obtained. The solubility of the disordered surface of the particles appeared to be the rate-determining factor during the initial dissolution phase, while the solubility of the crystalline core was the rate-determining factor during the final slower phase.

The effect of dry mixing on the apparent solubility of hydrophobic, sparingly soluble drugs.

The effect of dry mixing on the apparent solubility of two hydrophobic sparingly soluble drugs was studied. The materials were mixed with NaCl or glass beads in a Turbula mixer and the changes in solubility were monitored. It was shown that dry mixing caused an increase in the apparent solubility of test materials. It is suggested that the surfaces of the particles become activated and disordered during the dry mixing process. This peripheral surface disorder appears to be responsible for the increase in solubility. It was also shown that apparent solubility of the drugs after dry mixing was strongly dependent on the amount of drug added to the solvent, increasing with increasing concentrations. A plateau was established gradually at higher proportions of drug to solvent. Finally the applicability of the solubility model described by Mosharraf et al. (1999) [Mosharraf, M., Sebhatu, T., Nyström, C., 1999. The effects of disordered structure on solubility and dissolution rates of hydrophilic, sparingly soluble drugs. Int. J. Pharm. 177, 29-51] to the solubility behaviour of the hydrophobic sparingly soluble drugs tested in this study was confirmed. The results suggested that the equilibrium solubility plateau levels of a disordered material are determined by the degree and the location of disorder on the individual particles.

Characterisation of particle properties and compaction behaviour of hydroxypropyl methylcellulose with different degrees of methoxy/hydroxypropyl substitution.

The particle characteristics and compaction behaviour of hydroxypropyl methylcellulose (HPMC) powders from two different suppliers were studied regarding effects of methoxy/hydroxypropyl substitution. Samples included Methocel K4M (low substitution ratio), E4M (medium) and F4M (high) and the corresponding substitution ratios from Metolose: 90 SH 4000, 60 SH 4000, and 65 SH 4000. Characterisation of the particle properties and compaction behaviour of the pure polymers suggested that reported differences in drug release behaviour of Methocel E4M compared with the other two powders may be related to the lower powder surface area, differing particle morphology and lower fragmentation propensity during compaction. In addition, compacts of Methocel E4M were weaker when tested in both axial and radial directions and had different porosity and elastic recovery properties. There were no differences between the polymers in degree of disorder, as evaluated by solid-state nuclear magnetic resonance spectroscopy. The different behaviour of Methocel E4M could, however, be related to the overall higher total degree of substitution of this polymer and in particular the high content of methoxy groups compared to the other polymers. The methoxy substituent is hydrophobic and may, when present in sufficiently high concentrations, change the particulate and mechanical properties of the powder, thus potentially affecting the compactability. The high content of methoxy groups might also decrease the development of inter- and intraparticulate hydrogen bonds during compaction, and suppress the actions of the hydrophilic hydroxypropyl groups, both of which could affect drug release.

Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson's disease.

OBJECTIVE: To evaluate the effects of continuous duodenal infusion of levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of levodopa constant. MATERIAL AND METHODS: In view of the low water solubility of levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2 1/2 years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma levodopa concentrations were analysed every 15 min. RESULTS: The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2 1/2 years levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased. CONCLUSION: Continuous duodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.