Mini-matrix multiple unit dosage forms (MUDFs) of diclofenac sodium and S(+) ibuprofen have been prepared. Normal tabletting techniques were used to form the mini-matrices prior to their enclosure in hard gelatin capsules. Four natural hydrophilic gums, namely xanthan, karaya, locust bean and carrageenan gums as well as hydroxypropyl methylcellulose (HPMC) were used as the principle release-retarding agents. Various excipients - lactose, Encompress®, cellulose acetate phthalate (CAP), Veegum F® and Avicel PH101® - were added in different proportions to further modify drug release. The diclofenac sodium mini-matrices (4.5 mm in diameter) were produced by the wet granulation method. The release profiles from several encapsulated minimatrices in phosphate buffer solution (pH 7.0) showed that xanthan, karaya and locust bean gums could sustain the release of diclofenac sodium while the carrageenan gum did not produce a satisfactory sustaining effect. The rank order of decreasing swelling rate in both axial and radial dimensions was xanthan > karaya > locust bean gum and each of these gums showed almost Fickian swelling behaviour. The solvent penetration rates were consistent with the swelling rates. However, the order of decreasing drug release and erosion rates was locust bean> xanthan > karaya gum. For each of these gums, the release behaviour was anomalous indicating that both Fickian drug diffusion and polymer relaxation were involved in the release process. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution period. The study involving xanthan gum showed that the diclofenac sodium release rate declined linearly with a progressive increase in the gumcontent, without changing the release behaviour. However, for high drug: xanthan gum ratio (2:1), the release kinetics changed to Super Case II. Solubility differences between the excipients did not affect the release rate, but increasing proportions of each excipient produced a faster release rate with the release mechanism changing from anomalous to Case II and then to Super Case II transport. Mini-matrices containing HPMC produced faster drug release than those containing the three natural gums. There was no synergistic effect between xanthan and locust bean gums on the release of diclofenac sodium from mini-matrices. Variation in the stirring speed (used in the dissolution apparatus) and matrix volume had little effect on drug release, whereas the pH of the dissolution medium greatly affected the release of diclofenac sodium. Following on from the studies involving diclofenac sodium, xanthan and karaya gums were used to produce mini-matrices of S(+) ibuprofen. Excipients with good compressibility characteristics such as lactose, Encompress® and Avicel PH101® were needed in the formulations. At pH 7, higher drug release rates were obtained with karaya gum (Super Case II mechanism) compared with xanthan gum (anomalous behaviour). Solubility differences between the excipients slightly affected the release rate. Compression forces (11 - 26 kN) slightly affected the crushing strength. The minimatrices were relatively stable to variation in temperature (5 - 37°C) and relative humidity (10 - 75%) over a 2 month time period. These studies have shown that near zero-order release of diclofenac sodium and S(+) ibuprofen can be achieved using encapsulated mini-matrices formulations. The release mechanisms and release rates can be adjusted by variation of the type and content of gums and/or excipients.

This study considered the use of urea eutectics as fast release solid dosage carrier forms for the acaricide N-methylbis (2,4-xylyliminomethyl) methylamine (AmitrazTM). Wettol D2 and Arkopal N090 were chosen as the wetting agent and dispersants respectively. Their optimum levels were determined as the surfactant concentrations that yielded a minimum in the dispersion viscosity of a concentrated (30% m/m) Amitraz suspension. The optimum dosage levels were found to be ca. 2% Arkopal N090 and ca. 1% Wettol D2. Eutectic phase diagrams were obtained using the melting-cooling method. The components were ground together into a fine powder and heated in a glass tube immersed in a silicon oil bath. The liquid was allowed to cool down and solidify at ambient conditions. The time-dependant temperature change of the sample was tracked with a thermocouple. The data was captured in real time on a personal computer and analysed using an Excel spreadsheet programme. The melt-cast method was used to prepare eutectic mixtures. They were characterised using DSC, DTA, XRD and Light Microscopy. The XRD peaks showed the presence of the two separate crystal structures for the eutectic mixture constituents. The urea – CaBr2.2H2O combination was initially considered as carrier for Amitraz. However, this eutectic system was found to be too hygroscopic. Small additions of PEG 6000 improved the tablet strength but decreased the dissolution rate. Urea and acetamide formed a eutectic at ± 46oC with a composition of ca. 40 % m/m urea. Unfortunately acetamide is a suspected carcinogen. Therefore the urea - 1,3-dimethylurea was selected as Amitraz carrier system instead. The eutectic mixture comprised 40% m/m urea and 60% m/m 1,3-dimethylurea, which melt at ± 56oC. The melt-press method was used to prepare Amitraz containing pellets measuring 5 mm thick and 33 mm ö and weighing about 5,0 g. It was possible to suspend Amitraz powder in the eutectic melt mixture provided it remained in powder form. However, when liquefied (by melting), phase separation occurred. Thus the temperature of the eutectic mixture should be kept below the 80oC melting point of Amitraz. The dissolution tests were performed in a 10-liter Pyrex glass beaker with normal tap water (± 25oC). The time taken for complete dissolution was measured with a stopwatch. These results were confirmed with turbidity tests. Starch-based super disintegrants were used in an attempt to enhance the dissolution rate of the pellets. Explotab® improved the dissolution rate of 30% and 40% m/m Amitraz formulations slightly. The best formulation obtained in this study had the following composition (in m/m): 30% Amitraz; 8% CaCO3; 1 % Wettol D2; 2% Arkopal N090; 10% Explotab® and 49% urea – 1,3-dimethylurea eutectic. Such tablets disintegrated within 6,5 minutes when suspended in water. / Dissertation (MSc (Applied Science))--University of Pretoria, 2007. / Chemical Engineering / MSc / unrestricted

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is a complex genetic disorder caused by the triplication of human chromosome 21 (Hsa21). The presence of an extra copy of an entire chromosome greatly disrupts the copy number and expression of over 350 protein coding genes. This gene dosage imbalance has far-reaching effects on normal development and aging, leading to cognitive and skeletal defects that emerge earlier in life than the general population. The present study begins by characterizing skeletal development in young male Ts65Dn mice to test the hypothesis that skeletal defects in male Ts65Dn mice are developmental in nature.Femurs from young mice ranging from postnatal day 12- to 42-days of age (P12-42) were measured and analyzed by microcomputed tomography (μCT). Cortical defects were present generally throughout development, but trabecular defects emerged at P30 and persisted until P42. The gene Dual-specificity tyrosine-regulated kinase 1a (Dyrk1a) is triplicated in both DS and in Ts65Dn mice and has been implicated as a putative cause of both cognitive and skeletal defects. To test the hypothesis that trisomic Dyrk1a is related to the emergence of trabecular defects at P30, expression of Dyrk1a in the femurs of male Ts65Dn mice was quantified by qPCR. Expression was shown to fluctuate throughout development and overexpression generally aligned with the emergence of trabecular defects at P30. The growth rate in trabecular measures between male Ts65Dn and euploid littermates was similar between P30 and P42, suggesting a closer look into cellular mechanisms at P42. Assessment of proliferation of BMSCs, differentiation and activity of osteoblasts showed no significant differences between Ts65Dn and euploid cellular activity, suggesting that the cellular microenvironment has a greater influence on cellular activity than genetic background. These data led to the hypothesis that reduction of Dyrk1a gene expression and pharmacological inhibition of DYRK1A could be executed during a critical period to prevent the emergence of trabecular defects at P30. To tests this hypothesis, doxycycline-induced cre-lox recombination to reduce Dyrk1a gene copy number or the DYRK1A inhibitor CX-4945 began at P21. The results of both genetic and pharmacological interventions suggest that trisomic Dyrk1a does not influence the emergence of trabecular defects up to P30. Instead, data suggest that the critical window for the rescue of trabecular defects lies between P30 and P42.

Controlled-release formulations for pesticide applications act as depot systems that continuously release the active ingredients into the environment over a speci ed period, usually from months to years. However, some applications require fast-dissolving drug delivery. The interest of this research is in fast-release of water-insoluble pesticides into aquatic environments. This study considered the use of dextrin starch and urea eutectics as fast release, solid dosage carrier forms that contain an active ingredient. The chosen active for this study is an acaricide called amitraz (N-methylbis-(2,4-xylyliminomethyl)- methylamine). The focus is on matrix-based dosage forms such as tablets, granules or bres that either disintegrate or dissolve to release a water-insoluble active. These types of dosage forms can be fabricated using processes such as lyophilisation, spray drying, solvent casting, hot melt extrusion, compression moulding, wet granulation, compaction and electrospinning. A simple melt-casting procedure has been discussed in the present work. Dextrin is a water-soluble form of partially hydrolysed starch and is a promising candidate matrix material for dissolving solid dosage forms. The molecular weight of the dextrin was analysed with MALDI-TOF methods and rheological relations. Glycerolplasticized thermoplastic dextrin-based nanocomposites were prepared with a twin-screw extrusion-compounding process. The nano llers included a layered double hydroxide (LDH), cellulose nano bres (CNF) and stearic acid. The time-dependent retrogradation of the compounds was monitored by X-ray di raction (XRD) and dynamic mechanical thermal analysis (DMA). XRD showed that the inclusion of stearic acid in the formulations led to the formation of an amylose-lipid complex and a stable crystallinity during ageing. Dissolution rates in water for samples containing dextrin starch, were characterised using an iodine indicator and UV-visible spectroscopy. High pressure di erential scanning calorimetry (HPDSC) indicated that the addition of stearic acid led to the formation of amylose-lipid complexes (ALC's). An additive system containing stearic acid and CNF was deemed suitable for compounding with amitraz. Compounding at temperatures above the melting point of the latter led, on dissolution in water, to the release of much ner particles of the acaricide, which was con rmed with particle size analysis (PSA). The addition of the acaricide caused an apparent increase in the dissolution rate of the thermoplastic dextrin. Two eutectic urea systems were considered for casting with amitraz. A eutectic system of urea and acetamide was found to display a melting point of 44 C at a 37 wt.% urea composition. The other system consisting of urea and 1,3-dimethylurea displayed a eutectic point at 32 wt.% urea composition which melted at 59 C. Di erential scanning calorimetry (DSC), however, con rmed a melting point depression due to a high moisture content caused by the compounds high hygroscopicity. The endotherm of the sample containing no excess moisture showed a melting point of 70 C. The 1,3-dimethylurea system was deemed suitable for casting with amitraz. XRD of the eutectic composition indicated a small amount of co-crystallisation. The samples were cast as disks of various diameters while keeping the height of the disks constant. The creation of the cast disks showed automatic generation of a nely dispersed form of the active through the process of melting the deep eutectic solvent, the dissolution of the active and its phase separation on cooling and solidi cation of the eutectic. This implies that ne grinding of the actives might not be necessary. Eutectic casts containing 20 wt.% amitraz dissolved at a slower rate than casts not containing the hydrophobic active ingredient. The advantageous features of these casts were exempli ed using the acaricide incorporated into the urea & 1,3-dimethylurea eutectic. This work provides two safe, biodegradable and water soluble materials for use as a matrix to contain active ingredients. One material, the eutectic organic salt casts, can be produced at low temperatures (<100 C) and can be directly cast into storage containers. The complete dissolution of the cast compounded with a hydrophilic active is rapid (4-6 min). The second material, a thermoplastic dextrin, was melt compounded in an extruder at temperatures not exceeding 120 C. This compound containing 20 wt.% of the active dissolved over a 12 hour period. Dextrin, known to be widely used as an adhesive, will aid in the adhesion of the active ingredient to the surface where it must be used. / Dissertation (MEng (Chemical Engineering))--University of Pretoria, 2020. / PAMSA / Department of Science and Innovation under Grant DST/CON 0004/2019 / Chemical Engineering / MEng (Chemical Engineering) / Unrestricted

Little is known about dosage compensation in autosomal genes. Transcription-level compensation of deletions and other loss-of-function mutations may be a mechanism of dominance of wild-type alleles, a ubiquitous phenomenon whose nature has been a subject of a long debate. We measured gene expression in two isogenic Drosophila lines heterozygous for long deletions and compared our results with previously published gene expression data in a line heterozygous for a long duplication. We find that a majority of genes are at least partially compensated at transcription, both for 1/2-fold dosage (in heterozygotes for deletions) and for 1.5-fold dosage (in heterozygotes for a duplication). The degree of compensation does not vary among functional classes of genes. Compensation for deletions is stronger for highly expressed genes. In contrast, the degree of compensation for duplications is stronger for weakly expressed genes. Thus, partial transcriptional compensation appears to be based on regulatory mechanisms that insure high transcription levels of some genes and low transcription levels of other genes, instead of precise maintenance of a particular homeostatic expression level. Given the ubiquity of transcriptional compensation, dominance of wild-type alleles may be at least partially caused by of the regulation at transcription level.

This study investigated the influence of tobacco use on postoperative narcotic requirements of female patients following pelvic surgery. The history of tobacco use was taken by telephone survey, and the amount of postoperative narcotic used was obtained from a retrospective review of the patients’ hospital charts. Postoperative narcotic use for patients who never smoked was 10.9 mg/12 hr (n = 83, S.E. = 0.5), for former smokers was 13.0 mg/12 hr (n = 33, S.E. = 0.8) and for current smokers was 13.1 mg/12 hr (n = 53, S.E. = 0.7). Patients who never smoked used significantly less narcotic than former smokers (p =.02) or current smokers (p =.007). There was no difference between current and former smokers. Patients who have smoked required more narcotic for postoperative pain control. This effect was equally strong for former as for current smokers.

We report on 3 subjects with premenstrual magnification of major depression (PMMD) treated with nefazodone who benefited from a supplement of additional nefazodone premenstrually. During the 6-month study, subjects were given supplements of either additional nefazodone or placebo prior to the expected onset of menses (double-blind crossover design). Symptoms were assessed during the late luteal and follicular phases. All subjects showed significant improvement for the months in which they received nefazodone supplements, but not when given placebo. Premenstrual dose increase is a clinically promising intervention for women who experience PMMD.

Indiana University-Purdue University Indianapolis (IUPUI) / Root surface caries is an increasing problem in the United States as more of the population are retaining their teeth to an older age. The disease requires the recession of gingival tissue and resorption of alveolar bone prior to exposure of the root surface. Animal models for root surface caries provide a means to investigate the etiology and treatment of the disease. The Golden Syrian hamster has been used as a model, and alveolar bone loss and root exposure are induced by feeding the animals a high glucose diet. Significant bone loss, when compared to control groups, is usually detected within five weeks. At present, the use of non-steroidal anti-inflammatory drugs in the treatment of periodontal disease is an area of great interest. As there is a role of host response in the alveolar bone destruction seen in periodontitis, inhibition of this prostaglandin-mediated process may provide a means of treatment. Flurbiprofen (Ansaid™, Upjohn Co., Kalamazoo, Ml) has been widely studied and appears to inhibit this bone loss in a variety of animals, including man. The purposes of the study were to determine if the early alveolar bone loss occurring after three, four and five weeks' exposure to the high carbohydrate diet could be quantitated with fluorescent bone labels, and if this bone loss could be inhibited by daily administration of flurbiprofen. The animals received a series of four intraperitoneally-injected fluorochrome labels over a one-month period, then were fed ground lab chow, the high carbohydrate MIT-200GI diet or the MIT-200GI diet plus flurbiprofen. At the end of three, four and five weeks, animals were euthanized, and the mandibles were prepared for analysis. Statistical analysis of gross and histomorphometric measurements detected no significant differences between the experimental groups. It is suspected that the diets failed to produce periodontal disease in this experiment, possibly due to changes in the oral microflora caused by administration of tetracycline as the final bone label. There was much variation in the presence of bone labels, but they were able to provide the growth velocity of the alveolar complex. Flurbiprofen administration produced no measurable effects, but the animals did tolerate the dosage given. Future studies should consider variation of the labels and a different route of administration.

This pilot study adds to the limited literature by examining various forms of dosage (i.e., absence rate; stability in years) within a quality early childhood center and its links to multiple criterion-referenced indicators of school readiness (i.e., gross motor, fine motor, pre-writing, cognitive, language, self-help, personal/social developmental). The sample included 46 children between the ages of 3 and 4-years-old primarily from middle to upper-middle socioeconomic backgrounds. Absence rates were determined via daily sign-in sheets, while stability was determined according to center records. Results indicate stability, not absence rate, as a statistically significant predictor of better performance on two school readiness domains, namely gross motor and personal/social development. This preliminary exploration gives implications to programs, parents, and teachers as it relates to best practices in attendance in early childhood.

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