Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.     

Modifying drug release and tablet properties of starch acetate tablets by dry powder agglomeration

In this study three model drugs (N-acetyl-D-glucosamine (NAG), anhydrous caffeine, and propranolol hydrochloride) were agglomerated with starch acetate (SA) by mixing the binary powders on a stainless steel (SS) plate. Agglomeration was induced by triboelectrification of the particles during mixing, and it was evaluated as a method to achieve controlled drug release rate. These agglomerates, mixed with different amounts of a disintegrant, were compressed into tablets whose dissolution characteristics were determined. Triboelectric measurements showed that when the drugs were in contact with SS, charges of the opposite polarity were generated to SA (+) and caffeine and NAG (-) promoting adhesion. Instead, propranolol HCl was charged with the same polarity as SA. SEM micrographs showed that smaller caffeine particles, in spite of their larger negative charge, agglomerated less efficiently with SA than larger NAG particles. This emphasizes the importance of particle size in the agglomeration process. Propranolol HCl did not form agglomerates with SA since their particle sizes and charges were identical. As a result, agglomeration of powders prior to tablet compression allows for modification and control of the release rate of the drugs from the SA matrix tablets as well as the tensile strength of the tablets.     

Perfusion defect size predicts engraftment but not early retention of intra-myocardially injected cardiosphere-derived cells after acute myocardial infarction

Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [¹⁸F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 ± 9 and 38 ± 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = −0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival.     

Origins of serum semicarbazide-sensitive amine oxidase

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell-specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.     

Changes in vaginal morphology, steroid receptor and natural antimicrobial content following treatment with low-dose mifepristone

BACKGROUND: We have previously shown that the antigestagen mifepristone is contraceptive when given in a daily dose of 5 mg, po. Epidemiological studies suggest that gestagen-only contraceptives may increase the risk of transmission of human immunodeficiency virus (HIV) due to effects on the vaginal defenses to infection. We investigate the effects of mifepristone on vaginal thickness, steroid receptor and natural antimicrobial content and pharmacokinetics of mifepristone. METHODS: In a pilot study, eight women were given mifepristone 5 mg/day for an average of 33 days. Ovarian function was assessed by measurement of estradiol and progesterone in blood and their metabolites in urine and by serial ultrasound of their ovaries. Vaginal biopsies were collected before (late proliferative) and after taking mifepristone. RESULTS: All subjects showed a similar pattern of descending serum concentrations of mifepristone. The elimination phase half-life was 18+/-5.1 h (mean+/-SD). Mean Cmax measured at 1 h was 641.7 nmol/L (range, 502-740 nmol/L). All eight women reported amenorrhea for the duration of treatment and seven of eight women showed biochemical and ultrasound evidence of anovulation. There was no significant change in vaginal thickness following treatment [342+/-40 microm pretreatment, 303+/-69 microm posttreatment (mean+/-SEM); p>.05]. Estrogen (ERalpha, ERbeta) and androgen receptor were expressed in both vaginal epithelium and subepithelial stroma, whereas progesterone receptor was expressed predominantly in the subepithelial stroma. There was no change in receptor content and distribution following mifepristone treatment. Natural antimicrobial mRNA [secretory leukocyte protease inhibitor, human beta defensins mRNA (HBD1, HBD2, HBD3, HBD5), granulysin and elafin] was extracted from the vaginal tissues, and the content was unaffected by mifepristone treatment. CONCLUSION: The absence of changes in vaginal thickness, steroid receptor and natural antimicrobial content and its distribution in this preliminary study suggests that in contrast to other estrogen-free contraceptives, mifepristone is unlikely to be associated with the increased risk of transmission of HIV and other sexually transmitted infections.     

What is the Rate of Functional Improvement During Occupational Rehabilitation in Workers’ Compensation Claimants?

Objectives We examined the rate of functional change (using performance measures and a self-report questionnaire) during interdisciplinary occupational rehabilitation in workers?? compensation claimants with a variety of musculoskeletal conditions. We also estimated the rate of improvement that could be considered clinically important and examined factors associated with rate of functional improvement. Methods A prospective cohort design was used, with data collected before and after claimants participated in an interdisciplinary occupational rehabilitation program. A consecutive sample was formed of claimants admitted between July 2005 and June 2007. Measures included performance-based functional measures (functional capacity evaluation, FCE) and a self-report questionnaire (pain disability index, PDI). Results The sample included 582 compensation claimants with a variety of musculoskeletal conditions. The majority of claimants experienced functional improvement during rehabilitation. Claimants with the outcome status ??Return-to-Work Pre-accident?? had the highest rate of functional change (up to 5?kg/week on floor to waist lifting, ~7 points/week on the PDI). Conclusion The clinically important rate of functional change appears to be 5?kg/week on FCE floor-to-waist lifting and 7 points/week on the PDI (scored out of 100). Rate of functional change appears to be multifactorial, with a variety of physical, demographic, clinical, and environmental factors explaining rate of change.     

The fiber and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries when consumed together with added glucose in healthy human volunteers

This study was undertaken on the broad hypothesis that lingonberry (Vaccinium vitis-idaea L.) has potential to reduce postprandial glycemic and lipemic response. More specifically, 2 postprandial crossover studies with healthy normal-weight male subjects were conducted to study the influence of commercial lingonberry powder on postprandial glycemia and lipemia. The test meals contained fat-free yoghurt with either glucose (50 g) or triacylglycerols (35 g) with or without (control) the lingonberry powder. The lingonberry powder provided the meals with a known amount of fiber and a known amount and composition of sugars, and it was a rich source of polyphenols. Postprandial glucose, insulin, and triacylglycerol responses were analyzed. There were no significant differences in the postprandial glucose concentration between the meals in the glycemia trial despite the fact that the lingonberry meal contained more glucose and fructose. When the meal did not contain added sugar but, instead, added triacylglycerol, no glycemia or lipemia-lowering effect was detected. On the contrary, there were indications of higher glycemic and insulinemic effect after the lingonberry meal. The results of this study indicate that the fibers and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries when consumed together with added glucose. By contrast, the lingonberry powder did not affect the postprandial lipemic response.     

Visual processing affects the neural basis of auditory discrimination

The interaction between auditory and visual speech streams is a seamless and surprisingly effective process. An intriguing example is the "McGurk effect": The acoustic syllable /ba/ presented simultaneously with a mouth articulating /ga/ is typically heard as /da/ [McGurk, H., & MacDonald, J. Hearing lips and seeing voices. Nature, 264, 746-748, 1976]. Previous studies have demonstrated the interaction of auditory and visual streams at the auditory cortex level, but the importance of these interactions for the qualitative perception change remained unclear because the change could result from interactions at higher processing levels as well. In our electroencephalogram experiment, we combined the McGurk effect with mismatch negativity (MMN), a response that is elicited in the auditory cortex at a latency of 100-250 msec by any above-threshold change in a sequence of repetitive sounds. An "odd-ball" sequence of acoustic stimuli consisting of frequent /va/ syllables (standards) and infrequent /ba/ syllables (deviants) was presented to 11 participants. Deviant stimuli in the unisensory acoustic stimulus sequence elicited a typical MMN, reflecting discrimination of acoustic features in the auditory cortex. When the acoustic stimuli were dubbed onto a video of a mouth constantly articulating /va/, the deviant acoustic /ba/ was heard as /va/ due to the McGurk effect and was indistinguishable from the standards. Importantly, such deviants did not elicit MMN, indicating that the auditory cortex failed to discriminate between the acoustic stimuli. Our findings show that visual stream can qualitatively change the auditory percept at the auditory cortex level, profoundly influencing the auditory cortex mechanisms underlying early sound discrimination.