The role of excipients and package components in the photostability of liquid formulations

A phenyl ether-based drug substance exhibits photochemical degradation in citrate buffers with both ultraviolet (300-450 nm range) and visible light (380-700 nm range) exposure, even though the drug molecule itself is non-light absorbing at wavelengths > 300 nm. The major contributors to the observed photosensitivity are the citrate buffer, parts per billion (ppb) levels of iron, oxygen, and light exposure level. Although a primary phenol photodegradate is generated, there are at least eight other species formed as well. The molecular weights and abundance of these species suggest that the product distribution is generated by the reaction of hydroxyl radicals with the drug substance. The generation of the primary photodegradate is linearly proportional to the light exposure amount for a fixed concentration of iron present in the formulation. Conversely, the amount of photodegradation is also nearly linear with iron concentration (through 200 ppb levels) for a fixed amount of light exposure. The proposed mechanism for the photochemical generation of hydroxyl radicals has precedence in the literature for similar combinations of iron, oxygen, carboxylate buffers, and light. Since the buffer salt and oxygen molecular equivalents in the product are significantly higher than the ppb levels of iron employed and more difficult to remove, the control of the extent of photodegradation largely rests on the control of trace levels of iron in the formulated product and control of light exposure. Exposure of drug solutions to a series of transition metals clearly indicates that iron is the key transition metal involved in the observed photochemistry. At manufacture, the primary source of iron is the raw materials (water, drug or excipients) used in the formulation. The level of iron for product stored in glass increases with sample age and can be attributed to iron leaching from borosilicate glass vials. Consideration of adequate light control during the manufacturing and packaging processes will be discussed and can only be defined as a function of the amount of iron present at the time of manufacture in the formulation. The generality of this chemistry to other drug candidates and in the presence of other common buffers will also be discussed.     

Macular hole: improved understanding of pathogenesis, staging, and management based on optical coherence tomography

Optical coherence tomography (OCT) has improved the understanding and management of idiopathic macular hole. Images of precursor lesions and their progression demonstrate that antero-posterior as well as tangential traction are involved in macular hole formation. The staging of macular holes with biomicroscopic examination can be paralleled by optical coherence tomography staging with some modification. OCT is useful in differentiating simulating lesions and in allowing better counseling of patients regarding their disorder. Finally, OCT findings are prognostic of surgical success and can assist in evaluating the results of surgery.     

Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array

Despite the growing interest in selenium intervention of prostate cancer in humans, scanty information is currently available on the molecular mechanism of selenium action. Our past research indicated that methylseleninic acid (MSA) is an excellent reagent for investigating the anticancer effect of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in PC-3 human prostate cancer cells. After exposure to physiological concentrations of MSA, these cells exhibited a dose- and time-dependent inhibition of growth. MSA retarded cell cycle progression at multiple transition points without changing the proportion of cells in different phases of the cell cycle. Flow cytometric analysis of annexin V- and propidium iodide-labeled cells showed a marked induction of apoptosis by MSA. Array analysis with the Affymetrix human genome U95A chip was then applied to profile the gene expression changes that might mediate the effects of selenium. Gene profiling was done in a time course experiment (at 12, 24, 36, and 48 h) using synchronized cells. A large number of potential selenium-responsive genes with diverse biological functions were identified. These genes fell into 12 clusters of distinct kinetics pattern of modulation by MSA. The expression changes of 10 genes known to be critically involved in cell cycle regulation were selected for verification by Western analysis to determine the reliability of the array data. An agreement rate of 70% was obtained based on these confirmation experiments. The array data enabled us to focus on the role of potential key genes (e.g., GADD153, CHK2, p21(WAF1), cyclin A, CDK1, and DHFR) that might be targets of MSA in impeding cell cycle progression. The data also provide valuable insights into novel biological effects of selenium, such as inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling. The present study demonstrates the utility of a genome-wide analysis to elucidate the mechanism of selenium chemoprevention.     

A comparison of the sensitivity of APTT reagents to the effects of enoxaparin, a low-molecular weight heparin

Low-molecular weight heparin (LMWH) is the product of enzymatic or chemical degradation of unfractionated heparin (UFH). It has been found to have better bio-availibility, more predictable dose response and can be used as an alternative to UFH for prophylaxis and treatment of thrombotic disorders. It is claimed that no laboratory monitoring is necessary for LMWH therapy; however, for the aged, renal impaired, obese or grossly underweight, monitoring of dose effect with anti-Xa assay is recommended. The activated partial thromboplastin time (APTT), which is the test of choice for UFH monitoring, is believed to be insensitive to the effect of LMWH. The sensitivity of the APTT to heparin lies in the APTT reagent used. In this study, eight different APTT reagents were used to compare the APTT with anti-Xa activity in ex vivo plasma from patients who were on enoxaparin (LMWH, Clexane) therapy. It was found that, as with UFH, APTT reagents show variable sensitivity to LMWH. The APTTs from all eight reagents were found to have a linear relationship to anti-Xa activity. The APTT results using three of the reagents gave an indication of the use of LMWH therapy. It was also found that patients who were lupus anticoagulant (LA)-positive had much more prolonged APTTs when on LMWH therapy; however, a linear correlation between APTT and anti-Xa was not present in these patients.     

Expression, tissue distribution, and cellular localization of the antiapoptotic TIP-B1 protein

TIP-B1 is a novel 27-kDa protein isolated from the cytosol of tumor necrosis factor (TNF)-stimulated cells. Cells preincubated with TIP-B1 are protected from TNF-induced apoptosis. This study showed that, as with normal fibroblasts and U937 histiocytic lymphoma, human MCF7 mammary adenocarcinoma cells were protected from TNF in a concentration-dependent manner by pretreatment with either TNF or purified TIP-B1. Immunoblot and immunohistochemical analyses indicated expression of both TIP-B1 mRNA and protein in MCF7 cells and heart, kidney, brain, liver, ovary, uterus, thymus, spleen, lymph node, and mammary gland cells throughout their development. Expression of TIP-B1 was heterogeneous, with staining of specific cell types within tissues. Based on the ability of TIP-B1 to protect both normal and tumor cells from TNF-induced apoptosis and its broad tissue distribution, with expression only in select cells within those tissues, a role for TIP-B1 in the regulation of TNF-induced effects is strongly indicated.     

Knowledge of and attitudes toward sex among Chinese adolescents

This study was conducted to examine the knowledge of and attitudes toward sex of 178 Chinese secondary school students in Hong Kong. The data were collected using a questionnaire that comprised three parts: the Chinese version of the Mathtech Knowledge Test, the Chinese version of the Mathtech Attitude and Value Scale, and a demographic sheet seeking sociodemographic information. In general, students demonstrated a low level of sexual knowledge, especially in relation to adolescent marriage, the probability of pregnancy, and adolescent sexual activity. With regard to attitudes, students indicated positive attitudes toward importance of family and importance of birth control. Male students in comparison with their female counterparts had a higher level of agreement with premarital intercourse and the use of pressure and force in sexual activity.     

Reconstruction of forearm deformities in multiple cartilaginous exostoses

The management of complex forearm deformities in patients with multiple cartilaginous exostoses is controversial. The objective of this study is to look into the outcome of treatment with the combined use of ulna lengthening, radial osteotomy, and excision of exostosis in our six patients, who all had Masada type 1 deformity of the forearm. Clinical assessment was performed using the pre- and postoperative range of motion of the wrist, forearm and elbow. The chief symptom each patient had was noted as well as the demographic data of all patients. Radiological assessment was performed by checking the degree of negative ulna variance, the radial articular angle, and the degree of carpal slip. The degree of satisfaction of the patients and their parents were noted. Good clinical and radiological results were obtained at a mean follow-up of 2.5 years. All patients and parents were satisfied and there was no recurrence of deformity in the latest follow-up. The authors believe in early and aggressive treatment of Masada type 1 deformity of the wrist and forearm for multiple cartilaginous exostoses with a combination of excision of exostosis, ulna lengthening and radial osteotomy.     

Multiple brain abscesses in a patient with bilateral pulmonary arteriovenous malformations and immunoglobulin deficiency

A 34 year old Chinese man presented with grand mal seizures complicating multiple brain abscesses caused by mixed oral flora. Because of persistent hypoxaemia contrast spiral thoracic computed tomography was done, which revealed bilateral pulmonary arteriovenous malformations (PAVMs). Concomitant IgA and IgG subclass deficiency was also found. The combination of these two conditions appears to have predisposed this patient to presumably paradoxical septic embolism. The patient's cerebral condition responded to postoperative antibiotic treatment and he eventually received selective coil embolisation of right lower lobe PAVMs, which relieved his hypoxaemia and dyspnoea.     

Assessment of total energy expenditure in a Chinese population by a physical activity questionnaire: examination of validity

A physical activity questionnaire from which total daily energy expenditure (TEE) could be estimated was developed for adult Hong Kong Chinese subjects, and its reliability and validity examined. The questionnaire was based on questionnaires used in Caucasians, and adapted for local lifestyle after focus group meetings involving subjects of all age groups. The questionnaire was administered to 94 subjects, consisting of healthy adults, the elderly, and two patient groups (those with renal disease on continuous ambulatory peritoneal dialysis and those with cancer). Seventy-one subjects were reinterviewed within 14 days to test reliability. Validity was examined in 31 normal subjects by measuring the basal metabolic rate (BMR) by indirect calorimetry and multiplying by the physical activity level (PAL) obtained from published studies using the doubly labelled water method and also from FAO/WHO/UNU to obtain the TEE. The intraclass correlation coefficient of reliability rages from 0.7 to 0.8 for all subject groups. The mean estimated TEE from the questionnaire was not significantly different from the mean value derived from measured BMR x PAL. The mean bias ranged from an underestimation of 27 kcal to overestimation of 215 kcal. However, the limits of variability were wide. Age was inversely related to the energy expended for occupational activities, but was positively associated with energy expended in leisure activities. Women spent less energy on occupational and exercise activities, and more on caretaking activities. Those with disease were also less likely to participate in caretaking activities. We conclude that this questionnaire may be a useful tool for future studies where energy expenditure needs to be estimated in various settings in the Hong Kong Chinese population.