Development of a Risk Score to Predict Sudden Infant Death Syndrome.

Sudden Infant Death Syndrome (SIDS) is the third leading cause of death among infants younger than one year of age. Effective SIDS prediction models have yet to be developed. Hence, we developed a risk score for SIDS, testing contemporary factors including infant exposure to passive smoke, circumcision, and sleep position along with known risk factors based on 291 SIDS and 242 healthy control infants. The data were retrieved from death certificates, parent interviews, and medical records collected between 1989−1992, prior to the Back to Sleep Campaign. Multivariable logistic regression models were performed to develop a risk score model. Our finalized risk score model included: (i) breastfeeding duration (OR = 13.85, p < 0.001); (ii) family history of SIDS (OR = 4.31, p < 0.001); (iii) low birth weight (OR = 2.74, p = 0.003); (iv) exposure to passive smoking (OR = 2.64, p < 0.001); (v) maternal anemia during pregnancy (OR = 2.07, p = 0.03); and (vi) maternal age <25 years (OR = 1.77, p = 0.01). The area under the curve for the overall model was 0.79, and the sensitivity and specificity were 79% and 63%, respectively. Once this risk score is further validated it could ultimately help physicians identify the high risk infants and counsel parents about modifiable risk factors that are most predictive of SIDS.

Assessment of the amorphous solid dispersion erosion behavior following a novel small-scale predictive approach.

In general, the erosion rate of copovidone-based amorphous solid dispersions (ASDs) in contact with water diminishes with increasing drug load, causing poor drug release from the final drug product. A new easy-to-use tool with low material- and time-consumption, the microscopic erosion time test (METT), was established to allow prediction of the API-specific drug load threshold between an eroding and a non-eroding ASD. This API-specific drug load value is further described as the drug load dispersibility limit (DDL) and is the highest drug load at which an eroding ASD was still observed. A minor increase of 2.5% in drug load above the DDL already led to a non-eroding ASD and it was subsequently connected to the drug load-associated drop in API in vitro dissolution of ASD tablets and an impeded tablet disintegration. In total, 19 APIs in copovidone-based ASDs were characterized via the METT while a subset of these was investigated in more detail, namely indomethacin, celecoxib, dipyridamole, fenofibrate, naproxen and ritonavir. Furthermore, indomethacin- and celecoxib-containing ASDs with various drug loads were prepared and characterized to link the METT outcome with ASD tablet in vitro dissolution and disintegration performance.

Dissolution testing of modified release products with biorelevant media: An OrBiTo ring study using the USP apparatus III and IV.

During the OrBiTo project, our knowledge on the gastrointestinal environment has improved substantially and biorelevant media composition have been refined. The aim of this study was to propose optimized biorelevant testing conditions for modified release products, to evaluate the reproducibility of the optimized compendial apparatus III (USP apparatus III) and compendial apparatus IV (USP apparatus IV, open-loop mode) dissolution methods and to evaluate the usefulness of these methods to forecast the direction of food effects, if any, based on the results of two «ring¼ studies and by using two model modified release (MR) products, Ciproxin / Cipro XR and COREG CR. Six OrBiTo partners participated in each of the ring studies. All laboratories were provided with standard protocols, pure drug substance, and dose units. For the USP apparatus III, the dissolution methods applied to Ciproxin / Cipro XR, a monolithic MR product of an active pharmaceutical ingredient (API) with moderate aqueous solubility, were robust with low intra- and inter-laboratory data variability. Data from all partners were in line on a qualitative basis with food effect data in humans. For the USP apparatus IV, the dissolution methods applied to COREG CR, a multiparticulate, pH dependent, MR product of an API with low and pH dependent solubility led to high intra- and inter- laboratory data variability. Data from all partners were in line, on a qualitative basis, with the previously observed food effects in humans.

Breast cancer staging by subtype in the Lower Mississippi Delta region States.

INTRODUCTION: To evaluate disparities in breast cancer stage by subtype (categorizations of breast cancer based upon molecular characteristics) in the Delta Regional Authority (Delta), an impoverished region across eight Lower Mississippi Delta Region (LMDR) states with a high proportion of Black residents and high breast cancer mortality rates. METHODS: We used population-based cancer registry data from seven of the eight LMDR states to explore breast cancer staging (early and late) differences by subtype between the Delta and non-Delta in the LMDR and between White and Black women within the Delta. Age-adjusted incidence rates and rate ratios were calculated to examine regional and racial differences. Multilevel negative binomial regression models were constructed to evaluate how individual-level and area-level factors affect rates of early- and late-stage breast cancers by subtype. RESULTS: For all subtypes combined, there were no Delta/non-Delta differences in early and late stage breast cancers. Delta women had lower rates of hormone-receptor (HR+)/human epidermal growth factor 2 (HER2-) and higher rates of HR-/HER2- (the most aggressive subtype) early and late stage cancers, respectively, but these elevated rates were attenuated in multilevel models. Within the Delta, Black women had higher rates of late-stage breast cancer than White women for most subtypes; elevated late-stage rates of all subtypes combined remained in Black women in multilevel analysis (RR = 1.10; 95% CI = 1.04-1.15). CONCLUSIONS: Black women in the Delta had higher rates of late-stage cancers across subtypes. Culturally competent interventions targeting risk-appropriate screening modalities should be scaled up in the Delta to improve early detection.

Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation.

Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibuprofen and zafirlukast), this study attempts to determine the interlaboratory reproducibility using a similar protocol for a commercially available formulation of a weak base, indinavir. Fourteen partners including twelve industrial and two academic partners participated in this study. To ensure uniformity, all partners were provided with a standardized protocol to perform (i) a single medium dissolution test in fasted state simulated gastric and intestinal fluids (FaSSGF and FaSSIF, respectively) and (ii) a two-stage dissolution experiment simulating gastrointestinal transfer. Optionally, partners could run a single-stage dissolution test in fed state simulated intestinal fluid (FeSSIF). For each dissolution test, one Crixivan® capsule (containing 400 mg indinavir as its sulfate salt) was added as dose of interest. For the single medium dissolution test in FaSSIF, all partners observed rapid release of indinavir resulting in supersaturated concentrations, followed by precipitation to equilibrium solubility. The degree and period of supersaturation varied among the participating laboratories. Average dissolution profiles in FeSSIF appeared to be highly reproducible with dissolved concentrations remaining lower than the thermodynamic solubility of indinavir in FeSSIF. For the two-stage dissolution test, most partners observed supersaturated concentrations in the intestinal compartment; two partners observed no supersaturation due to immediate precipitation. Given the fact that a high interlaboratory but low intralaboratory variability was observed when supersaturation/precipitation occurred, an undefined factor was hypothesized as a potential cause of the variability in precipitation. Hence, the impact of several experimental factors on the supersaturation and precipitation behavior of indinavir was investigated in a next step. The investigation indicated that variability is likely attributable to a combination of factors, especially, the time elapsed between sampling and dilution of the sample with the mobile phase. Therefore, when designing a test in which supersaturation and precipitation is anticipated, stringent control of the test methodology, especially regarding sampling and dilution, is needed.

Disparities in breast cancer subtypes among women in the lower Mississippi Delta Region states.

PURPOSE: To describe and elucidate rates in breast cancer incidence by subtype in the federally designated Mississippi Delta Region, an impoverished region across eight Southern/Midwest states with a high proportion of Black residents and notable breast cancer mortality disparities. METHODS: Cancer registry data from seven LMDR states (Missouri was not included because of permission issues) were used to explore breast cancer incidence differences by subtype between the LMDR's Delta and non-Delta Regions and between White and Black women within the Delta Region (2012-2014). Overall and subtype-specific age-adjusted incidence rates and rate ratios were calculated. Multilevel negative binomial regression models were used to evaluate how individual-level and area-level factors, like race/ethnicity and poverty level, respectively, affect rates of breast cancers by subtype. RESULTS: Women in the Delta Region had higher rates of triple-negative breast cancer, the most aggressive subtype, than women in the non-Delta (17.0 vs. 14.4 per 100,000), but the elevated rate was attenuated to non-statistical significance in multivariable analysis. Urban Delta women also had higher rates of triple-negative breast cancer than non-Delta urban women, which remained in multivariable analysis. In the Delta Region, Black women had higher overall breast cancer rates than their White counterparts, which remained in multivariable analysis. CONCLUSION: Higher rates of triple-negative breast cancer in the Delta Region may help explain the Region's mortality disparity. Further, an important area of future research is to determine what unaccounted for individual-level or social area-level factors contribute to the elevated breast cancer incidence rate among Black women in the Delta Region.

Spatial Accessibility to Mammography Services in the Lower Mississippi Delta Region States.

PURPOSE: To characterize spatial access to mammography services across 8 Lower Mississippi Delta Region (LMDR) states. These states include the Delta Region, a federally designated, largely rural, and impoverished region with a high proportion of black residents and low mammography utilization rates. METHODS: Using the enhanced 2-step floating catchment area method, we calculated spatial accessibility scores for mammography services across LMDR census tracts. We compared accessibility scores between the Delta and non-Delta Regions of the LMDR. We also performed hotspot analysis and constructed spatial lag models to detect clusters of low spatial access and to identify sociodemographic factors associated with access, respectively. We obtained mammography facility locations data from the Food and Drug Administration and sociodemographic variables from the American Community Survey and the US Department of Agriculture. RESULTS: Overall, there were no differences in spatial accessibility scores between the Delta and non-Delta Regions, though there was some state-to-state variation. Clusters of low spatial access were found in parts of the Arkansas, Mississippi, and Tennessee Delta. Spatial lag models found that poverty was associated with greater spatial access to mammography. CONCLUSIONS: The lack of identified differences in spatial access to mammography in the Delta and non-Delta Regions suggests that psychosocial or financial barriers play a larger role in lower mammography utilization rates. Identifying clusters of low spatial access to mammography services can help inform resource allocation. Further, our study underscores the value of using coverage-based methods rather than travel time or container measures to evaluate spatial access to care.

Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study.

Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons.

Evaluation of the drug loading capacity of different lipid nanoparticle dispersions by passive drug loading.

When using lipid nanoparticles as drug carrier system it is important to know how much drug can be loaded to the nanoparticles. The mainly used drug loading procedure is an empirical approach dissolving the drug in the liquid lipid during preparation of the nanoparticles. This approach does not necessarily lead to the truly loadable amount, as the lipid can, e.g. be overloaded, in particular when it is processed in the heat. In this work, a different procedure, passive drug loading, was evaluated to determine the drug loading capacity of various lipid nanoparticles (supercooled trimyristin emulsion droplets, solid trimyristin nanoparticles, tristearin nanoparticles in the α-modification and cholesteryl myristate nanoparticles in the supercooled smectic as well as in the crystalline state). The nanoparticle dispersions were exposed to eight different model drug compounds (betamethasone-17-valerate, carbamazepine, diazepam, flufenamic acid, griseofulvin, ibuprofen, retinyl palmitate, ubidecarenone) in the bulk state, which varied in partition coefficient and aqueous solubility, and equilibrated over time. The passive loading procedure had no relevant impact on the particle sizes or the physicochemical state of the nanoparticles. The loadable drug amount differed distinctly for the different model compounds and also between the different types of lipid nanoparticles. For most compounds, the loaded amount was much higher than the aqueous solubility. Trimyristin-based dispersions generally had the highest loading capacity, the emulsion usually being equal or superior to the solid trimyristin nanoparticles. For betamethasone-17-valerate, however, solid lipid nanoparticles exhibited by far the highest drug load. The extremely lipophilic model drugs retinyl palmitate and ubidecarenone could not be loaded with the passive approach.

Case-control study of cervical cancer and gynecologic screening: A SEER-Medicare analysis.

OBJECTIVE: To determine the association between Pap smear and pelvic examination screenings and the development of invasive cervical cancer in a Medicare population using a matched case-control design. METHODS: Matched case-control data sets were constructed from the SEER-Medicare database that links the Surveillance Epidemiology End Results (SEER) cancer registry data and Medicare enrollment and claims data of subjects who received care between the years 1991 and 1999 aged 65years or older. The study identified 1267 cervical cancer cases. Controls (N=10.137) were matched to cases representing up to eight matched controls (on age and registry geographic location) for a single case. The association between gynecologic screenings and the development of invasive cervical cancer was ascertained using conditional logistic regression analysis. RESULTS: Having had a Pap smear during the PIDP (pre-invasive detectable phase - 2 to 7years prior to diagnosis) was significantly negatively associated with the development of invasive cervical cancer (OR=0.64, 95% CI=0.53-0.78) which was reduced after taking into account the estimated prevalence of hysterectomy among controls (OR=0.38, 95% CI=0.32-0.46). The negative association between Pap smear screenings and cervical cancer was strongest for squamous tumors (OR=0.48, 95% CI=0.37-0.61). Restricting the subjects to those 72 and over did not affect risk. CONCLUSIONS: There is a reduction in risk for invasive cervical cancer when women over age 65 are screened. This suggests that cervical cancer screening in the aged population may be beneficial.

Breast cancer among women in Michigan following exposure to brominated flame retardants.

In this updated follow-up, we investigated the breast cancer experience among women in Michigan exposed to brominated flame retardants, some 30 years following exposure. Michigan residents were enrolled in a study cohort after exposure to polybrominated biphenyls (PBBs) through the consumption of contaminated food products. PBB concentrations were measured in serum at the time of enrolment. Cancer experience was determined by linkage to the Michigan Cancer Registry. We conducted a nested case-control study that included 51 women diagnosed with breast cancer during 1974-2004 and 202 age-matched controls. While the data suggest an increase in breast cancer risk with higher PBB exposure, this did not reach statistical significance. The OR of having breast cancer among women with PBB concentrations ≥10 ng/mL compared to women with PBB concentrations at or below the limit of detection of 1 ng/mL was 2.60, 95% CI 0.93 to 7.27, (p=0.07), when adjusted for age and family history of cancer in a first-degree female relative. It remains important to examine exposure to brominated chemicals and possible health effects, and to continue following the cancer experience of participants in this study.

What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion?

Our aim was to explore the influence of micelles and microparticles emerging in aqueous dispersions of amorphous solid dispersions (ASDs) on molecular/apparent solubility and Caco-2 permeation. The ASD, prepared by hot-melt extrusion, contained the poorly soluble model drug ABT-102, a hydrophilic polymer, and three surfactants. Aqueous dispersions of the ASD were investigated at two concentrations, one above and one close to the critical micelle concentration of the surfactants blend in the extrudate. Micelles were detected at the higher concentration and no micelles at the lower concentration. Apparent solubility of ABT-102 was 20-fold higher in concentrated than in diluted dispersions, because of micelles. In contrast, Caco-2 permeation of ABT-102 was independent of the ASD concentration, but three times faster than that of crystalline suspensions. Molecular solubility of ABT-102 (equilibrium dialysis) was also independent of the ASD concentration, but by a factor 2 higher than crystalline ABT-102. The total amount of ABT-102 accumulated in the acceptor during Caco-2 experiments exceeded the initial amount of molecularly dissolved drug in the donor. This may indicate that dissolution of amorphous microparticles present in aqueous dispersions induces lasting supersaturation maintaining enhanced permeation. The hypothesis is supported by a slower drug permeation when the microparticles were removed.

Reproductive factors and risk of lung cancer in female textile workers in Shanghai, China.

PURPOSE: Hormonal factors may play a role in the development of lung cancer in women. This study examined the relationship between lung cancer and reproductive factors in a large cohort of women, most of whom never smoked (97%). METHODS: A cohort of 267,400 female textile workers in Shanghai, China, enrolled in a trial of breast self-examination provided information on reproductive history, demographical factors, and cigarette smoking at enrollment in 1989-91. The cohort was followed until July of 2000 for incidence of lung cancer; 824 cases were identified. Hazard ratios (HR) and 95% confidence intervals (CI) associated with selected reproductive factors were calculated using Cox proportional hazards modeling, adjusting for smoking, age, and also parity when relevant. RESULTS: Nulliparous women were at increased risk compared to parous women (HR = 1.33, 95% CI 1.00-1.77). Women who had gone through menopause at baseline were at increased risk compared to women of the same age who were still menstruating. Risk was higher in women with a surgical menopause (HR = 1.64, 95% CI 0.96-2.79) than in those with a natural menopause (HR = 1.35, 95% CI 0.84-2.18), and risk was highest in those postmenopausal women with a hysterectomy and bilateral oophorectomy at baseline (HR = 1.39, 95% CI 0.96-2.00), although the risk estimates were not statistically significant. CONCLUSIONS: These results support experimental data that demonstrate a biological role for hormones in lung carcinogenesis.

The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility.

Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 µg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).

Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement.

Amorphous solid dispersions (ASDs) represent a promising formulation approach for poorly soluble drugs. We explored the formulation-related impact of ASDs on permeation rate, apparent solubility and molecular solubility of the poorly soluble drug ABT-102. The influence of fasted state simulated intestinal fluid (FaSSIF) as dispersion medium was also studied. ASDs were prepared by hot-melt extrusion. Permeation rate was assessed by the Caco-2 transwell assay. Cell viability and barrier integrity were assured by AlamarBlue©, TEER and permeability of the hydrophilic marker carboxyfluorescein. Apparent solubility and molecular solubility were evaluated by using centrifugation and inverse dialysis, respectively. The in vitro permeation rate of ABT-102 from aqueous dispersions of the ASD was found 4 times faster than that from the dispersions of the crystals, while apparent solubility and molecular solubility of ABT-102 were increased. Yet, a further increase in apparent solubility due to micellar solubilization as observed when dispersing the ASD in FaSSIF, did not affect molecular solubility or permeation rate. Overall, a good correlation between permeation rate and molecular solubility but not apparent solubility was seen.

Impact of FaSSIF on the solubility and dissolution-/permeation rate of a poorly water-soluble compound.

The poorly water-soluble drug ABT-102, a potent TRPV1 (transient receptor potential cation channel subfamily V member 1) antagonist, was investigated in terms of its solubility and dissolution-permeation rate across Caco-2 cell monolayers in the presence and absence of fasted state simulated intestinal fluid (FaSSIF). ABT-102 showed a more than 30-fold higher apparent solubility in FaSSIF, compared to Hank's balanced salt solution (HBSS). On the other hand, the amount of truly dissolved API in the suspension, as assessed by inverse dialysis, was found hardly influenced by FaSSIF. Neither the drug nor FaSSIF adversely affected cell viability or integrity of the Caco-2 monolayer. P-gp-inhibition experiments confirmed that the drug was not a substrate of the export pump. The flux of ABT-102 across the Caco-2 barrier was found virtually the same in FaSSIF and in buffer, i.e. in vitro overall dissolution-/permeation rate of ABT-102 from suspensions appears not affected by its enhanced apparent solubility due to association with TC/PC-micelles.

Genital powder exposure and the risk of epithelial ovarian cancer.

BACKGROUND: We conducted a population-based, case-control study to examine the association between the use of genital powder and ovarian cancer risk, including measures of extent and timing of exposure. We also assessed the relationship of powder use with risk of disease subtypes according to histology and degree of malignancy. METHODS: Information was collected during in-person interviews with 812 women with epithelial ovarian cancer diagnosed in western Washington State from 2002 to 2005 and 1,313 controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Overall, the perineal use of powder after bathing was associated with a slightly increased ovarian cancer risk (OR = 1.27, 95% CI: 0.97-1.66), which was most evident among women with borderline tumors (OR = 1.55, 95% CI: 1.02-2.37). We noted no clear pattern of risk increase on the basis of the extent of use, assessed as years in which powder was used, or as lifetime number of applications for invasive or borderline tumors, or their histologic subtypes. There was no alteration in the risk of ovarian cancer associated with other types of powder exposure (e.g., on sanitary napkins or diaphragms). CONCLUSIONS: The International Agency for Research on Cancer has designated perineal exposure to talc (via the application of genital powders) as a possible carcinogen in women. A modest association of ovarian cancer with this exposure was seen in our study and in some previous ones, but that association generally has not been consistent within or among studies. Therefore, no stronger adjective than "possible" appears warranted at this time.

Oral contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai.

From 1998 to 1991, an in-person baseline interview was administered to approximately 267,400 female textile workers in Shanghai, China. The cohort was followed until July 2000 for incident cancer cases. Incidence rate ratios (RR) for 12 types of cancers in users of oral contraceptives (OCs) were calculated using Cox Proportional Hazards analysis. There was a reduced risk of uterine corpus cancer for women who had ever used OCs (RR = 0.68, 95% CI = 0.45-1.04) and a trend of decreasing risk with increasing duration of use (p = 0.015). There was an increased risk of colon cancer in women who had used OCs for 10 years or more (RR = 1.56, 95% CI = 1.01-2.40) and an increased risk of rectal cancer in women who had ever used OCs (RR = 1.31, 95% CI = 0.98-1.75), with a trend of increasing risk with increasing duration of use (p = 0.017), but these associations may have been due to uncontrolled confounding by physical activity or other non-causal factors. No associations were observed between OCs and the risk of all cancers combined or for any of the nine other cancers. It is unlikely that the use of OCs has contributed to the temporal trends in cancer incidence in China in recent decades.

Poly(vinyl alcohol) as emulsifier stabilizes solid triglyceride drug carrier nanoparticles in the alpha-modification.

Colloidal dispersions of solid lipids are under intensive investigation as drug delivery systems. In the present study, poly(vinyl alcohol) (PVA) was tested as an alternative stabilizer for triglyceride nanoparticles. The dispersions contained 10% triglyceride (trimyristin or tristearin) and 5% PVA and were prepared by high pressure melt homogenization. The nanoparticle dispersions were investigated for their thermal behavior and storage stability with special regard to the polymorphic transitions of the triglyceride matrix, including effects of storage temperature and the incorporation of model drugs (diazepam, ubidecarenone) using photon correlation spectroscopy, differential scanning calorimetry, X-ray diffraction, and transmission electron microscopy. The release of the model drug diazepam from a selected nanoparticle dispersion was investigated with differential pulse polarography. Triglyceride nanoparticles prepared with PVA displayed an unusually high stability of the metastable alpha-modification depending on the type of triglyceride and the storage conditions. In tristearin nanoparticles, the alpha-polymorph was stable for at least 9 months at refrigerator temperature and the particles exhibited a spherical shape in electron microscopic investigations. Moreover, the alpha-form in PVA-stabilized tristearin nanoparticles seemed to be highly disordered, as it did not lead to a pronounced small-angle X-ray reflection. Storage at higher temperatures led to a transformation of the particles into the beta-modification, which usually was accompanied by an increase in particle size. Incorporation of the two model drugs did not change the crystal modification of the particle matrix to a large extent. After dilution into a large volume of release medium, a large fraction of the model drug diazepam was released immediately but there was no further release over several hours. The high stability of PVA-stabilized tristearin nanoparticles with regard to particle size and alpha-modification makes them suitable as a model for investigations on the influence of the polymorphic form (e.g., in comparison with nanoparticles in the more stable beta-modification) on pharmaceutically important parameters such as drug load and drug release.

Monthly injectable contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai.

PURPOSE: The risk of 12 types of cancer in relation to use of monthly injectable contraceptives was assessed in a prospective study in Shanghai, China. METHODS: From 1989 to 1991, an in-person interview was administered to 267,400 female textile workers to ascertain information on risk factors for breast cancer, contraceptive use and induced abortions. The cohort was followed until July 2000 for incident cancer cases. Cox proportional hazards analysis was used to calculate incidence rate ratios for specific types of cancer in women who ever had used monthly injectable contraceptives and by length of use. RESULTS: There was a reduced risk of uterine corpus cancer for women who had ever used monthly injectable contraceptives. No association was observed between the use of monthly injectable contraceptives and the risk of all cancers combined and for any of the 11 other cancers considered. CONCLUSION: There appears to be no evidence of an increased risk of cancer after exposure to monthly injectable contraceptives in our study.