Formulation of Ebastine Fast-Disintegrating Tablet Using Coprocessed Superdisintegrants and Evaluation of Quality Control Parameters.

Ebastine is a long-acting, nonsedating, second-generation antihistaminic drug that prevents histamine action, mainly in immediate hypersensitivity. This project was aimed to formulate and characterize orodispersible tablets of ebastine, utilizing different proportions of three disintegrants, namely crospovidone, sodium starch glycolate, and coprocessed superdisintegrant. Initially, fifteen trial batches of ebastine orodispersible tablets were outlined using the central composite design of Minitab software. The tablets were formulated by the direct compression method. The compressed tablets were then evaluated for precompression and postcompression physicochemical parameters, such as angle of repose, Carr's index, Hausner's ratio, hardness, thickness, weight variation, drug content, friability, wetting time, disintegration time, dispersion time, and water absorption ratio. The in vitro dissolution test was conducted according to Indian Pharmacopeia 2018, with the help of the rotating paddle method using 0.5% w/v sodium lauryl sulfate buffer in 0.1 N HCl. For the optimized batch (8th batch), all the physicochemical parameters like angle of repose (33.77°), Carr's index (19.34%), Hausner's ratio (1.24), weight variation (202.5 mg), hardness (4.3 kg/cm2), friability (0.44%), thickness (3.16 mm), dissolution (95.78%), and drug content (101.67%) were within the acceptable limit as per Indian Pharmacopeia 2018. The wetting time, disintegration time, dispersion time, and water absorption ratio were reported to be 25.1 seconds, 16.0 seconds, 38.6 seconds, and 91.92%, respectively. Hence, the results suggested that orodispersible tablets of ebastine can be formulated. Furthermore, the mixing of crospovidone, sodium starch glycolate, and coprocessed super disintegrants can result in excellent desirable properties in the orodispersible tablet.

Brain reorganization in patients with spinal cord compression evaluated using fMRI.

OBJECTIVE: This prospective study characterizes the reorganization that occurs within the primary sensorimotor cortices following decompression of cervical spinal stenosis. METHODS: Twelve right-handed patients with cervical myelopathy underwent blood oxygenation level dependent functional MRI (fMRI) prior to decompression and 6 months following surgery. Ten right-handed controls also underwent fMRI. All subjects performed a finger-tapping paradigm with the right hand. Volume time course data were corrected for temporal serial correlation and % normalized before inclusion in the general linear model. Activation maps were created for each group using a threshold of p < 0.005 with Bonferroni correction. Between-group differences in left hemisphere volume of activation (VOA) were measured along the precentral gyrus (PrCG) and postcentral gyrus (PoCG). Each subject also completed clinical questionnaires. RESULTS: Prior to surgery, patients demonstrated a larger VOA (1.23 cm(3), t(max) = 11.8) in comparison to controls within the PrCG. This difference increased following surgery (2.99 cm(3), t(max) = 13.6). Within the PoCG, controls demonstrated a larger VOA (0.53 cm(3), t(max) = 8.28) than preoperative patients. This difference decreased by 0.12 cm(3) (t(max) = 7.05) following surgery. Preoperatively, patients had a 21.7 cm(3) VOA (t(max) = 29.4) within the sensorimotor cortex with the center of gravity located within Brodmann area (BA) 3. Following surgery, the VOA increased to 23.1 cm(3) (t(max) = 26.1) within BA 3. There were significant improvements in clinical outcomes following surgery. CONCLUSIONS: Spinal cord compression resulted in an increase in volume of activation (VOA) within the precentral gyrus (PrCG) and a loss of VOA within the postcentral gyrus (PoCG) in comparison to controls. Surgical decompression results in cortical reorganization with enlarging VOA within both the PrCG and PoCG.

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Sarcoidosis: social predictors of severity at presentation.

To determine relationships among social predictors and sarcoidosis severity at presentation, demographic characteristics, socioeconomic status, and barriers to care, A Case-Control Etiologic Study of Sarcoidosis (ACCESS) was set up. Patients self-reported themselves to be Black or White and were tissue-confirmed incident cases aged > or =l8-yrs-old (n=696) who had received uniform assessment procedures within one of 10 medical centres and were studied using standardised questionnaires and physical, radiographical, and pulmonary function tests. Severity was measured by objective disease indicators, subjective measures of dyspnoea and short form-36 subindices. The results of the study showed that lower income, the absence of private or Medicare health insurance, and other barriers to care were associated with sarcoidosis severity at presentation, as were race, sex, and age. Blacks were more likely to have severe disease by objective measures, while women were more likely than males to report subjective measures of severity. Older individuals were more likely to have severe disease by both measures. In conclusion, it was found that low income and other financial barriers to care are significantly associated with sarcoidosis severity at presentation even after adjusting for demographic characteristics of race, sex, and age.

Clinical characteristics of patients in a case control study of sarcoidosis.

Sarcoidosis may be affected by sex, race, and age. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled 736 patients with sarcoidosis within 6 mo of diagnosis from 10 clinical centers in the United States. Using the ACCESS sarcoidosis assessment system, we determined organ involvement for the whole group and for subgroups differentiated by sex, race, and age (less than 40 yr or 40 yr and older). The study population was heterogeneous in terms of race (53% white, 44% black), sex (64% female, 36% male), and age (46% < 40 yr old, 54% > or = 40 yr old). Women were more likely to have eye and neurologic involvement (chi(2) = 4.74, p < 0.05 and chi(2) = 4.60, p < 0.05 respectively), have erythema nodosum (chi(2) = 7.28, p < 0.01), and to be age 40 yr or over (chi(2) = 6.07, p < 0.02) whereas men were more likely to be hypercalcemic (chi(2) = 7.38, p < 0.01). Black subjects were more likely to have skin involvement other than erythema nodosum (chi(2) = 5.47, p < 0.05), and eye (chi(2) = 13.8, p < 0.0001), liver (chi(2) = 23.3, p < 0.0001), bone marrow (chi(2) = 18.8, p < 0.001), and extrathoracic lymph node involvement (chi(2) = 7.21, p < 0.01). We conclude that the initial presentation of sarcoidosis is related to sex, race, and age.

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Sarcoidosis severity and socioeconomic status.

Several chronic diseases are more severe in persons who are Black, of low socioeconomic status (SES), and underinsured. The authors ask if this is true for sarcoidosis. Associations among sarcoidosis disease severity, SES, insurance coverage, and functional limitations were analysed. Back and White sarcoidosis patients (n=110) of a municipal and university hospital sarcoidosis registry were interviewed by telephone. Data on disease severity were abstracted from patient charts. Most patients reported good or excellent health by demographic characteristics. Low SES and no or public insurance were associated with worse health status and more severe dyspnoea. More advanced radiographic stage was associated with lower income, and forced vital capacity impairment with less education. Physical and social activity limitations due to physical and emotional disability were related to no or public insurance and lower income, but not education. Sarcoidosis severity is associated with socioeconomic status and insurance indicators; no or public insurance and low income are associated with functional limitations. Sarcoidosis-associated limitations are substantial, emphasizing the social significance of sarcoidosis. Lack of private insurance may inhibit the use of medical care, contributing to disease severity and impairment.

Repeat cerebrospinal fluid shunt infection in children.

BACKGROUND: In this study, we investigated the treatment of cerebrospinal fluid (CSF) shunt infection and the risk factors for repeat shunt infection (RSI) in a cohort of children treated at the Hospital for Sick Children, Toronto, Canada. METHODS: Between 1996 and 2000, a total of 51 children were identified with shunt infection (mean age 5.8 years). The medical records of these children were reviewed to identify cases of RSI within 6 months of the initial shunt infection (ISI). RESULTS: In the 51 ISIs, the infecting organisms were coagulase-negative Staphylococcus (43.1%), Staphylococcus aureus (37.3%) and others (19.6%). The initial mode of treatment of the shunt infection was using an external ventricular drain (EVD) with removal of the shunt apparatus (54.9%), externalization of the shunt (37.3%) or shunt removal only (7.8%). The mean number of days of external CSF drainage (either EVD or externalized shunt) was 11.2 days. Ten patients (19.6%) developed RSI. The actuarial risk of RSI plateaued after 90 days at 24.4%. The following variables were tested as risk factors for RSI using survival analysis, although none reached statistical significance: initial organism (p = 0.09), age (p = 0.42), etiology of hydrocephalus (p = 0.45), number of days of CSF drainage (p = 0.45), type of surgical treatment of the ISI (p = 0.58) and the presence of bacteriologically positive CSF at ISI (p = 0.85). CONCLUSIONS: The risk of RSI is substantial and greater effort needs to be directed towards understanding the risk factors. Such studies will need a greater sample size in order to obtain sufficient statistical power.

Antibodies to SOX13 (ICA12) are associated with type 1 diabetes.

SOX13 is an islet cell autoantigen (ICA12), identified by antibody screening of an islet cDNA library, using sera from patients with Type 1 diabetes. We ascertained the frequency of antibody reactivity to SOX13 and compared it with other Type 1 diabetes autoantibody reactivities. Antibodies were measured by radioimmunoprecipitation (RIP) using (35) S labelled SOX13 expressed in rabbit reticulocyte lysate. Sera from 109 subjects with Type 1 diabetes, 29 with Type 2 diabetes, 144 with other autoimmune diseases and from 201 controls were tested for anti-SOX13, and results were compared with the frequency of antibodies to glutamic acid decarboxylase (anti-GAD), islet cell antigen 512 (anti-ICA512) and islet cell cytoplasm (ICA). Anti-SOX13 were detected in 20 (18.3%) of 109 subjects with Type 1 diabetes, and more frequently in adults than in children (29% vs 10%). Anti-SOX13 usually occurred with anti-GAD but rarely with anti-ICA512. Seven sera positive for anti-SOX13 did not react with either GAD, ICA512 or islet cell cytoplasm indicating that anti-SOX13 represented a distinct population of antibodies. Reactivity to SOX13 represents a further autoantibody response in adults with Type 1 diabetes and may provide a useful disease marker in subjects in whom other autoantibody tests are negative.

A pictorial review of coronary artery anatomy on spiral CT.

Coronary artery calcification quantification (scoring) has been done with electron beam CT (EBCT), but is now being done with spiral or helical CT. Many radiologists and cardiologists who do not have EBCT but do have access to spiral CT will now be able to do coronary artery calcification scoring, and will now need to know the spiral CT appearance of the coronary artery anatomy. This pictorial review will demonstrate the anatomy needed for coronary artery calcium scoring.

Posthospitalization home health care use and changes in functional status in a Medicare population.

OBJECTIVE: The objective of this work was to estimate the effect of Medicare beneficiaries' use of home health care (HHC) for 6 months after hospital discharge on the change in functional status over a 1-year period beginning before hospitalization. DATA SOURCES AND STUDY SETTING: Data came from the Medicare Current Beneficiary Survey, which is a nationally representative sample of Medicare beneficiaries, in-person interview data, and Medicare claims for 1991 through 1994 for 2,127 nondisabled, community-dwelling, elderly Medicare beneficiaries who were hospitalized within 6 months of their annual in-person interviews. STUDY DESIGN: Econometric estimation with the instrumental variable method was used to correct for observational data bias, ie, the nonrandom allocation of discharged beneficiaries to the use of posthospitalization HHC. The analysis estimates a first-stage model of HHC use from which an instrumental variable estimate is constructed to estimate the effect on change in functional status. PRINCIPAL FINDINGS: The instrumental variable estimates suggest that HHC users experienced greater improvements in functional status than nonusers as measured by the change in a continuous scale based on the number and mix of activities of daily living and instrumental activities of daily living before and after hospitalization. The estimated improvement in functional status could be as large as 13% for a 10% increase in HHC use. In contrast, estimation with the observational data on HHC use implies that HHC users had poorer health outcomes. CONCLUSIONS: Adjusting for potential observational data bias is critical to obtaining estimates of the relationship between the use of posthospitalization HHC and the change in health before and after hospitalization. After adjustment, the results suggest that efforts to constrain Medicare's spending for HHC, as required by the Balanced Budget Act of 1997, may lead to poorer health outcomes for some beneficiaries.

Pulmonary sarcoidosis: comparison of patients at a university and a municipal hospital.

Charts and radiographs of sarcoidosis patients seen at a private university hospital and at a municipal hospital were reviewed to determine whether there was a difference in the severity of disease retrospectively. A standardized abstract form was used to identify and abstract information on new and continuing sarcoidosis patients seen at either Georgetown University Medical Center (GUMC) or District of Columbia General Hospital (DCGH) during a 2-year period. Because there were too few white sarcoidosis patients for comparison, analysis was done for African-American patients only. African-American patients at GUMC were slightly older, with a higher percentage of women. For GUMC patients, 76% had private insurance and 21% had public insurance, and for DCGH patients, one-half had public insurance and 29% had no insurance. Significantly fewer GUMC patients (7% versus 36%) reported moderate to severe dyspnea. Chest radiographs showed a larger percentage of patients with stage 1 disease at GUMC and more patients with stage 4 disease at DCGH. Spirometry showed more impairment of forced expired volume in one second (FEV1) in GUMC patients, but diffusing capacity of the lung for carbon monoxide (DLCO) values were significantly lower among DCGH patients. Less than 8% of GUMC patients showed disease progression compared with almost one-third of DCGH patients. These results demonstrate that substantially less severe pulmonary sarcoidosis was seen in African-American patients treated at a private, nonprofit university hospital compared with a municipal hospital. Factors that determine the use of municipal hospitals, such as limited financial access to care and sources of patients, may have played a major role in the differences seen.

Why menopausal women do not want to take hormone replacement therapy.

OBJECTIVE: A survey was designed to determine why menopausal women do not take hormone replacement therapy (HRT). DESIGN: A sample of 3,600 women > 50 years old were randomly selected from six zip codes in northwest suburban Chicago. They received a maximum of three survey mailings. Those who did not respond were called and asked to respond over the phone. The data that were obtained included knowledge of, physician discussion about, use of, and reason for not currently taking HRT, menopausal status, last physician visit, and age grouping. RESULTS: A total of 1,966 (65%) women responded. Of these, 1,448 (74%) knew about HRT, 1,193 (61%) had discussed HRT with their physicians, and 815 (41%) had been treated with HRT in the past. A total of 552 women (28%) were currently being treated with HRT, of whom 419 (76%) had been treated for > 2 years. A total of 1,356 respondents were not being treated with HRT. Of these, 1,114 (82%) were menopausal, of whom 742 (67%) knew about HRT, 551 (50%) had discussed HRT with their physicians, 837 (75%) had seen their physician in the past year, and 236 (21%) had been treated with HRT in the past. Reasons for not taking HRT included the following: 49% no longer had menopausal symptoms, 45% did not want to take HRT, 33% were not offered it by their doctors, 28% were afraid to use it, and 27% were not menopausal. CONCLUSIONS: Seeing a physician in the past year did not ensure that these women understood the symptom course of menopause. Confirming women's knowledge about menopausal health or assisting physician education about menopausal health may offer opportunities both to assist women's decision making about HRT and to improve women's health care.

Adapting an effective primary care provider STD/HIV prevention training programme.

Sexually acquired human immunodeficiency virus (HIV) infection continues to be the major source of HIV infection in the USA. Preventing sexual transmission of HIV can be accomplished through patient behaviour change. Such behaviour change can also decrease risk of other sexually transmitted diseases (STDs) and unwanted pregnancies, both far more common problems than HIV infection. Primary care physicians and other providers can increase patients' safe sex practices by conducting effective sexual risk assessment (RA) and risk reduction (RR) counselling, but physicians both infrequently and incompletely do sexual RA and RR. A programme was developed to improve primary care physicians' prevention practice using Simulated Patient Instructors (SPIs) and mailed educational materials. Programme evaluations showed improved sexual RA and RR practice both by self-report as well as by observation by Simulated Patient Evaluators (SPEs). This paper briefly reviews these findings and then presents adaptations made to improve the programme's content, decrease its cost and increase its availability for training many other care providers. Evaluation of the adapted programme indicates that content and training methods are highly regarded by a diverse array of trainees. To disseminate the modified programme beyond the local area, a Train-the-Trainer programme and manual have been developed, including discussion of recruiting, training and using SPIs for sexual risk reduction. Wider use of this training, as well as more effective and more readily available STD/HIV prevention training, are needed to attain national goals of provider clinical prevention practice.

Commentary on the federal role in clinical prevention research.

Effective clinical prevention practice is the objective of the long journey from laboratory and epidemiologic studies to clinical understanding, interventions, and prevention practice with individual patients. The ability to ask ever more fundamental questions about the molecular basis of disease, as is rapidly being developed by NIH's Human Genome Project, promises to make this journey even longer and more complicated, but eventually to make screening and intervention for preventable disease even more amenable to clinical intervention. As we expect in the future, much of what we currently do in clinical prevention practice had its genesis in earlier federal support for basic and clinical research. We comment on the content and major points of the papers on the federal role in prevention research. These papers, in addition to describing the past accomplishment, current state, and future opportunities for prevention research, raise questions about the ultimate application of the enormous and successful national investment in prevention research. A fault line exists among the increasing knowledge of prevention practice, the rapid changes in the way services are delivered, and demonstration of the effectiveness of prevention procedures applied for the good of the whole population. The federal agencies most concerned with the application of prevention knowledge are those most limited in their research budgets: the Agency for Health Care Policy and Research (AHCPR) and the Centers for Disease Control and Prevention (CDC). The National Institutes of Health (NIH), with the greatest research dollars for investment, also has the broadest mandate for investment in research. Meeting all the demands to fund high-quality research is challenging; however, NIH may have review procedures that disadvantage clinical researchers and, among these, applied prevention researchers. The restructuring of the health care system by managed care promises opportunity for more effectiveness research. However, the same competition that fosters the development of managed care may limit the extent of prevention experimentation and the dissemination of results. Current national concerns for the weakening of support for clinical research are in part due to the reduced availability of patient care revenue to support clinical research brought about by managed care. The academic and practice communities that share concern for prevention research should recognize the increasing gap between basic and applied prevention knowledge. Those committed to the clinical application of this knowledge should encourage increased federal research support to assure that what we think we know is indeed so, that what is efficacious is available to all in the society that so generously supports research.

Association of ventricular ectopy with nuclear scintigraphic perfusion defects during dipyridamole stress testing.

BACKGROUND AND HYPOTHESIS: No information is available regarding the significance of ventricular ectopic activity induced during dipyridamole nuclear scintigraphic stress testing. This study tested the hypothesis that dipyridamole-induced ventricular ectopy predicts a thallium-201 or technetium-99m sestamibi perfusion defect. METHODS: A group of 186 consecutive patients with premature ventricular contractions and/or couplets occurring during dipyridamole stress testing (ventricular tachycardia did not occur) was compared with a control group of 194 patients without ventricular ectopy during dipyridamole stress testing. RESULTS: The results indicated that ventricular ectopy induced during dipyridamole infusion occurred more frequently in patients demonstrating either a fixed or reversible perfusion defect on scintigraphic imaging (p < 0.01). The higher frequency of perfusion defects in this group of patients was attributable to a higher frequency of "fixed" compared with "reversible" defects (p < 0.05). This finding is consistent with the additional observation that ventricular ectopy induced by dipyridamole was associated with the presence of Q waves on the resting ECG (p < 0.05). The positive and negative predictive values of the presence of ventricular ectopy in predicting a fixed myocardial perfusion defect were 59 and 54%, respectively. CONCLUSIONS: Ventricular ectopy induced during dipyridamole infusion suggests the presence of a fixed myocardial perfusion defect.

A cost and outcome model of fertility treatment in a managed care environment.

OBJECTIVE: To build a financial model of a fertility practice operating under managed care. DESIGN: Financial model in Microsoft Excel (Redmond, Washington). SETTING: University-affiliated infertility practice, assuming primary care referral of patients and total revenue a function of the capitation contract. PATIENT(S): Female infertility patients and their partners with assumed mean age of 35 years. MAIN OUTCOME MEASURE(S): Breakeven capitation rate. RESULT(S): Every other month ovulation induction produced the lowest breakeven capitation rates in the model. Breakeven capitation rates increased from $0.85 up to $4.70 per member per month as utilization increased from 0.1% to 1% of health plan members. Decreasing the cost of an IVF-ET cycle $2,050 decreased breakeven capitation rates from $0.05 up to $0.80 per member per month as utilization of fertility services increases from 0.1% to 1% of health plan members. Decreasing average yearly pregnancy rate from 56% to 41% increased breakeven capitation rate from $0.10 to $0.80 per member per month across similar utilization. The average cost of pregnancy per year ranged from $6,787 to $21,075. CONCLUSION(S): As utilization of fertility services increases, cost reductions no longer exist to offset increasing breakeven capitation rates. Financial modeling, using actual data, can evaluate any medical decision in terms of outcome and the cost of that outcome. Modeling is an effective means for physicians to educate themselves concerning the cost of their fertility and medical decisions.

Insulin signaling in mice expressing reduced levels of Syp.

Syp is a protein tyrosine phosphatase implicated in insulin and growth factor signaling. To evaluate the role of syp in insulin's regulation of plasma glucose, we generated knockout mice. Homozygous knockout mice die prior to day 10.5 of embryonic development. Hemizygous mice express half the levels of syp protein compared with their wild type littermates but do not display any gross morphological changes. Total body weight (age 2-10 weeks) and plasma insulin and glucose levels both in fasting and glucose-challenged states were comparable in the wild type and the hemizygous mice. No differences were observed in insulin-induced glucose uptake in soleus muscle and epididymal fat; insulin inhibition of lipolysis was also similar. We injected insulin into the portal vein of the mice to examine upstream events of the insulin signaling cascade. Tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 (IRS-1) from hemizygous tissue was similar to that of wild type tissue. Association of the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 increased an average of 2-fold in both groups. We did not observe an increase of IRS-1/syp association after insulin administration, but we did note a significant basal association in both wild type and hemizygous tissue. Our results do not support a major role for syp in the acute in vivo metabolic actions of insulin.