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By considering published structural information we have designed high throughput biaryl lipophilic acid arrays leveraging facile chemistry to expedite their synthesis. We rapidly ...identified multiple hits which were of suitable IP agonist potency. These relatively simple and strategically undecorated molecules present an ideal opportunity for optimization towards our target candidate profile.
This phase 1 trial was conducted to evaluate the safety and tolerance of didanosine (ddI) in subjects with AIDS or AIDS-related complex (ARC) who previously had demonstrated hematologic intolerance ...of zidovudine. Thirty subjects, 21 with AIDS and nine with ARC, were enrolled. Initially, didanosine was administered orally twice daily for a total daily dose of either 750 mg or 1,500 mg. Subsequently, the dosage for those receiving 1,500 mg/d was reduced to a maximum of 750 mg/d (375 mg twice daily) when data from this and other phase 1 studies showed that the dosage of 1,500 mg/d (750 mg twice daily) was associated with an unacceptable risk of developing neuropathy. The subjects were studied for 46 weeks (mean time; range, 7–122 weeks). The dose-limiting toxic effect observed was peripheral neuropathy, which occurred in eight patients. Other significant toxic effects included pancreatitis in three patients and xerostomia in eleven. In general, didanosine was well tolerated from a hematologic standpoint by the majority of patients during prolonged administration.
To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to ...envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro.
Phase 1 trial with dose escalation.
Two university-affiliated hospital clinics.
Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex.
The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored.
Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively.
At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.
To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic ...intolerance to zidovudine.
A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured.
For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing.
Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.
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Diagnosis of breast cancer at early stages is associated with better clinical and survival outcomes. How the costs of care vary depending on the stage at which breast cancer was diagnosed has not ...been thoroughly examined.
To quantify the stage-dependent average per capita cost of breast cancer treatment for a commercially insured population of women with newly diagnosed breast cancer.
This retrospective analysis of claims data was based on a population selected from the Truven Healthcare MarketScan commercial claims database. The study comprised women aged 18 to 64 years with breast cancer who had ≥2 claims in 2010 that were ≥30 days apart and included an International Classification of Diseases, Ninth Revision diagnosis code for breast cancer (174.xx, 233.0) in any position of the claim. Two years of postdiagnosis claims data were analyzed by stage at diagnosis (ie, 0, I/II, III, and IV).
In total, 8360 women met the criteria for study inclusion (stage 0, N = 2300; stage I/II, N = 4425; stage III, N = 1134; and stage IV, N = 501). The costs were higher for patients whose cancer was more advanced at diagnosis, for all cumulative 6-month periods (months 0-6, 0-12, 0-18, and 0-24). The average costs per patient allowed by the insurance company in the year after diagnosis were $60,637, $82,121, $129,387, and $134,682 for disease stage 0, I/II, III, and IV, respectively. The average costs allowed per patient in the 24 months after the index diagnosis were $71,909, $97,066, $159,442, and $182,655 for disease stage 0, I/II, III, and IV, respectively. The cost difference based on the stage at diagnosis was largely driven by the cost of chemotherapy and noncancer treatments.
Treating advanced- versus early-stage breast cancer is associated with significant increases in incremental costs. Knowledge of the relevant stage-specific cost data provides support for strengthening programs, such as breast cancer screening, that are designed to shift breast cancer diagnosis to earlier disease stages.
As the fourth highest cancer in Indonesia, colorectal cancer (CRC) is one paramount cancer issue that requires urgent healthcare management. Most CRC survivors must undergo ostomy surgery to prevent ...malignancy and death. The stoma formation negatively impacts the ostomates’ quality of life as it predominantly affects these people’s sexual function, satisfaction, and social life. This study explores in-depth sexual experiences and perspectives of people living with a stoma and their physical, psychological, and cultural influences. This phenomenological qualitative study involved 12 female and male ostomates recruited purposively from the National Cancer Centre Hospital in Indonesia. Qualitative data were collected through semi-structured interviews, managed using Nvivo 12, and analysed thematically. The contextual findings highlighted four significant themes: sexual disruptions, revealing strategies for sexual adjustments, support from the marital partner, and limited support from the healthcare professionals. An interdisciplinary team supporting the sexual needs of the ostomates is necessary to improve strategies for adjusting to the sexual disruptions after CRC therapy. Pre- and post-stoma surgery counselling is recommended for CRC patients and their partners.
This study explicated associations between trauma-related cognitions and condomless sex, examining avoidance coping style and behavior (i.e., substance use) as intermediate variables, among a group ...disproportionately affected by both trauma and HIV. Two hundred and ninety HIV-negative MSM with a history of childhood sexual abuse (CSA) completed a cross-sectional psychosocial battery. Trauma-related cognitions were positively associated with more acts of condomless sex. Indirect associations on condomless sex were driven by avoidance coping, but not substance use. Findings indicate a need to address trauma-related cognitions and avoidance coping within interventions for reducing HIV risk among MSM with a history of CSA.
Objective: To assess the economic burden of cardiovascular events in Medicare beneficiaries with type 2 diabetes mellitus (T2DM).
Methods: This claims-based actuarial analysis queried 2013 and 2014 ...Medicare 5% samples, defining a denominator of fee-for-service beneficiaries. Average per patient per month allowed cost ($PPPM) was calculated for T2DM, demographically adjusted non-T2DM, and denominator. Per member per month allowed cost ($PMPM) was calculated by dividing total population cost by member months in the denominator. Costs of five pre-specified cardiovascular events were calculated as a contribution to denominator $PMPM, as contribution to $PPPM in T2DM, and as incremental cost.
Results: During the study period, 22.1% of Medicare fee-for-service beneficiaries had T2DM; of these, 9.68% experienced a cardiovascular event or cardiovascular-related death. T2DM cost represented 37.9% of total allowed $PMPM for the denominator. Average total allowed $PPPM for a T2DM beneficiary was $1,834, compared with $850 for a non-T2DM beneficiary (2.2-times higher). Annual rates of myocardial infarction, stroke, unstable angina admission, heart failure admission, and coronary revascularization in T2DM were 3.3-, 2.4-, 3.2-, 4.0-, and 2.8-times higher than in non-T2DM, and utilization of health services was also greater in T2DM. Cardiovascular events in T2DM accounted for 50% of denominator cardiovascular event cost; 3.6% of denominator population $PMPM was attributable to cardiovascular events in T2DM. Risk-adjusted incremental cardiovascular event cost represented 18.1% of $PPPM in T2DM or 6.9% of $PMPM in the denominator population.
Conclusions: Cardiovascular events in Medicare fee-for-service beneficiaries with T2DM contribute substantially to Medicare cardiovascular events, resource utilization, and cost.
