A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852.

Integrating pharmacokinetics knowledge into a drug ontology: as an extension to support pharmacogenomics.

The newly developed U.S. Common Medication Information Infrastructure was used as a basis to capture and formally express the properties of drugs relevant to research and the clinical application of pharmacogenomics. Two associated taxonomies within the model, Mechanism of Action and Physiologic Effect, were enriched to accommodate pharmacogenomic use-cases; the 4,000 active ingredients in the VA NDF-RT drug file were related to the enhanced taxonomies. Pharmacokinetics were independently modeled for pharmacogenomics and tested against thirty-one high-profile drugs to demonstrate our approach.

Public health and clinical implications of high hemoglobin A1c levels and weight in younger adult Native American people with diabetes.

BACKGROUND: Type 2 diabetes mellitus is a major public health issue for Native American people. Because glycemic levels are predictive of diabetes outcome, understanding determinants of high hemoglobin A(1c) (HbA(1c)) levels may provide targets for prevention efforts. OBJECTIVES: To investigate determinants of high HbA(1c) levels in Native American people. METHODS: We conducted a population-based, cross-sectional study of 206 participants with diabetes from 8 Native American communities in New Mexico. We used linear regression to assess the relationship of HbA(1c) level with age, body mass index (BMI), treatment type, duration of diabetes, physical activity, and diet. RESULTS: Age, dietary pattern, and treatment type were determinants of HbA(1c) levels. Participants younger than 55 years had the highest adjusted HbA(1c) levels at 9.5% and those 65 years and older had the lowest levels at 7.8%. According to a participant's dietary intake, HbA(1c) levels were highest for those who consumed the most fat and sugar, and high consumption of fat and sugar affected HbA(1c) levels most among those younger than 55 years. Participants treated with insulin had the highest hemoglobin A(1c) levels. Physical activity was not associated with HbA(1c) level. CONCLUSIONS: We found an increasing severity of diabetes among younger people. To avoid increased morbidity and mortality in the future, young Native American adults with diabetes need vigorous therapy to maintain tight glucose control. Arch Intern Med. 2000;160:3471-3476.

A colorimetric detection system for Calymmatobacterium granulomatis.

OBJECTIVE: To incorporate the first polymerase chain reaction (PCR) assay for Calymmatobacterium granulomatis into a colorimetric detection system for use in routine diagnostic laboratories. METHODS: A capture oligonucleotide specific for the Klebsiella phoE gene was covalently linked to tosyl activated magnetic beads. Biotinylated phoE PCR products obtained from 14 positive specimens from patients with donovanosis and isolates of Klebsiella pneumoniae, K rhinoscleromatis, and K ozaenae were cleaved with HaeIII for the purpose of differentiation, captured by the prepared beads, and subjected to standard EIA detection methodology. Eight samples from unrelated genital conditions underwent the same procedure. It was anticipated from the sequence data that the biotinylated fragment would be cleaved from the capture oligonucleotide target region in the three Klebsiella phoE products (that is, a negative colorimetric result) while the entire fragment of interest would remain intact in the positive C granulomatis phoE products (that is, a positive colorimetric result). RESULTS: All 14 positive specimens from patients with donovanosis gave strong colorimetric readings with this detection system. Isolates of K pneumoniae, K rhinoscleromatis, K ozaenae, and the eight specimens from unrelated genital conditions were negative. CONCLUSION: The successful development of a colorimetric detection system for C granulomatis incorporating two levels of specificity enables the molecular diagnosis of this condition to be undertaken by routine diagnostic laboratories. This should have an important role in the Australian government's campaign to eradicate donovanosis by 2003 though the test still needs to undergo trials and be validated using a larger number of samples from geographically diverse parts of the world in order to ascertain the generalisability of the methodology.

Challenges to participating in a lifestyle intervention program: the Native American Diabetes Project.

PURPOSE: This paper describes the factors that American Indian teachers in the Native American Diabetes Project (NADP) reported affected participation in the NADP lifestyle education sessions. METHODS: A postsession exit interview was conducted with each of the 7 mentors (teachers) of the NADP sessions. Interview questions addressed general perceptions of the sessions, factors that kept participants from coming to the sessions, and attitudes toward diabetes and persons with diabetes. Interviews were transcribed and responses reflecting factors related to participation were marked and organized into topic areas. RESULTS: Mentors reported a range of factors that affected participation in the sessions, such as conflicts with community activities and beliefs/attitudes about diabetes. The latter factor includes program knowledge, recruitment methods, attitudes toward the program, and beliefs about diabetes. CONCLUSIONS: Asking community members what factors they believe affect participation is an important component of increasing participation in community-based programs. Community members can provide a valuable personal perspective of actual and potential conflicts in the community.

Phylogenetic evidence for reclassification of Calymmatobacterium granulomatis as Klebsiella granulomatis comb. nov.

By sequencing a total of 2089 bp of the 16S rRNA and phoE genes it was demonstrated that Calymmatobacterium granulomatis (the causative organism of donovanosis) shows a high level of identity with Klebsiella species pathogenic to humans (Klebsiella pneumoniae, Klebsiella rhinoscleromatis). It is proposed that C. granulomatis should be reclassified as Klebsiella granulomatis comb. nov. An emended description of the genus Klebsiella is given.

Communicating through stories: experience of the Native American Diabetes Project.

Stories appear to provide an indirect way of confronting the inherent conflict between the concepts of disease and wellness and assisting in the transition to a new concept of living well with the disease. This new concept may engender feelings of acceptance and hope that can facilitate application of knowledge and behavior change. In addition, culturally appropriate stories allow people to draw from their own personal beliefs and values to interpret and apply new information to their own lives. A good story takes listeners on a collective journey with many paths; each path is uniquely suited to the needs of the individual, with wisdom gained that is uniquely suited to their own life.

Participant satisfaction with a culturally appropriate diabetes education program: the Native American Diabetes Project.

PURPOSE: The purpose of this paper is to report on participant satisfaction with the Native American Diabetes Project diabetes education program. METHODS: A questionnaire was designed to measure satisfaction among participants in the diabetes education program, which consisted of five sessions designed according to the Transtheoretical Model of Change and Social Action Theory with input from community members. Eight pueblo communities participated in the program. Sessions were taught by community mentors in three sites in New Mexico. One site taught sessions in a one-on-one format, and two sites taught sessions in a group format. RESULTS: The results showed that participant satisfaction did not vary based on session delivery type or by session site. Overall, participants responded positively to sessions designed according to Social Action Theory and with cultural competency. Retention rates for the sessions were 81% for group sessions and 91% for one-one-one sessions. CONCLUSIONS: Using a strong theoretical framework and community input to design diabetes education sessions may be important factors in participant satisfaction and retention in diabetes lifestyle education sessions.

Knowledge, attitudes and behaviors related to physical activity among Native Americans with diabetes.

OBJECTIVE: Native Americans (NA) have higher diabetes morbidity and mortality compared to other ethnic groups. Although exercise plays an important role in diabetes management, little is known about exercise among Native Americans with diabetes. Our goal was to describe knowledge, attitudes and behaviors related to exercise in Native American participants in New Mexico. DESIGN: Bilingual community members administered a questionnaire to assess knowledge, stage of change (a measure of exercise readiness), and physical activity behavior. Hemoglobin A1c (HbA1c) was measured by DCA 2000 analyzer. Height and weight were measured to calculate body mass index (BMI). Average random blood glucose (RBS) levels and diabetes duration were assessed through chart audit. SETTING: Questionnaires were completed in offices in or near the communities. PARTICIPANTS: 514 Native Americans with diabetes were identified as potential participants, 40% (142 women, 64 men) participated. RESULTS: 37% of participants knew exercise lowers blood sugar. 82% reported they were in the preparation, action, or maintenance stage of change for exercise behavior. Seventy seven percent of this population did not meet the Surgeon General's recommendation for accumulating 30 minutes of leisure time endurance exercise on most days of the week. However, 67% of participants fell within the "high activity" category for all moderate and vigorous activities. Average age, BMI and HbA1c were 58.5 yrs., 30.5 kg/m2, 8.6%, respectively. CONCLUSIONS: Interventions to increase physical activity awareness and participation could improve diabetes management and overall health for Native Americans. When evaluating physical activity, researchers need to consider usual activities of daily living and leisure time activities specific to that population. Failure to do so would be ethnocentric and could lead to inappropriate conclusions.

Design and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as selective cyclooxygenase-2 inhibitors.

A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.

Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors.

A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.

4,5-Diaryloxazole inhibitors of cyclooxygenase-2 (COX-2).

A series of methysulfonyl or sulfonamido substituted 4,5-diaryloxazole were prepared and evaluated for their ability to inhibit the inducible form of cyclooxygenase (COX-2) in vitro and in vivo. Several unique substitution patterns were identified that led to potent and selective inhibitors of COX-2. In general, 2-trifluoromethly-4,5-diaryloxazoles substituted with a methylsulfonyl or sulfonamido group were particularly potent inhibitors. One of the more potent compounds with a selectivity for COX-2 of about 800 fold was 4b (SC-299). SC-299, a highly fluorescent molecule, may be useful for spectroscopic studies on preferential inhibitor binding to COX-2.

Diabetic amputations in the VA: are there opportunities for interventions?

Lower limb amputation (LLA) is a devastating complication experienced by some veterans with diabetes. The Veterans Affairs (VA) Healthcare system has identified the prevention of LLA as a priority goal. This study was designed to describe the sources of outpatient care received by veterans with diabetes who have undergone LLA, to determine whether these persons would have been impacted by a VA amputation prevention program. This study was also designed to describe prior amputation history, footwear history, and the pivotal events that led to these amputations. We found that the vast majority of these subjects identified the VA as their primary source of care, and thus would have been available for enrollment in a prevention program. Since over one-half of them had had a prior amputation, diabetics with a prior amputation should be particularly targeted for foot care interventions. Lastly, prescription of protective footwear has the potential to reduce the incidence of shoe-related ulcers and amputations.

Adaptation of the Dartmouth COOP Charts for use among American Indian people with diabetes.

OBJECTIVE: To adapt the Dartmouth COOP Charts for use among American Indians with diabetes and to evaluate the operating characteristics of the adapted charts because measures of health status have not been evaluated for use among American Indians with diabetes. RESEARCH DESIGN AND METHODS: American Indian adults participated in focus group conferences to adapt and review the Dartmouth COOP Charts for use in American Indian communities. American Indian participants with diabetes were interviewed and administered the adapted charts. The operating characteristics of the charts were evaluated by measuring internal and external consistency, reliability, and acceptability. RESULTS: Some of the wording and pictures were considered to be offensive and culturally inappropriate in American Indian communities. The adapted charts showed internal consistency in a comparison of interchart variables. CONCLUSIONS: The adapted Dartmouth COOP Charts are more culturally acceptable than the original charts and appear to measure constructs adequately.

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

Temporal trends in diabetes mortality among American Indians and Hispanics in New Mexico: birth cohort and period effects.

Rates of diabetes mortality are disproportionately high among ethnic minorities in the United States. To describe ethnic trends and cohort effects in diabetes mortality in New Mexico, the authors examined the trends in mortality rates for non-Hispanic whites. Hispanics, and American Indians in the state during the period 1958-1994. Age-specific rates were examined graphically to qualitatively describe the contribution of calendar period and birth cohort effects to changes in the rates. The authors also fit age-period-cohort models to these data. Age-adjusted diabetes mortality rates for American Indians and Hispanics surpassed rates for non-Hispanic whites for all but the earliest two time periods. In the 1993-1994 period, the age-adjusted mortality rate for American Indians was 3.8 times higher for men and 5.6 times higher for women than for their non-Hispanic white counterparts. Rates for American Indian men and women increased sharply over the 37-year period, by 565% and 1,105%, respectively. Mortality rates increased among Hispanics over the period of study but less rapidly than did rates among American Indians. Graphical analyses of age-specific rates were consistent with birth cohort effects among both American Indians and Hispanics and also with a period effect among American Indians. Results from age-period-cohort models indicate a birth cohort effect starting with the 1912 cohort in American Indians and the 1902 cohort in Hispanics. A period effect was present during the 1960s in American Indians. American Indians have experienced an epidemic rise in diabetes mortality in New Mexico; if current trends continue, diabetes may become the leading cause of mortality among American Indians in the state.

Non-insulin-dependent diabetes mellitus in minorities in the United States.

PURPOSE: To review the available information on prevalence, complications, and mortality of non-insulin-dependent diabetes mellitus and primary and secondary prevention activities in black persons, Hispanic persons, Native Americans, and Asians and Pacific Islanders in the United States. DATA SOURCE: MEDLINE search from 1976 to 1994 through the PlusNet search system. STUDY SELECTION: Use of the key words non-insulin-dependent diabetes mellitus, the names of each specific minority group, socioeconomic status, acculturation, genetics, diet, complications, mortality, treatment, and intervention (lifestyle or medication) produced 290 unduplicated articles. Additional articles cited in the original articles were also included. DATA EXTRACTION: Risk factors, incidence, prevalence, complications, and mortality of non-insulin-dependent diabetes mellitus. DATA SYNTHESIS: All minorities, except natives of Alaska, have a prevalence of non-insulin-dependent diabetes mellitus that is two to six times greater than that of white persons. Most studies show an increased prevalence of nephropathy that can be as much as six times higher than that of white persons. Retinopathy has variably higher rates in black persons, Hispanic persons, and Native Americans. Amputations are done more frequently among black persons than among white persons (9.0 per 1000 compared with 6.3 per 1000), and Pima Indians have 3.7 times more amputations than do white persons. Diabetes-related mortality is higher for minorities than for white persons, and the rate is increasing. The relative importance of genetic heritage, diet, exercise, socioeconomic status, culture, language, and access to health care in the prevalence, incidence, and mortality of diabetes is not clear. Studies of interventions in minority populations are in progress. CONCLUSION: Diabetes should be treated as a public health problem for minority populations.