The effects of synthetic conjugated estrogens, a (cenestin) on trabecular bone structure and strength in the ovariectomized rat model.

This study evaluated the effect of Cenestin, a synthetic conjugated estrogens product, on the maintenance of trabecular bone microarchitecture, bone strength, and of bone turnover in the ovariectomized (ovx) rat model. Two doses of Cenestin were chosen in an attempt to approximate the equivalent human oral doses of 0.3 mg and 0.625 mg. Forty-nine 6-month-old retired female breeder Sprague-Dawley rats were randomly assigned to one of four groups: (1) sham-operated + vehicle; (2) ovx + vehicle; (3) ovx + day 1 post-ovariectomy Cenestin (8.12 mg/kg); (4) ovx + day 1 post-ovariectomy Cenestin (16.24 mg/kg) for 8 weeks. Trabecular structure of the right proximal tibia of each rat was imaged noninvasively by microCT. A compression test to induce a tibial plateau fracture was performed to determine the mechanical properties of the proximal tibia. Urine was collected on days 0, 14, 28, 42 and 56 and serum on days 0, 28 and 56 to assess biochemical markers of bone turnover including deoxypyridinoline crosslinks and osteocalcin. Both biochemical markers of bone turnover were analyzed by ELISA. Trabecular bone mass, structure, and connectivity density in the Cenestin-treated groups did not differ statistically ( p>0.05) from those of the sham-operated + vehicle-treated rats, but all were significantly higher ( p<0.05) than in the ovx + vehicle-treated rats. Structure Model Index, a measure of trabecular plate morphometry, in Cenestin-treated rats maintained a more equal mix of plate- and rod-like structures similar to the sham group, whereas the ovx group had predominantly rod-like trabeculae. Fracture load in the Cenestin (16.24 mg/kg) treated group was 31% ( p<0.01) higher than in the sham + vehicle-treated group and 61% ( p<0.05) higher than in the ovx + vehicle-treated group. Both the sham-operated + vehicle-treated and Cenestin-treated groups showed significantly lower urinary deoxypyridinoline crosslink excretion at all timepoints and serum osteocalcin at day 56 compared with the ovx + vehicle-treated group. In summary, Cenestin maintained trabecular bone microarchitecture and strength in an ovariectomized rat model of estrogen deficiency.

Evaluation of single- and multiple-dose pharmacokinetics of synthetic conjugated estrogens, A (Cenestin) tablets: a slow-release estrogen replacement product.

A multiple-dose, placebo-controlled, randomized pharmacokinetic study was performed in 15 early (i.e., 1-3 years) postmenopausal women to evaluate the single and steady-state pharmacokinetics of 0.625 mg Cenestin (Synthetic Conjugated Estrogens, A) tablets, administered once daily for 90 days. Plasma concentration-time profiles for both total (conjugated and unconjugated) estrone and equilin, two major estrogens in Cenestin, were nearly superimposable between Day 1 (single dose) and Day 90 (multiple dose), indicating equivalent drug exposure from one dose to the next. For total estrone, the mean estimates of Cmax and AUC0-24 were 2.5 ng/ml and 35.0 ng x h/ml for Day 1 and 3.0 ng/ml and 39.8 ng x h/ml for Day 90, respectively. Similarly, Cmax and AUC0-24 mean values for total equilin were 1.4 ng/ml and 17.4 ng x h/ml after Day 1 and 1.5 ng/ml and 17.3 ng x h/ml after Day 90, respectively. The mean tmax value for total estrone was 8.3 hours on Day 1 and 8.6 hours on Day 90, indicating a slower rate of absorption. The average estimate for observed drug accumulation index for the 24-hour dosing interval was calculated to be 1.1 for total estrone and 1.0 for total equilin. These data, taken together, indicate a slow and steady rate of absorption, minimal drug accumulation at steady state, and consistent drug exposure between Cenestin doses.

Perimenopausal women in estrogen vasomotor trials: contribution to placebo effect and efficacy outcome.

OBJECTIVE: To determine the difference, if any, in the placebo response when both perimenopausal and postmenopausal women are enrolled, compared with postmenopausal women alone, in a study assessing the efficacy of synthetic conjugated estrogen tablets on moderate-to-severe vasomotor symptoms (MSVS). METHODS: A total of 120 healthy women (72 active; 48 placebo) complaining of moderate-to-severe vasomotor symptoms were enrolled in a randomized, placebo-controlled, double-blind, multicenter clinical trial. In all, 109 patients completed treatment to week 12. Women were enrolled using minimal inclusion and exclusion criteria, and included perimenopausal women (n = 34; 0 to 6 months since last menses) as well as menopausal women (n = 79; > 12 months since last menses). RESULTS: Changes in MSVS in the intent-to-treat (ITT) population showed differences between the active and placebo treatments at weeks 4 (p < 0.022), 8 (p < 0.010) and 12 (p < 0.010). At week 12, the mean percentage reduction in MSVS was 81% for the active treatment group and 58% in the placebo treatment group. To examine the placebo response, the ITT population was broken down into groups defined by the time since their last menses. The perimenopausal group (0 to 6 months since last menses) demonstrated a consistently higher placebo response than that of the postmenopausal groups (> 12 months since last menses). CONCLUSIONS: Perimenopausal women contributed to a higher placebo response, compared with the rate of response previously reported in clinical studies of estrogen replacement in postmenopausal women. Including perimenopausal women in future vasomotor symptom trials will require study populations of sufficient size to maintain the statistical power to demonstrate a difference between therapeutic response to active or placebo treatment.

A 12-week clinical trial determining the efficacy of synthetic conjugated estrogens, A (SCE), in the treatment of vasomotor symptoms in menopausal women.

OBJECTIVE: To compare the clinical effects of a new oral synthetic conjugated estrogens, A (SCE), versus placebo in a clinically relevant population on the reduction in the mean number of moderate to severe vasomotor symptoms. DESIGN: A total of 120 healthy pre- and postmenopausal women (72 active, 48 placebo) were enrolled into a randomized, placebo-controlled, double-blind, multi-center clinical trial. Women of all races were enrolled, using minimal inclusion and exclusion criteria. Each subject received either orally administered SCE, in doses of 0.3 mg, 0.625 mg or 1.25 mg per day, or placebo. Analysis of variance was performed on the primary efficacy variable (change from baseline to weeks 4, 8, and 12 in the mean number of moderate to severe vasomotor symptoms). RESULTS: Changes in moderate to severe vasomotor symptoms in the intent to treat population showed statistically significant differences between the active and placebo treatments at week 4 (P < .022), week 8 (P < .010), and week 12 (P < .010). By week 12, the mean percentage reduction in moderate to severe vasomotor symptoms was 81%, from an average baseline of 96.8, to 16.5 hot flashes per week for the active treatment group. The overall incidence of expected estrogen-related adverse effects was modest. Laboratory tests and vital sign measurements did not reveal clinically significant changes or abnormalities from screening to the final visit in either treatment group. CONCLUSIONS: The results of this study confirm the efficacy and safety of SCE in the treatment of moderate to severe vasomotor symptoms in menopausal women. In addition, the study also demonstrated that the use of more liberal entry criteria did not materially affect the efficacy outcome.

Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer.

BACKGROUND AND METHODS: We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS: Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS: The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.

Radiotherapy for the treatment of giant cell tumor of the spine: a report of six cases and review of the literature.

Optimal treatment for giant cell tumors in the axial skeleton (GCTS) remains challenging. Surgical excision remains the treatment of choice, but the potential spinal cord injury may limit the extent of resection. We report the long-term results of treatment of six patients diagnosed with giant cell tumor of the spine treated with radiotherapy and review the literature regarding therapy. Between 1971 and 1995, six patients with GCTS were treated with conservative surgery and radiotherapy. The surgery consisted of either biopsy or subtotal resection of tumor. The involved vertebrae were then irradiated with doses ranging from 3000 to 5400 cGy. The mean follow-up was 13 years, and three of six patients had follow-up of 17 or more years. Five of six patients are alive with no evidence of disease. One is alive with disease, although it is not clinically apparent. No patient was lost to follow-up. We conclude that radiotherapy is useful in the management of GCTS and that conservative surgery with local radiotherapy is a reasonable treatment alternative for tumors that cannot be completely excised or in which surgery would result in significant functional morbidity. Although there is no clear dose response, review of the literature suggests that doses ranging from 3500 to 4500 cGy are safe and effective in controlling giant cell tumor.

A comparison of staging systems for nasopharyngeal carcinoma.

BACKGROUND: The fifth edition of the American Joint Committee on Cancer staging manual defines new rules for classifying nasopharyngeal carcinoma. The authors tested the value of this new system by applying these rules retrospectively to their previously treated patients and comparing the results with those obtained using the fourth edition of the AJCC staging manual or the Ho staging system. METHODS: Information from 107 patients who had biopsy-proven squamous cell carcinoma of the nasopharynx that was treated in a constant fashion with definitive-intent radiation therapy alone at one institution provided the data base for this analysis. The extent of disease of each patient was staged according to the rules of 1) the fourth edition of the AJCC staging manual, 2) the Ho staging system, and 3) the fifth edition of the AJCC staging manual. RESULTS: The new system appears to be better than the two previous systems. It separated patients into cohorts of more equal size than did either of the other systems. It also correlated with outcome for the study population more appropriately than did the fourth edition of the AJCC staging manual or the Ho staging system. CONCLUSIONS: The fifth edition of the AJCC staging manual appears to be an improvement over the previous AJCC or Ho staging systems for the staging of nasopharyngeal carcinoma.

Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulations (Carbatrol and Tegretol-XR).

A major limitation of conventional carbamazepine (CBZ) formulations is their pharmacokinetics, which typically require q.i.d. dosing. Two extended-release formulations of CBZ have been developed recently to support b.i.d. dosing. One, Carbatrol (CBTL) uses immediate-, extended-, and enteric-release beads in a capsule. The other, Tegretol-XR (TXR), uses an osmotic pump (Oros tablet). To our knowledge, this is the first head-to-head comparison of the multidose pharmacokinetics of these two new formulations. The objective of the study was to evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10,11-expoxide (CBZ-E) after multidose b.i.d. dosing with CBTL or TXR. In this randomized, crossover study, 15 normal healthy adults received 400 mg of each formulation b.i.d. for 5 days. Blood samples for CBZ and CBZ-E analysis were obtained prior to morning doses on all days and hourly for 12 h after the Day 5 dose. There was a minimum interperiod washout of 9 days. For CBTL and TXR, the key CBZ pharmacokinetic measures of area under the curve of concentration versus time (AUC(0-tau)), maximum concentration (Cmax), and minimum concentration (Cmin) were bioequivalent. The ratio for CBTL-to-TXR was 98% (90% confidence intervals, 92-104%), 107% (96-118%), and 96% (89-104%), respectively. Similar ratios were also observed for CBZ-E: 102% (97-107%), 99% (92-107%), and 93% (83-109%), respectively. In conclusion, CBTL b.i.d. and TXR b.i.d. were bioequivalent in their pharmacokinetic parameters for CBZ and CBZ-E after 5 days of dosing.

Fluoridation and the private practice of dentistry.

Water fluoridation holds an important place in the history of Grand Rapids. This paper recounts the firsthand professional experiences of a dentist before and after he joined his father's established dental practice in Grand Rapids, only two years after fluoridation of the city's water supply began. The benefits of water fluoridation are documented through a review of office records. The prevalence of dental caries in patients who were born in Grand Rapids after water fluoridation began is low, and no case of a missing first permanent molar was found. Quadrant dentistry is no longer practiced. Children of parents born in Grand Rapids after the start of water fluoridation experience less decay than their parents, suggesting that factors in addition to water fluoridation have played a role in the downward trends in caries. The complete destruction of mouths of patients seen in this practice 50 years ago no longer happens, providing evidence of the benefits of water fluoridation, the most important advance ever in dentistry.

Patient, revenue and cost analyses for medical practices.

Authors Robert Stevens and Thomas Chatham write that revenue and cost analysis can be performed by medical groups from historical data they maintain. Such analysis provides the administrator with a data base for developing realistic objectives and identifying areas which should be more fully developed or even eliminated.

The public's image of doctors, dentists, and pharmacists.

The basic purpose of this study was to evaluate the public's image of three health professions. Q questionnaire was administered by telephone to a random sample of 150 residents of a southern metropolitan area. Respondents were asked to evaluate seven professions on (1) social standing (prestige), (2) honest and ethical standards, (3) importance to society and nation, and (4) interesting and challenging occupation. Overall findings indicate that doctors rated significantly higher than dentists, and pharmacists in all areas except honest and ethical standards. The three groups were rated equally on this factor. Cross tabulations of respondents by income, age, education, and sex revealed that there were no significant differences in the ratings of these groups on the basis of socio-economic characteristics of respondents except for pharmacists. Male respondents rated pharmacists significantly lower than female respondents.

Mycobacterium chelonei keratopathy with visual rehabilitation by a triple procedure.

We report a chronic keratouveitis following an eye injury, the etiology of which remained obscure despite repeated corneal scrapings and cultures. Eventually, the diagnosis was established by culturing Mycobacterium chelonei from a corneal biopsy specimen. Topical amikacin resolved active inflammation, but dense corneal scarring and a cataract remained. Visual rehabilitation was achieved through a combined penetrating keratoplasty, extracapsular cataract extraction, and intraocular lens implantation. This case illustrates that there should be a high index of suspicion of atypical mycobacteria when faced with any unusual keratitis, particularly following penetrating injuries and corneal grafts.

Segmenting the mental health care market.

The authors report the results of a segmentation study of the mental health care market. A random sample of 387 residents of a western city were interviewed by telephone. Cluster analysis of the data identified six market segments. Each is described according to the mental health care services to which it is most sensitive. Implications for targeting the segments are discussed.

The nature of physician's services: marketing implications.

A specific system for classifying services is applied to physicians' services in an attempt to better understand those services. Other services organizations are identified that are similar to these services along each of the dimensions suggested by the classification system. In addition, marketing insights and implications are offered for marketing physicians' services.

Idiopathic presenile cataract formation and galactosaemia.

Five hundred patients undergoing cataract surgery were prospectively examined, and 46 Caucasian patients were found to have strictly idiopathic cataracts severe enough to warrant surgery on or before age 55. In a masked fashion we determined the activity of galactokinase (GK) and galactose-1-phosphate uridyl transferase (GPUT) in these patients as well as on 53 age matched controls. With respect to GK no cataract patient had an enzyme level of less than 2 standard deviations below the control mean. However, 3 of 45 (6.7%) patients in the cataract group had a GPUT level less than 2 standard deviations below the mean for controls, and were presumably heterozygotes for this enzyme. In comparison with the expected population rate of 0.8% this is highly significant (p = 0.006). Abnormalities in galactose pathway enzymes may therefore predispose to development of presenile cataracts. In affected people there is a possibility of treating these patients clinically by dietary restriction of dairy products or by using aldose reductase inhibitors to prevent or reverse cataract formation.

Segmenting health care markets: large versus small businesses.

What differences exist between provision of health care benefits, cost containment measures, and health care concerns between large and small companies? This issue of DRG Monitor examines these differences through the analysis of responses to a survey and suggests strategies that hospitals and other health care providers may employ to target both markets.

Dissecting health care markets: large versus small businesses.

This article reports the results of a mail survey of businesses in Tulsa, Oklahoma (population 377,900 in the city and 745,300 in the surrounding metropolitan area). The purpose of the research was to analyze differences in health care provision and perspectives between large and small businesses. The survey of 3,200 members of the city's chamber of commerce yielded 640 responses. Analysis of the data revealed distinct differences between the two segments of the health care industry. The findings suggest that market opportunities exist for the development of health care delivery system programs aimed at small businesses.

Feasibility analysis for medical services.

Feasibility analysis is an important aspect of business planning. A feasibility study is a study of the impacts of revenues, cost, and returns on a decision. It helps answer the questions of "What share of total sales can be attained?" "What revenues will be generated?" "What costs will be incurred?" "What will be the return on investment?" The discipline of going through a systematic approach to analyze market demand, cost requirements, and return on investment will improve business decisions by eliminating risk and increasing the possibility of successful ventures.