Synthesis of (+/-)-bakkenolide-A and its C-7, C-10, and C-7,10 epimers by means of an intramolecular Diels-Alder reaction.

(+/-)-bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi- and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition, using dimethyl malonate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the corresponding alpha-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro center by a radical cyclization resulted chiefly in reductive deselenization.

A dose-ranging study of fluticasone propionate administered once daily via multidose powder inhaler to patients with moderate asthma.

STUDY OBJECTIVE: This dose-ranging study evaluated the clinical efficacy and safety of inhaled fluticasone propionate administered once daily via a multidose powder inhaler in patients with moderate asthma (FEV(1), 45 to 75% predicted). MATERIALS AND METHODS: In this multicenter trial, 330 patients (> or = 12 years old) previously receiving inhaled corticosteroids or beta(2)-agonists alone were randomized in a double-blind manner to receive fluticasone propionate at 100, 200, or 500 microg once daily or matching placebo for 12 weeks. RESULTS: Once-daily treatment with fluticasone propionate resulted in an improvement in efficacy variables, such as FEV(1), morning and evening peak expiratory flow (PEF), asthma symptom scores, nighttime awakenings, albuterol use, and duration of study participation. A dose-related trend was observed for improvements in morning and evening PEF and albuterol use. Statistical significance for pairwise comparisons was achieved for 200 microg and 500 microg fluticasone propionate vs placebo for all efficacy variables, and for 100 microg fluticasone propionate vs placebo for morning and evening PEF at most or all time points. Drug-related adverse events were few (< or = 5%) and mostly related to the topical effects of inhaled corticosteroids. No dose-response effect or clinically relevant differences were observed in morning plasma cortisol concentrations or after cosyntropin stimulation. CONCLUSION: Once-daily treatment with fluticasone propionate was well tolerated and demonstrated some dose-related trends in improvements in lung function and asthma control in patients with moderate asthma.

Low-dose ranitidine for the relief of heartburn.

BACKGROUND: Approximately 30% of adults in the USA suffer from heartburn or related symptoms monthly; more than 20% of these sufferers experience heartburn at least once per day. Although many rely on self-medication with antacids for the relief of their symptoms, treatments that decrease gastric volume as well as increase the pH of refluxed material should be more effective in relieving heartburn. AIM: To compare the safety and efficacy of low-dose regimens of ranitidine for the relief of heartburn. METHODS: Adults with at least a 3-month history of heartburn were eligible for this randomized, double-blind, parallel group, multicentre dose-ranging study. Following a 1-week open-label run-in phase to document baseline heartburn frequency, subjects were randomized to receive treatment with one tablet of either ranitidine 75 mg (n = 491), ranitidine 25 mg (n = 504), or placebo (n = 494), to be taken as needed up to four times daily for 2 weeks for the relief of heartburn. RESULTS: The ranitidine 75 mg regimen was clinically (> 10 percentage points) and statistically (P < 0.05) significantly more effective than placebo for all measured efficacy end-points in relieving heartburn and reducing antacid consumption. In addition, the ranitidine 75 mg regimen was superior to placebo in providing heartburn relief within 30 min of dosing that lasted for up to 12 h. Ranitidine 25 mg was observed to be statistically superior (P < 0.05) but not clinically different from placebo, as defined a priori, in providing heartburn relief. All treatments were well tolerated and adverse events occurred no more frequently with the ranitidine regimens than with placebo. CONCLUSIONS: Ranitidine 75 mg provides prompt relief of heartburn that lasts for up to 12 h and has a safety profile comparable to that of placebo.

A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn.

BACKGROUND: Ranitidine 75 mg (Zantac 75) has been shown to be effective for the treatment of pre-existing heartburn symptoms. AIM: To compare the efficacy of dosing ranitidine 75 mg or placebo 30 min prior to a proven heartburn-provoking meal in completely preventing or reducing subsequent heartburn symptoms. METHODS: A randomized, double-blind, parallel methodology was used at nine investigative centres. Following a screening visit, patients ate a standard test meal consisting of chili, chips and a soft drink on two occasions. On the first occasion, patients received single-blind placebo 30 min before the meal. This meal was used to qualify patients and to ensure the onset of a minimum level of heartburn. Patients who qualified were randomized (n = 284) to receive double-blind ranitidine 75 mg or placebo 30 min before a second test meal administered 4-14 days later at the treatment visit. Patients recorded whether heartburn was present and rated heartburn severity by completing visual analogue scales at 15-min intervals over the 4. 5 h meal evaluation periods. RESULTS: Statistically significant differences favouring ranitidine 75 mg were determined for complete prevention of heartburn (P < 0.006), heartburn severity area under the curve (P < 0.001), a clinical success end-point (P < 0.001), and all other end-points (P < 0.001). CONCLUSIONS: These data clearly demonstrate that ranitidine 75 mg is effective in completely preventing or decreasing heartburn when administered 30 min prior to a provocative meal.

An evaluation of increasing doses of ranitidine for treatment of heartburn.

BACKGROUND: This was a randomized, double-blind, placebo-controlled, multicentre, parallel group, dose-ranging trial of ranitidine tablets for relief of episodic heartburn. Adult out-patients who reported heartburn relieved by antacids at least seven times per week were eligible. METHODS: Patients who successfully completed a 1-week single-blind placebo run-in phase and who did not achieve adequate relief in more than 50% of heartburn episodes were randomized to a 1-week, double-blind treatment phase during which they received ranitidine doses of 25, 75 or 125 mg, or placebo. RESULTS: Of 577 patients randomized, 566 had at least one evaluable heartburn episode and were included in the intention-to-treat analysis. All three ranitidine doses were statistically significantly superior to placebo in providing overall episodic heartburn relief for the first episode (P < 0.002), last episode (P

A concise total synthesis of (+/-)-bakkenolide A by means of an intramolecular Diels-Alder reaction.

(+/-)-Bakkenolide A was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide nd cis-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction as the key step. The known 7-epibakkenolide A and novel 10-epi- and 7,10-diepibakkenolide A stereoisomers were obtained as minor byproducts.

Population and economic growth: a cointegration analysis of lesser developed countries.

PIP: The authors examine the temporal relationship between population growth and economic growth in Nepal, India, Ghana, Sri Lanka, Bolivia, Philippines, Guatemala, Syria, Peru, Thailand, Chile, Argentina, and Mexico, conducting Granger-causality tests in the context of error correction models when cointegration is present. Their goal is to provide additional time series econometric evidence on the short-run and long-run time series behavior of population growth and the growth of real per capita gross domestic product for a sample of low to middle income developing countries. Cointegration was found in only 3 of the 13 countries examined. Even though 10 countries in this study exhibited no properties of cointegration, researchers conducting time series studies of the relationship between population growth and economic growth using differenced data should nonetheless evaluate the possible long-term relationship. Capturing the short- and long-run behaviors of the respective time series may give the researcher a more robust test of Granger-causality.^ieng

Independently predictive prognostic variables after resection for colorectal carcinoma.

BACKGROUND: Clinical variables such as surgical morbidity, comorbidity and follow-up have been claimed to influence ultimate survival in patients who have resection for colorectal cancer. It is unclear whether the effect of clinical covariates is confounding or independent. We have attempted to build a comprehensive model, which is capable of testing the dependence and importance of prognostic factors. METHODS: A consecutive series of patients admitted between 1970 and 1988 and followed until 1992 had data recorded about presentation, pathology, hospitalization, aftercare and long-term outcome. The patients were also divided into two approximately equal groups that were cared for by one and seven surgeons, respectively. Clinical and pathological covariates were built into a Cox (multivariate) proportional hazard model of crude survival. This was achieved with the SPSS advanced statistical package version 6.1. Comparison between groups was then performed of clinical and pathological factors and subsequent cancer management. RESULTS: There were 207 patients whose average age was 75 years, median survival was 43 months and operative mortality was 4%. The Cox model was robust. Covariates that had independent survival effects were pathological stage (P = 0.0000), grade (P = 0.014), age (P = 0.018), heart disease (P = 0.001), and group (P = 0.0008). Some of the dependent variables were symptoms, type of surgery, complications and length of stay. The groups, however, were well matched for age, stage, substage and comorbidity. Furthermore there were no substantial differences in mortality, complications or follow-up frequency. There was a significant survival difference (P = 0.0003) between groups, which was restricted to patients who were in clinicopathological stages B and C. Within stages B and C there was a significant (P = 0.008) survival difference between patients who were or were not treated for recurrent disease. Diagnosis of recurrence was pursued more aggressively (P < 0.01), and decisions to treat recurrent disease were made more frequently in group 1 (P = 0.0002). CONCLUSIONS: Pathology, comorbidity and management of recurrence all have a significant independent effect upon crude survival after colorectal carcinoma resection.

The influence of other diseases upon the outcome of colorectal cancer patients.

Little attention may be paid during follow up of colorectal cancer patients to other medical problems because the follow up is normally focused upon the diagnosis of recurrence and the detection of metachronous neoplasms. Attention directed at improving the medical condition of patients would be justified if it were shown that other diseases had a significant effect upon survival. Review of a selected consecutive series of 207 patients included collection of data about variables relating to demography, pathology, presentation, smoking, present and past health, performance, surgery, complications, length of stay, mortality, follow up and cause of death. Significance of relationships between medical and surgical problems and the outcome was determined by analyses of variation. Medical problems were present in 79% of patients; correlated with advancing age. Medical problems were not associated with complications, or with inpatient death. Previous cerebrovascular accident, dementia, limited mobility and increasing numbers of problems were associated with prolonged stay. Prolongation of stay, however, was related mainly to surgical complications. Smoking, which was present in 50% of patients, did not alter performance status, stage or substage, stay or survival significantly. Smoking and respiratory complications were associated significantly. Patients with heart or peripheral vascular disease had significantly poorer survival (P = 0.007) than those without those problems. Survival was reduced significantly for patients known to have diabetes, cardiovascular and cerebrovascular disease and limited mobility. Other malignant neoplasms were responsible for 18% of deaths which were unrelated to colorectal cancer. Residual or recurrent colorectal cancer had a more rapid adverse influence upon outcome than did medical problems.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of treatment of 686 gunshot wounds of the trunk at Los Angeles County-USC Medical Center: implications for the community.

The Los Angeles County-University of Southern California (LAC-USC) Medical Center, a level I trauma center, has experienced a rapidly increasing incidence of gunshot wounds (GSWs). We sought to enumerate the annual monetary costs and medical consequences of thoracoabdominal gunshot wounds in the epicenter of urban violence. A consecutive series of patients admitted from September 1, 1989 to August 31, 1990 was studied. Their records were coded by trauma nurse reviewers and held in the Trauma Emergency Medical Information System (TEMIS) and Automated Medical Record Abstracting and Reporting System (AMRARS). Diagnoses, procedures, and complications were verified by chart review. An estimate of disability 3 months after discharge was made from the record and reported on a functional activity scale. The total number of patients with GSWs admitted to all of the level I Los Angeles County trauma centers was 2771 during the study period. The total number of patients with major gunshot injuries admitted to LAC-USC Medical Center was 1007. Thoracoabdominal wounds without any head wound component occurred in 686 gunshot patients. Three quarters of the injured patients with truncal gunshot injuries were Hispanic. Total length of stay at the LAC-USC Medical Center for those with truncal wounds was 4666 hospital bed days including 432 ICU bed days, representing a minimum estimated total medical cost of $5,441,334. Annual medical cost of all admissions including rehabilitation, however, could be as great as $12 million for the Medical Center and $53 million for the County of Los Angeles. Thirty percent of patients had MediCal insurance. Payment could not be recovered from another 57% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Carnitine deficiency associated with long-term pivampicillin treatment: the effect of a replacement therapy regime.

A 51 year old female developed a skeletal muscle myopathy after 3 months of pivampicillin therapy. Pivampicillin can cause carnitine deficiency due to the pivalic acid side group. Plasma carnitine content and the patients symptoms failed to improve significantly on discontinuing the drug. Oral carnitine replacement therapy was administered for 6 weeks but the patient's plasma carnitine levels responded only slowly to this treatment. It is suggested that pivampicillin inhibits uptake of carnitine from the gut and may either directly or indirectly depress endogenous carnitine synthesis. In such cases a more aggressive carnitine replacement regime is indicated and pivampicillin should be avoided in patients requiring long-term antibiotic administration.

Six week safety study of 2% MK-927 administered twice daily to ocular hypertensive volunteers.

Ocular hypertensive patients were enrolled in a 6-week double-masked safety study of 2% MK-927 (27 patients), a topically active carbonic anhydrase inhibitor, administered bilaterally b.i.d.; 9 additional patients received 0.5% timolol as the control agent. Intraocular pressure (IOP) was measured weekly prior to a.m. drug administration; twelve hour diurnal curves were performed prestudy and at 3 and 6 weeks. The mean reduction of IOP prior to a.m. drug administration ranged from 1.2 +/- 4.4 mm Hg (SD) to 3.0 +/- 4.2 mm Hg with MK-927 and from 4.7 +/- 3.9 mm Hg to 8.8 +/- 0.6 mm Hg with timolol. Mean outflow facility measured tonographically prestudy and on days 33 to 42 four hours after a.m. drug administration was unchanged in both groups. Corneal sensitivity (Cochet-Bonnet), corneal thickness (ultrasound pachymetry), Schirmer tear testing, and extensive ophthalmologic and medical examinations, and hematologic studies were not substantially altered throughout the study. In this longest chronic administration study to date, MK-927 did not cause adverse ocular or systemic side effects.

Effects of Furegrelate (Upjohn 63557A) on patency and platelet deposition after canine carotid endarterectomy.

Platelet deposition upon endarterectomy sites is a likely cause for early postoperative thrombosis, embolism and restenosis. Platelets aggregate by the thromboxane-prostacycline mechanism. Thromboxane synthetase inhibitors which have been safely administered to humans should reduce platelet deposition after surgical therapy and therefore reduce peri-operative mortality and the prevalence of stroke. A randomized prospective controlled trial was designed to determine vessel patency and platelet deposition associated with the use of 3 mg/kg and 30 mg/kg of Furegrelate (Upjohn U63557A) daily in dogs, who were to have carotid endarterectomy. The 46 treated and 46 control dogs had total carotid patency of 96% and 76% respectively (P less than 0.01). Fourteen dogs treated with 30 mg/kg Furegrelate had no occlusions, compared with a 19% prevalence in 13 controls (P less than 0.02). Furegrelate 10 mg/kg significantly lowered platelet aggregation. Platelet deposition was not significantly changed, however. The reason for this disparity was a probable persistence of vessel wall factors which promoted platelet deposition. This approach might therefore lower rates of peri-operative thrombosis but it would be very unlikely to alter the incidence of restenosis or embolism. Further research could be directed towards modifying the stimuli for platelet deposition upon the endarterectomy site.

Colorectal carcinogenesis.

It is generally accepted that genetic and environmental factors combine in the aetiology of bowel cancer. Epidemiological studies have shown that the environmental factors effects are shown more clearly in the left colon, and that they are related to living in western societies whose diets contain high levels of protein, fat and energy. There has been recent awareness that consumption of alcoholic beverages, particularly beer, may be causally related to cancers of the left colon and rectum. This review attempts to relate the general epidemiological data to more specific mechanisms of colorectal carcinogenesis. Dimethylhydrazine (DMH) and N-nitroso chemicals are potent colorectal carcinogens in animals. They have not been thought very relevant to humans because their existence in appropriate forms in the environment has been debatable and analytical methods for the specific detection of non-volatile nitrosamines and nitrosamides have not been available. Recently, however, relevant alkylating activity has been detected in foods incubated in quasi-gastric conditions, and several epidemiological studies have shown a protective effect for Vitamin C, which may inhibit the development of rectal cancer through beer consumption. As Vitamin C prevents nitrosation and as precursors of nitrosamides are present in prepared foods, further dietary studies with hypotheses based on N-nitroso carcinogenesis are required. Unfortunately, these studies will probably not show clear dose-response relationships. Many of the complex reasons for this are discussed; however, one of the most important could be related to an interplay between inherited and environmental factors. The inherited factors demonstrated by chromosomal analysis in cancer and polyposis syndromes are a reminder that other genetic (oncogenetic) changes may occur in sporadic colorectal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in amputation stump infection by antiseptic pre-operative preparation.

The prevalence of ischaemic or infective delayed wound healing in amputations for peripheral vascular disease may vary from 18 to 40%. A prospective trial to test the efficacy of 12 h pre-operative preparation with 10% povidone-iodine was performed in a 1-year period, during which time 80 consecutive amputations were performed on 73 patients. Accrual to the treatment arm was incomplete and was principally due to extreme nursing shortages. Failure of randomization resulted in the study being analysed as if it were retrospective. Infection occurred in 14 (23%) of unprepared limbs but was not found in any of the 19 prepared limbs (P less than 0.05). Infection occurred in 11 of 34 unprepared limbs which had distal ulcers or moist gangrenous lesions; however, 15 prepared limbs which had similar distal lesions had no infection (P less than 0.025). The reduction of wound breakdown and infection resulted in a significant reduction in hospitalization prior to commencement of prosthetic fitting (P less than 0.001). Pre-operative antiseptic preparation played an important role in the reduction of infection following amputation for peripheral vascular disease, particularly for those patients whose amputation was required because of contaminated peripheral ischaemic lesions. However, these preliminary results should be confirmed by further study.

International colorectal carcinoma staging and grading.

Pathologic (Dukes) and clinicopathologic staging systems (Australian and TNM) are all used for the staging of colorectal cancer. Many modifications of the systems, with different standards of evidence, are currently used for a variety of purposes. It is not yet possible to readily exchange data from one staging system to another because of the lack of uniform anatomic and pathologic subdivisions. It would also be an advantage if staging systems more confidently predicted potential for cure. It is proposed that the TNM based system be modified to satisfy these requirements. Modifications identify common ground between the various systems, use prognostic variables shown to be significant by multivariate analyses, and introduce an abbreviated form of tumor grading. Grading improves prediction of cure and allows standardization of the composition of stages and substages because distant metastatic potential is shown to be related to the presence of high grade. The modifications are considered necessary and appropriate for epidemiologic and clinical studies.

The cost of resection for colorectal cancer.

The aim of this study was to determine the average total cost and component costs of the surgical management of colorectal cancer (CRC) in a large teaching hospital and to examine the relationships between cost and several characteristics of the patients. Data were compiled for 97 consecutive patients undergoing resection for CRC at Concord Hospital in 1979. The cost of the following components was calculated for each patient: (a) pre- and postoperative bed occupancy; (b) investigations; (c) operation; (d) anaesthetic; (e) prescribed drugs; (f) allied health services. The cost of bed occupancy was by far the largest item in the average total cost (72%), followed by the cost of investigations (11%). There was no correlation between pre- and postoperative bed occupancy and no patient characteristic had a statistically significant effect on pre-operative stay. Several factors were associated with prolonged postoperative stay including the number of clinical problems, operation for rectal as opposed to colonic cancer, having a two-stage procedure, surgical complications and wound infection. By far the greatest reduction in total cost could be achieved by reducing the length of postoperative stay.

Gland to gland heterogeneity in histologically normal mucosa of colon cancer patients demonstrated by monoclonal antibodies to tissue-specific antigens.

Two of three monoclonal antibodies to tissue-specific antigens of isolated colonic glands revealed gland to gland heterogeneity of antigen expression in sections of the histologically normal colonic mucosa from patients with colorectal adenocarcinoma or various nonmalignant conditions. A colon-specific goblet cell antigen (designated 3NM) was absent from rare, solitary glands randomly distributed among the otherwise strongly stained glands of distal colon. These 3NM-negative glands stained normally for the other two antigens studied and appeared morphologically and histochemically normal. They occurred in 11 of 13 cancer patients and in each of the five patients with benign conditions with median incidences of 2.2 and 0.4 per 1000 glands, respectively. Gland heterogeneity was also demonstrated in both patient groups for a cell membrane antigen (designated 6NM). In cecum and ascending colon, glands staining strongly and weakly for 6NM were found intermixed. The weakly stained glands tended to predominate in cecum and first part of ascending colon, but they were completely replaced by strongly stained glands in more distal colon. The heterogeneity shown by both 3NM and 6NM appeared due to phenotypically distinct cell clones. Our observations indicate that histologically normal colonic mucosa contains antigenically diverse gland populations.