Solid-state stability testing of drugs by isothermal calorimetry.

A new technique has been developed to calculate rapidly the solid-state room-temperature degradation rate of drugs and drug candidates. The technique utilizes measurements of the initial rate of heat output at several elevated temperatures by isothermal calorimetry and the degradation rate of the compound determined at a single elevated temperature by chromatography. The activation energies and degradation rates at 25 degrees C calculated by conventional methods and by isothermal calorimetry are compared and discussed. The compounds studied were phenytoin, triamterene, digoxin, tetracycline, theophylline, diltiazem, and several proprietary ICI compounds.

Age-specific incidence of cancer in Kingston and St. Andrew, Jamaica. part 1: 1978-1982

A total of 3,396 malignant neoplasms were recorded in Kingston and St. Andrew, Jamaica during 1978 to 1982. There were 1,477 males and 1,919 females. Histological confirmation was achieved in 88.4%. The crude incidence rate for males for all age group was 107.8 per 100,000 per year, in females, the figure was 123.0. The age-standardized rates (world population) were 157.9 for females. Age-specific rates by site, sex, and age are tabulated.

The role of arterial reconstruction in penetrating carotid injuries.

The outcome of 80 patients with 85 penetrating injuries to the extracranial carotid artery (CA) were analyzed after three types of treatment: (1) 54 patients, 17 with a neurologic deficit, who underwent arterial reconstruction; (2) 18 patients, eight with a neurologic deficit, who had CA ligation or non-operative management of a CA occlusion; and (3) eight patients, two with a deficit, who had minimal nonocclusive injuries managed nonoperatively. Outcome was analyzed using a Carotid Neurologic Score (CNS). The CNS is a quantitative measure of neurologic outcome and survival and ranges from -1 to +3. The higher the CNS, the more favorable the outcome. The conditions of nine patients in group 1 neurologically improved after treatment, 41 were the same, and four were worse. Forty-four patients were neurologically intact and three died. The mean (+/- SD) CNS was 1.9 +/- 0.8. In group 2, one patient's condition improved, 13 stayed the same, and four deteriorated. Ten patients were intact and two died. The mean CNS was 1.3 +/- 1.13. In group 3, two patients' conditions improved and six stayed the same. All eight patients were intact; there were no deaths. The mean CNS was 2.3 +/- 0.35. There was a significantly higher CNS for groups 1 and 3 compared with group 2. The CNSs of groups 1 and 3 were not significantly different. Arterial reconstruction provides the best outcome for all penetrating CA injuries except nonocclusive limited intimal injuries that require only observation.

Computerized edge tracking and lesion measurement in coronary angiograms. A pilot study comparing smokers with non-smokers.

Comparison of coronary atherosclerosis change in a pilot angiographic study of retrospectively matched smokers and controls indicates more rapid progression in smokers. The findings indicate the feasibility of small-scale angiographic trials of treatment designed to ameliorate arterial damage in atherosclerotic smokers who cannot quit.

Clinical data versus noninvasive testing as an estimate of coronary status.

The step from coronary angiography to surgery is taken primarily on the basis of the ejection fraction (EF) and number of diseased vessels (NV), taken jointly as coronary status (CS). This study reviewed (1) how well EF, NV and CS are estimated from clinical data, (2) how much improvement is gained by adding noninvasive data, (3) how good this model is when applied to a larger cohort and (4) whether the decision to angiography can be made on the basis of CS estimated from clinical data alone. A quantitative definition of CS was established as a principal component of EF and NV. Estimates of EF, NV and CS were made from clinical data of 60 patients. Correlations with the actual values were EF 87%, NV 93% and CS 93%. When noninvasive data were added to this model, the correlations increased to EF 95%, NV 99% and CS 98%. When the clinical data model was applied to 169 patients, the correlations decreased to EF 77%, NV 71% and CS 74%. CS estimated from clinical data alone was set up as a test for angiography for 169 patients. This test had a sensitivity of 98% and a specificity of 63%, demonstrating the feasibility of using clinical data alone in deciding angiography.

Diagnostic performance of enzymes in the discrimination of myocardial infarction.

We apply rigorous statistical methods to assess the diagnostic value of creatine kinase, creatine kinase-MB, aspartate aminotransferase, lactate dehydrogenase, and alpha-hydroxybutyrate dehydrogenase in realistic circumstances. The trade-off between false positives and false negatives obtained with various decision rules is examined with the receiver-operator characteristic function and with discriminant analysis. During the three days after an infarction, lactate and alpha-hydroxybutyrate dehydrogenase can provide diagnostic thresholds of constant sensitivity and specificity. By contrast, sensitivity progressively decays for creatine kinase, creatine kinase-MB, and aspartate aminotransferase. The diagnostic uncertainty introduced by the infarction's varying age at hospitalization is evaluated by subjecting the mixed patient population to discriminant analysis. For some enzymes, repeating the same assay on the second day contributes to sensitivity, while adding a different assay on the first day enhances specificity. The effects of lower or higher infarction prevalences on sensitivity and specificity are most favorable when creatine kinase-MB is combined with lactate or alpha-hydroxybutyrate dehydrogenase. Adding a third assay is ineffective. The further differentiation according to infarction stage produces only 81% correct classifications, even when five different assays are used on two consecutive days. As a general strategy, we recommend the assay of two enzymes on two consecutive days.

Additive, multiplicative, and mixed analytical errors.

Depending on the change in magnitude of analytical error occuring with change in concentration of analyte, two limiting types of error properties can be defined: additive and multiplicative. We investigated whether one of these two error types also characterizes the overall error of methods involving multiple procedural steps, or whether mixed error properties result in these cases. Using "open" quality-control data (i.e., and analyst identifies controls) from each of two hospitals and "blind" quality-control data from one hospital for 11 different assays, we found: (a) With current methodology, overall errors typically are mixed, though predominantly additive and multiplicative overall errors exist as well. (b) "Blinding" the quality-control system typically augments the multiplicative but not the additive error component.

Reproducibility of a consensus panel in the interpretation of coronary angiograms.

This report describes the consistency of coronary angiogram evaluation by a four man panel of experts rendering "consensus opinion." The panel evaluated films from 38 patients at two grading sessions separated by an interval of seven months. Fourteen patients' films were selected at random for duplicate evaluation. These contained 186 lesion sites. The panel was 95% consistent in designating significant stenosis (greater than or equal to 70%). "Consensus" panel reading appears more consistent than "group opinion" panel reading. The over-all standard deviation of the difference in panel reading was 14%. The panel was most consistent in evaluating the right coronary artery, proximal LAD, and proximal circumflex. In the left main segment two of fourteen duplicate evaluations showed major discrepancy.

The rate of atherosclerosis change during treatment of hyperlipoproteinemia.

The rate of change of femoral atherosclerosis has been determined in 25 treated hyperlipoproteinemic patients. There were 13 Type II patients and 12 Type IV patients. Serial angiograms had been performed at an interval averaging 13 months. Film densities were analyzed by digigal image processing to yield a computer estimate of atherosclerosis (CEA). Serial measurements of CEA on each patient were used to determine atherosclerosis percent change per month in that patient. CEA percent change per month was significantly correlated ;ith triglyceride and cholesterol level. Lower lipid levels were associated with more rapid regression. When hyperlipoproteinemic types were considered separately, significant single correlates were confined to Type IV. Triglyceride level and CEA/age significantly predicted atherosclerosis change rate and accounted for 72% of the variability observed in Type IV patients.

Measurement of atherosclerotic luminal irregularity and obstruction by radiographic densitometry.

This report describes a procedure to quantify stenosis and to detect enface plaques in single plane angiograms. We derived an optical density function proportional to local arterial chord length from arteriographs over a wide range of conditions. Standard radiographs were made of silicone rubber bolus used as the radiopaque medium in cadaver arteries. Replicate arterial casts filled with iodine-bearing contrast medium were radiographed for comparison. Identical atherosclerotic areas in both film sets were scanned with a microdensitometer and vessel chord lengths used to construct arterial cross sections for comparison with vessel casts. Cross-sectional areas derived from cadaver and phantom films were highly correlated with those derived from cast slices (r = 0.997). Thus, luminal cross-sectional areas were accurately estimated independent of plaque location, and accuracy of chord length measurement was +/- 0.28 mm in vessels four to 10 mm in diameter.

Computer densitometry for angiographic assessment of arterial cholesterol content and gross pathology in human atherosclerosis.

Sequential change studies in human atherosclerosis are desirable in disease regression trials but are now limited by dependence on the occurrence of epidemiologic end-points. Prior radiographic studies have pertained to advanced obstructive atherosclerosis. This is a study of measures applied by computer-generated densitometry of angiograms to assess early to advanced nonobstructive atherosclerosis. Measures are based on pathologic and angiographic appearance of all stages of atherosclerosis and include image edge roughness, local width, and local contrast density changes. Femoral angiograms were made in 21 cadavers under simulated clinical conditions, with a pressurized radiopaque casting material. Full-size color photographs were made of 10 cm. segments of opened artery, with matching cast and arterial specimens analyzed for cholesterol content. Four graders, on two occasions, sequenced the photographs in increasing order of disease on the basis of the International Atherosclerosis Grading scheme. The correlation between the two sessions was 0.93. Thirteen computer indices correlated significantly with visual grade and cholesterol and were allowed to compete in a step-wise regression for best indices of prediction. Computer index correlation coefficient for visual grade prediction was 0.86, and for cholesterol content, 0.84. Computer densitometry measurement appears useful in the evaluation of all stages of atherosclerosis as recorded angiographically and obviates the necessity for exacting visual comparisons of large numbers of films.

Regression and progression of early femoral atherosclerosis in treated hyperlipoproteinemic patients.

Femoral angiograms were done to evaluate change in early atherosclerosis in 12 patients with type IV hyperlipoproteinemia and 13 with type II hyperlipoproteinemia. The patients' average age was 48 years; only one had claudication. Elevated blood lipids and blood pressure were treated with drugs and diet. Repeat angiograms after an interval of 13 months showed regression of atherosclerosis in nine patients, no change in three, and progression in 13. Comparison of preangiogram levels with average levels between angiograms showed significant reduction in serum cholesterol, triglyceride, and blood pressure in the group with lesion improvement but not in the group with lesion progression. Sporadic examples of human atherosclerosis regression are known, but most other studies in man indicate only atherosclerosis progression. Our different result appears due to our selection of patients and radiographic method. We have studied patients with earlier atherosclerosis than previous workers, using a radiographic procedure more sensitive to small changes in lesions.