The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group.

PURPOSE: To determine whether angiotensin-converting enzyme (ACE) inhibition with captopril reduces the progression of microalbuminuria to overt proteinuria in normotensive patients with insulin-dependent diabetes mellitus (IDDM). PATIENTS AND METHODS: This study was a prospective randomized, double-blind, placebo-controlled trial involving 26 centers in the United States and Canada. One hundred forty-three subjects, 14 to 57 years of age, with IDDM for 4 to 33 years, blood pressure < 140/90 mm Hg in the absence of antihypertensive therapy, and persistent albumin excretion 20 to 200 micrograms/min were randomized to double-blind treatment with captopril 50 mg or placebo BID. Albumin excretion rate (AER), blood pressure, and glycohemoglobin were determined every 3 months, and creatinine clearance (CrCl) and urea excretion were measured every 6 months. RESULTS: Within 24 months, 6.0% (4/67) of captopril-treated subjects and 18.6% (13/70) of placebo-treated subjects progressed to clinical proteinuria, defined as AER > 200 micrograms/min and at least 30% above baseline (risk reduction = 67.8%, P = 0.037). AER increased at an annual rate of 11.8% (95% confidence interval [CI] -3.3% to 29.1%) in the placebo group, while it declined by 17.9% (CI -29.6% to -4.3%) in the captopril group (P = 0.004). CrCl decreased by 4.9 mL/min per 1.73 m2 per year in the placebo group, while it remained stable in the captopril group (0.9 mL/min per 1.73 m2 per year, P = 0.039 between groups). Ten subjects required treatment for hypertension; 8 in the placebo group and 2 in the captopril group. There was little correlation between the 24-month changes in mean arterial blood pressure and AER in either group. Glycohemoglobin and urinary urea excretion did not differ between groups. CONCLUSIONS: After 24 months of therapy with captopril, compared with placebo, normotensive subjects with IDDM experienced significantly less progression of microalbuminuria to clinical proteinuria, reduced albumin excretion, and preserved CrCl rate. The ACE inhibitor, captopril, was well tolerated.

Nonsteroidal anti-inflammatory drugs: an analysis of the relationship between laboratory animal and clinical doses, including species scaling.

The pharmacologic activity of nonsteroidal anti-inflammatory drugs (NSAID) has generally been studied in multiple tests. We examined four commonly used tests [i.e., the carrageenan edema test (CARR), the ultraviolet light-induced erythema test (UVE), the phenyl benzoquinone stretching test (PBQ), and the acetic acid stretching test (RWTH)] to determine by statistical criteria which was the best predictor of human clinical dose. We found that CARR greater than UVE greater than PBQ greater than RWTH. The CARR test, but not UVE or PBQ, showed dose proportionality between laboratory test dose and clinical dose. The RWTH test appeared to show proportionality, but the sample size was quite small. With proportionality, the scaling factor between test dose and human dose could be examined. Dose was found to scale as surface area for CARR. This relationship could not be generalized and thus each pharmacologic test must be examined individually for scaling behavior between the test and human doses.

Cluster significance analysis contrasted with three other quantitative structure-activity relationship methods.

Cluster significance analysis (CSA), a new statistical method to analyze structure-activity relationships in graphically displayed data, is contrasted with linear discriminant analysis, SIMCA, and the method of "relative odds". The data sets evaluated are as follows: antibacterial lasalocid derivatives, antimalarial naphthoquinones, and carcinogenic polycyclic aromatic hydrocarbons. CSA gives results comparable to these other methods, involves fewer assumptions, can be more reliable, and in general is easier to understand.

On the significance of clusters in the graphical display of structure-activity data.

A method is presented to evaluate the statistical significance of an apparently clustered group in the graphical display of structure-activity data. Two variations are described; each is implemented by means of a computer program. The first is applicable in situations with relatively small sets of compounds where a complete enumeration of all possible clusters can be accomplished reasonably on a high-speed electronic computer. The second is applicable in cases where such a calculation would be too time consuming. This latter variation uses random sampling of the set of all possible clusters. An application for each variation is given: for the smaller case a reevaluation of a study on aminotetralin and aminoindan monoamine oxidase inhibitors; for the larger case the discovery of some physical parameters that influence mutagenicity among some aminoacridine derivatives. It is proposed that this new technique be called cluster significance analysis (CSA).

Assays of sulbactam in the presence of ampicillin.

Three assays for sulbactam, a beta-lactamase inhibitor, in serum in the presence of ampicillin were compared. A synergistic bioassay, a gas chromatographic assay with detection by mass spectrometry, and a high performance liquid chromatography assay were similar with respect to both accuracy and precision.

A simple method based on broken-line interpolation for displaying data from long-term clinical trials.

In displaying data from long-term clinical studies, variation across patients in the times at which readings are recorded often presents a problem. A simple method for treating such data is proposed, which avoids arbitrary conventions and methodological difficulties inherent in other approaches. It is based on within-patient broken-line interpolation, and is easy to implement on a computer. The method is tested and compared to others with computer-simulated data whose time-pattern is known. Though the comparison is of limited scope, the method appears to compare favourably with the 'closest-reading' and 'window' approaches.

A comparison of the carrageenan edema test and ultraviolet light-induced erythema test as predictors of the clinical dose in rheumatoid arthritis.

Twelve non-steroidal anti-inflammatory agents (NSAI's) and one steroidal anti-inflammatory agent, dexamethasone, were examined in the carrageenan edema test (CET) in the rat and in the ultraviolet light-induced erythema test (UVE) in the guinea pig to evaluate the correlation between those models of inflammation and the clinical dose of the NSAI's in the treatment of rheumatoid arthritis. The regression of the logarithm of the clinical dose with the logarithm of the ED50 for UVE gave a slope of 0.54 implying a non-parallelism of assays and a difference in mechanism. Dexamethasone failed to inhibit the UVE thereby corroborating this point. The parallelism of the logarithm of the clinical dose with the logarithm of the ED50 for the CET was substantially better (slope = 0.86). Dexamethasone was active in CET and its dose would be predicted by the CET regression. When only one variable was used for a prediction, log(CET) was a better predictor of log (clinical dose) than log(UVE). Standard methods for best regression selection indicated that even when both predictor variables were considered, log(CET) alone gave the best regression equation for predicting clinical dose. The view that inhibition of prostaglandin biosynthesis is the primary anti-inflammatory mechanism of NSAI's in rheumatoid arthritis is discussed in terms of these findings.