An overview of the safety pharmacology career of Dr. C.R. Hassler.

Each year the Safety Pharmacology Society (SPS) recognizes an investigator who has had a marked impact upon the discipline. The 2016 recipient of the SPS Distinguished Service Award (DSA) was Dr. Craig R. Hassler. Dr. Hassler is one of the founding members of the SPS and has been actively engaged in physiological research for over 46years. Dr. Hassler delivered a talk entitled "My 43Years at Battelle Memorial Institute" to meeting attendees. In this article an overview is provided of the illustrious career of Dr. Hassler along with an account of the numerous animal models that were developed at Battelle under his guidance over the years.

Prediction of carrier status in Duchenne dystrophy by creatine kinase measurement.

Serum creatine kinase (CK) was measured in 515 healthy white women and 28 obligate carriers for Duchenne muscular dystrophy. There was substantial overlap between the control and carrier populations. To analyze the impact of the degree of overlap, the predictive value of a CK result was determined by (1) using sensitivity and specificity analysis, which assumes dichotomization into a positive or negative result based on a particular cut-off value; and (2) using likelihood ratio analysis, which evaluates an individual result based on the continuum observed for control and carrier populations. There was no clinically important difference whether an observed 57% or a hypothetical 33% overlap between control and carrier results was used. Because of the substantial overlap, the CK test utility is limited to those suspected carriers whose results fall above the healthy population interval. A low CK result does not provide sufficient assurance of noncarrier status.

Are reference limits for serum creatine kinase valid in detection of the carrier state for Duchenne muscular dystrophy?

We evaluated serum creatine kinase (CK) as an index to heterozygosity in Duchenne muscular dystrophy. When the 97.5th percentile of the CK normal reference interval was selected as the cutoff point, only 31% of 28 obligate carrier mothers and 24% of 43 mothers of simplex cases (those with only one occurrence of dystrophy in the kindred) exceeded this cutoff value. The outcome depended to some degree on the method used for establishing the reference limit for 379 presumably non-carrier, ambulatory women. The considerable overlap of CK activities between the control and carrier population as well as the non-gaussian distribution of the data permitted no satisfactory approach for differentiating these two populations. Neither the application of likelihood ratios, which evaluates a continuum of results without the dichotomy of a cutoff point, nor the application of predictive value based on sensitivity and specificity, which involves use of a cutoff value for decision making, provided a reliable estimate of carrier status. There was no significant difference (2 alpha = .19) between the median CK activity of obligate carrier mothers and mothers of simplex cases. The serum CK test does not provide data that either support or reject the Haldane hypothesis.

An orally administered microcapsule system for treating chronic renal failure patients.

Ingestible adsorbents for the removal of uremic metabolites are being investigated as adjunctive therapy in the treatment of chronic uremia. In particular, a microcapsule product containing urease and zirconium phosphate (UZP) has been investigated for removing urea. A dog model, simulating chronic uremia, was developed to investigate: (1) the concentration of various nitrogenous metabolites (urea, creatinine, and uric acid) in the GI tract, (2) flux rates of H2O and various nitrogenous metabolites in the GI tract, and (3) the efficacy of the microcapsule product. The results of these perfusion studies suggest that urea and creatinine can be removed from the GI tract via ingestible adsorbents. In addition, the model may be useful in investigating suspect uremic toxins, e.g., guanidinosuccinic acid (GSA). The reduction of blood urea nitrogen levels in the dog model when the animal was fed the microcapsule product was limited by the capacity of the zirconium phosphate to bind ammonium ion. Preliminary clinical studies with the microcapsule product indicate that it may be of potential adjunctive therapy in patients suffering from chronic renal failure.

Experimental automobile-pedestrian injuries.

Fifteen fresh cadaver impacts were conducted in simulation of pedestrian-automobile accidents. The test sled configuration simulated an automobile bumper and hood in "standard" and "nosedive" situations as well as "hard" and "soft" impact surfaces. Instrumentation and film demonstrated large axial compression forces in the struck leg and considerable angular velocity of the torso in all modes. Dissection revealed primary injury at the impact site at low velocities with added remote injury at high velocities. Fracture of the lateral tibial plateau was most common. Lowering the bumper height offered the greatest protection against injury at moderate impact velocities.