Benjamin Gerson

Development of metabolic alkalosis after massive transfusion during orthotopic liver transplantation.

Five patients undergoing orthotopic liver transplantation were investigated for changes in acid-base homeostasis secondary to large volume transfusions. All patients developed a transient acidemia during the operative period, followed by alkalemia which persisted into the early postoperative period. The patients received an estimated mean of 750 mEq of citrate, which appeared to cause metabolic alkalosis. The biochemical basis underlying the regulation of citrate metabolism that may have led to the timing, extent, and duration of the subsequent metabolic alkalosis is presented. Finally, the time course for the development of metabolic alkalosis may be a potentially sensitive indicator of early allograft function.

Rapid antidepressant response to alprazolam in depressed patients with high catecholamine output and heterologous desensitization of platelet adenylate cyclase.

The present study examined the relationship between 24-hr urinary catecholamine (norepinephrine and epinephrine) output and measures of platelet adenylate cyclase (AC) activity in depressed patients (n = 17) and control subjects (n = 10). In both groups, significant inverse correlations were observed when 24-hr urinary catecholamine levels were examined in relation to measures of both receptor-mediated (prostaglandin D2 and alpha 2-adrenergic) and postreceptor-mediated (NaF) platelet AC enzyme activities, suggesting that circulating catecholamines may regulate platelet AC by heterologous (agonist-nonspecific) desensitization of the AC enzyme complex. Depressed patients who had favorable antidepressant responses to alprazolam had significantly higher pretreatment urinary catecholamine output and lower receptor-mediated platelet AC enzyme activities than control subjects, whereas the nonresponders did not. After 8 days of treatment with alprazolam, urinary catecholamine levels declined significantly. In responders, receptor-mediated measures of platelet AC activity increased significantly by day 8 to values comparable to those in control subjects; but similar changes were not observed in nonresponders. Prior to treatment, responders showed a strict linear relationship between receptor-mediated (prostaglandin D2) and postreceptor-mediated (NaF) stimulation of platelet AC activity through the stimulatory guanine nucleotide regulatory protein (Ns), whereas nonresponders did not. This suggests the presence of two distinct coupling interactions between platelet prostaglandin D2 receptors and the stimulatory guanine nucleotide regulatory protein in responders and nonresponders to the antidepressant effects of alprazolam prior to treatment. The authors propose that catecholamines, possibly acting through prostaglandins, may regulate platelet AC enzyme activity by heterologous desensitization occurring through postreceptor mechanisms.

The Biological Activity in Vivo of Recombinant Murine Interleukin 1 in the Rat

Abstract The present study summarizes the biological response of rats to infusion with recombinant murine IL-1 (rIL-1) cloned in Escherichia coli. Thirty-seven male rats (135-180 g) were infused over a 6-hr period with either 0.008 M guanidine hydrochloride (the vehicle) or E. coli product (both groups are controls) or 1000, 3750, 7500, 15,000, or 37,500 LAF units/hr of rlL-1. The controls and the group receiving 1000 LAF units/hr of rIL-1 did not exhibit a change in body temperature during the experiment. A mild fever was noted with 3750 LAF units/hr which became significantly elevated with 7500 and 15,000 LAF units/hr. At a dose of 37,500 LAF units/ hr of rIL-1 (in 0.08 M guanidine hydrochloride) the rats became hypothermic and died. An equivalent dose of guanidine hydrochloride alone (0.08 M) was not fatally toxic although the rats did become hypothermic. Plasma zinc levels were significantly depressed and white blood cell count elevated at 6 hr postinfusion onset. Resting energy expenditure (REE) was significantly depressed during an infusion of 7500 and 15,000 LAF units/hr of rIL-1 despite a concurrent elevation in body temperature. Whole-body leucine kinetics were unchanged by infusion with rIL-1. Plasma fibrinogen and serum haptoglobin and copper levels were not altered by rIL-1. In conclusion, murine rIL-1 is similar to monocytic-derived IL-1 in that it produces a fever, hypozincemia, and leukocytosis; however, rIL-1 does not induce changes in protein metabolism.

Urinary 3-Methoxy-4-hydroxyphenylglycol and the: Depression-Type Score as Predictors of Differential

Pretreatment 24 hr urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the Depression-type (D-type) scores (derived from a multivariate discriminant function equation based on levels of urinary catecholamines and metabolites) were examined as possible predictors of antidepressant responses to either imipramine or alprazolam. In the case of imipramine, the responders had significantly lower pretreatment urinary MHPG levels (p = 0.002) and D-type scores (p less than 0.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p less than 0.05) and D-type scores (p = 0.02) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. For each drug, the effect size for the difference in mean log-transformed D-type scores between responders and nonresponders was greater than the effect size for the difference in mean log-transformed MHPG levels. The difference between the effect sizes was statistically significant for imipramine (p = 0.02) and tended toward significance for alprazolam using two-tailed tests. These results suggest that the D-type equation, which was initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, can also be used to predict differential responses to certain antidepressant drugs in patients with unipolar depressions.

Trazodone: A simple, clean extraction and rapid quantification by high pressure liquid chromatography

We have developed an HPLC technique which is precise, rapid and reliable. Sample preparation involves simple alkaline extraction into an organic solvent mixture. Trazodone elutes at 3.2 min in this reverse phase system. There is no requirement for elevated column temperature. The method is linear to 3000 ng/ml. The availability of a technique which is transferrable to the clinical laboratory may help to define the proper role of therapeutic monitoring of trazodone.

Quality Control in Therapeutic Drug Monitoring: Intralaboratory Precision and Medical Requirements

Summary Formal quality control procedures have become a part of the clinical laboratory. Application of these procedures to therapeutic drug monitoring, which has been introduced into the clinical laboratory relatively recently, is incomplete. Most attention has been directed toward questions of accuracy and laboratory-to-laboratory precision, particularly with respect to antiepileptic agents. Intralaboratory precision must be addressed first, since it is fundamental to accuracy and laboratory-to-laboratory variability and most patients are treated based on results generated by a single laboratory. Intralaboratory precision data were gathered from laboratories already offering therapeutic drug monitoring services. In addition, the intralaboratory precision demands of good medical management was gathered from physicians who use therapeutic drug monitoring services. For 20 specified drugs, most laboratories reported intralaboratory precision (relative standard deviations) of 10% or less. Managing physician responses demonstrated that most require precision of 10 to 15% or 20 to 25%. Individual laboratories should use these data as an indication of the level of intralaboratory precision that may be achieved and that is required. The state of the art of intralaboratory precision is acceptable relative to medical management, but may need improvement as it contributes to laboratory-to-laboratory variability.

The dexamethasone suppression test (DST) and platelet monoamine oxidase (MAO) activity as predictors of psychosis in depression

The Dexamethasone Suppression Test (DST) has been used extensively to identify patients with endogenous and/or melancholic depressions. Moreover, patients with psychotic forms of endogenous depression have been found to be more likely to have abnormal DSTs than are patients with nonpsychotic forms of these depressions (Carroll et al. 1980; Coryell et al. 1982; Rudorfer et al. 1982; Caroff et al. 1983; Evans et al. 1983; Schatzberg et al. 1983a). Focusing on the specific values of 4:00 PM postdexamethasone serum cortisol levels, rather than simply on the qualitative distinction between suppression and nonsuppression, Schatzberg et al. (1983a) showed that depressed subjects with very high cortisol levels tend to be psychotic. For example, in patients with major depression, they found psychosis in over 70% (7/9) of the patients with postdexamethasone cortisol levels over 15 kg/dl, but in less than 20% (7/36) of the patients with postdexamethasone cortisol levels less than 15 p,g/dl. Platelet monoamine oxidase (MAO) activity has also been widely studied in affective illness. Findings by Meltzer et al. (1980) and by Schildkraut et al. (1977) suggest that high platelet MAO activity might be associated with psychotic depression. particularly in female patients. Furthermore, Schatzberg et al. (1983b) found a significant association between high platelet MAO activity (37.0 nmol tryptamine deaminatedlhrimg protein) and DST nonsuppression in depressed patients. Given the apparent relationship between DST nonsuppression and psychosis in depressed patients. these findings of Schatzberg ct al. would be compatible with an association between high platelet MAO activity and psychotic depression. In the following case report. the authors suggest that the combination ot‘ an extremely

Quantitation of Tobramycin by Solid-Phase Immunofluorescence

Tobramycin usage, as for most aminoglycoside antibiotic usage, may require careful monitoring to avoid irreversible toxicity. Several methods for tobramycin quantitation are available. The purpose of this study was to evaluate the performance of solid-phase immunofluorescence as an alternative. Tobramycin was quantitated in the sera of 81 patients by radioimmunoassay and solid-phase immunofluorescence. No statistically significant or medically important difference was demonstrated (bias, 0.006 μ/ml, t =0.09, s =1.02, r = 0.97). Within-run and run-to-run precision for the two methods were comparable. Interference by gentamicin could not be demonstrated. Solid-phase immunofluorescence may be an acceptable alternative method for tobramycin quantitation in some laboratories.

Therapeutic monitoring of tricyclic antidepressants: quality-control considerations.

Summary While the correlation between plasma levels of some tricyclic antidepressants and therapeutic efficacy is well documented and the value of tricyclic antidepressant plasma level measurements is reasonably well established, the sources of error in the collection and analysis of specimens are not generally known and understood. An outline of the factors affecting the interpretation and utilization of plasma level measurements and the procedures needed to insure the accuracy and precision of tricyclic antidepressant plasma level determinations is presented. Problems facing the clinical laboratory attempting to set up a quality-control program for its tricyclic antidepressant analyses are also discussed.