Joyce J. Kaufman

Narcotic and narcotic antagonist pKa's and partition coefficients and their significance in clinical practice.

The pKas, partition coefficients and drug distribution coefficients (apparent partition coefficients) have been investigated for a number of narcotics and where possible for their congener narcotic antagonist. These studies were carried out by a novel microelectrometric titration technique as a function of temperature and pH. This method enables one to determine not only the dissociation constants to deconvolute overlapping pKas, but also to determine the solubilities and oil-water distribution of these various drugs. The drug distribution coefficients displayed marked sensitivity to pH at values which span the range of attainable human physiological pH values. This has significant pharmacological implications for proper choice and scaling of drug dosages under various clinical situations among which are cited hyperventilation under a general anesthetic while concomitantly under a narcotic analgesic, obstetetrical analgesia, and medical and anti-abuse usage of narcotic antagonists. The partition coefficients and drug distribution coefficients were noticeably different at 20degreesC (where such measurements are customarily made) from those at 37degreesC (body temperature). Furthermore, various drugs exhibit very non-equivalent increases in drug distribution coefficients with increasing temperature, ranging from 21% for naltrexone. This non-regularity indicates that it will not be valid to extrapolate by any constant factor the measurements made at lower temperatures. Even the true partition coefficients increase with temperature from 20degrees to 37degreesC.

A systems and control theory approach to dynamic neurotransmitter balance in narcotic addiction and narcotic antagonism

Abstract We have formulated a pharmacological-physiological systems analysis and control theory based on interactive neuronal feedback loops (the effects of endogenous neurochemical diseases and exogenous CNS drugs on neurotransmitter synthesis and release, reuptake and metabolism) for normal, abnormal and catastrophic situations. We set up the systems diagrams for neurotransmitter systems and in that single framework were able to describe endogenous neurochemical disorders, the effect that their drug treatment modalities had on the dynamic neurochemical balance and the effect other CNS drugs such as narcotics and narcotic antagonists had on neurochemical balance. This led to a hypothesis that narcotic addiction is caused by negative feedback induced increase in synthesis and release of certain neurotransmitters, tolerance arises in a related manner, narcotic withdrawal symptoms are caused by out-of-phase feedback and a major mechanism of antagonist action of narcotic antagonists is not merely competitive displacement of a narcotic from its “receptor site” but rather is due to an increase in the concentration of catecholamines in the synaptic cleft.

AB‐INITIO MODPOT/VRDDO/MERGE CALCULATIONS ON LARGE BIOMEDICAL MOLECULES AND ELECTROSTATIC MOLECULAR POTENTIAL CONTOUR MAPS*

We have been interested in several areas since the early 1960s: 1. Quantum chemical calculations on large drugs and biomolecules. (The first three-dimensional all-valence electron calculations on any drugs or biological molecules were those we carried out on the pyridine aldoxime antagonists to the organophosphorus intoxicants, using a then-state-of-the-art m e t h ~ d ~ . ~ (later named the extended Huckel method by Hoffman, who used the methodology suggested in the same two fundamental articles) and computer programs written by members of our group in late 1962 and early 1963). 2. Derivation of improved computational strategies for quantum chemical calculations6 (our semi-rigorous LCAO-MO-SCF methods for three-dimensional molecular calculations appeared in the same issue as Poples original CNDO and NDDO paper^^.^). 3. Ab-initio quantum chemical calculations on a variety of polyatomic molecules using Gaussian basis functions and more efficient computer programso [our ab-initio Gaussian calculation on diborane, B,H,, using 56 basis functions: was among the earliest on polyatomic molecules and the MOSES program, written by members of our group, was one of the first efficient ab-initio Gaussian LCAO-MO-SCF programs). We have continued our involvement with these interests since that time, carrying out, first, semi-rigorous and, starting in the early 1970s. ab-initio calculations on quite large biological and drug molecules. (Overviews of the further improvements we have made in the intervening years to semi-rigorous

Temperature and pH sensitivity of the partition coefficient as related to the blood-brain barrier to drugs.

The true drug distribution (apparent partition coefficient) coefficients of a number of CNS- active drugs were measured as a function of pH and temperature. It was found that the distribution coefficients of narcotics and narcotic antagonists are very sensitive to pH in the range of human physiological blood pHs and are strongly temperature dependent. Therefore, body temperature and blood pH of the patient must be considered when assessing blood-brain and blood-CSF exchange of a given drug.

Quantum chemical and theoretical predictions of toxicity

Abstract Theoretical and quantum chemical predictions of toxicity and toxicology are even more challenging than prediction of pharmacology, which is usually a one‐stage event at a target site. For toxicity and toxicology, we have developed the concept of the “toxic triggering event,”; which then leads to the cascade of subsequent physiological events. The strategy for computer‐generated predictions in this area includes as the major components chemical automated substructure and “toxicophore”; identification by powerful chemical structure and substructure searching techniques, quantum chemical calculations (desirably ab‐initio, incorporating optimal strategies for such computations on large molecules) on both the toxicant and its metabolites (the structures of which were generated by computer‐assisted tracing of metabolic pathways), generation of the three‐dimensional electrostatic molecular potential contour maps around the toxicants and tneir metabolites and matching of these maps by reverse image holog...