Joseph E. Manno

Drug Excretion in Human Breast Milk

SummaryThe excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk.Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk — impaired behaviour and development — is discussed from the standpoint of emerging animal data.Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

Toxicology of Ipecac: A Review

The general effectiveness and safety of Ipecac syrup, per se, has not been questioned, but rather an attempt has been made to consolidate pertinent literature dealing with the toxic manifestations of Ipecac fluid extract. Ipecac contains both emetine and cephaeline and the toxicity of Ipecac fluid extract is consistent with reports on the toxicity of both compounds. The majority of the work has involved emetine since it is in higher concentration in Ipecac fluid extract than is cephaeline. Comparison of the clinical picture presented in syrup or fluid extract of Ipecac overdose and emetine toxicity in amebiasis treatment permits us to summarize the general characteristics of Ipecac alkaloid toxicity as involving primarily gastrointestinal, cardiovascular, and neuromuscular foci.

Topographic quantitative EEG sequelae of chronic marihuana use: a replication using medically and psychiatrically screened normal subjects

In two previous studies it was reported that chronic marihuana (THC) use was associated with unique quantitative EEG features which were present in the non-intoxicated state. THC users, as contrasted with controls, had significant elevations of Absolute Power, Relative Power, and Coherence of alpha activity over the bilateral frontal cortex. Furthermore, a quantitative EEG discriminant function analyses permitted a 95% correct user versus non-user classification. However, because all of the THC users and 58% of the non-user controls were psychiatric inpatients, diagnostic and medication effects, if any, were uncontrolled. In the present study the same quantitative EEG methods were used to study daily THC users and non-user controls who underwent a rigorous screening process to insure that they were medically and psychiatrically healthy. The results of previous studies were replicated and an additional EEG correlate of chronic THC exposure (reduced alpha frequency) was identified.

Auditory and visual P300 event related potentials are not altered in medically and psychiatrically normal chronic marihuana users

Attempts to use Event Related Potentials, particularly the cognitive or P300 evoked potential, as measures of CNS effects of THC use have been infrequent and have produced inconsistent results. We published a pilot study in which psychiatric patient THC users had significantly prolonged auditory P300 latencies and reduced amplitudes as contrasted with non-users. Because psychiatric diagnoses and medication effects could not be controlled, we repeated the study with medically and psychiatrically normal subjects selected with extremely stringent exclusion criteria and screening procedures. P300 latency differences between THC users and controls were not detected. Using all subjects, THC users displayed reduced auditory and visual P300 amplitudes. However, when age differences between THC users and controls were removed, all significant P300 amplitude differences were removed as well. The contaminating effect of using psychiatric patients in THC research is discussed and the importance of using carefully screened normal subjects in studies of neurophysiological abuse drug effects is stressed.

Comparison of Efficacy of Ginger with Various Antimotion Sickness Drugs

UNLABELLED Ginger and several other medications were compared with scopolamine and d-amphetamine for effectiveness in prevention of motion sickness. METHODS Double-blind techniques were used. The subjects were given the medications two hours before they were rotated in a chair making head movements until a symptom total short of vomiting was reached. Standardized N.A.S.A. techniques were used for speed of rotation and end-point of motion sickness. RESULTS The three doses of ginger were all at the placebo level of efficacy. Amitriptyline, ethopropazine and trihexyphenidyl increased the tolerated head movements but the increase was not statistically significant. Significant levels of protection were produced by dimenhydrinate, promethazine, scopolamine and d-amphetamine. Protection was further increased by combination of these latter drugs with d-amphetamine. Efficacy was greatest as the dose was increased. CONCLUSIONS The medication of choice in this study was scopolamine 0.6 mg with d-amphetamine 10 mg. This combination provided good protection with acceptable side effects.

Early and Middle Latency Evoked Potentials in Medically and Psychiatrically Normal Daily Marihuana Users: A Paucity of Significant Findings

The use of evoked potentials to study CNS effects of marihuana (THC) have produced inconsistent findings. Our previous pilot studies suggested that auditory P300 latencies and amplitudes, auditory P50 and somatosensory P30 amplitudes and brainstem auditory evoked potential latencies were altered in THC users. Because these findings were flawed by uncontrolled psychiatric diagnostic and medication variables, we undertook a controlled investigation of screened medically and psychiatrically normal THC users and controls. When age effects were controlled, THC related alterations of brain stem and both auditory and visual P300 responses could not be seen. This report extends our analyses to other auditory, somatosensory and visual evoked potentials. With the possible exception of an elevated auditory P50 amplitude, significant evoked potential correlates to daily THC use were not seen when normals were studied and age effects controlled.

Acute Marihuana (THC) Exposure Produces a “Transient” Topographic Quantitative EEG Profile Identical to the “Persistent” Profile Seen in Chronic Heavy Users

In two published pilot studies and a controlled replication using screened normals, chronic marihuana (THC) use was associated with a unique topographic quantitative EEG profile, consisting of significant elevations of Absolute and Relative Power and Coherence of alpha activity over the bilateral frontal cortex as well as a significant decrease in alpha frequency. This report attempts to establish the causal influence of THC in the above findings by the transient production of this exact quantitative EEG profile in subjects who did not display it at the beginning. Using paced smoking of marihuana with high and low dose THC content and placebo marihuana in a counterbalanced design under double blind conditions, all four of the topographic features of chronic THC exposure were produced as transient effects by THC but not by placebo.

PURSUIT METER II, A COMPUTER-BASED DEVICE FOR TESTING PURSUIT-TRACKING PERFORMANCE

The Pursuit Meter II, a microcomputer-based device developed for the quantitative determination of human pursuit-tracking performance, is described. Computer-generated moving patterns are displayed on a high resolution color video monitor. For the subject the task is to attempt to superimpose a red line presented on the screen, the vertical location of which he controls with a steering device, over a blue line the computer generates as the problem. Both lines, each composed of 279 segments, are generated at the same rate, left to right on the monitor. The individual differences between the subjects response and the problem are summed and stored by the computer as an error score which correlates inversely to the subjects ability to perform the task. Three Pursuit Meter II problems were presented to 26 male college students. Our data demonstrated that different levels of performance to the problems resulted and that the Pursuit Meter II can be used to quantify human pursuit-tracking performance.

Lack of effect of respiratory syncytial virus infection on theophylline disposition in children

Conflicting reports raise a question about decreased plasma clearance (Clp) of theophylline in man during viral infections. Thus a dilemma exists concerning requisite dose adjustments. We examined this issue by retrospectively evaluating theophylline Clp in children infected with respiratory syncytial virus (RSV). Two pharmacokinetic approaches were applied to a one-compartment open model to fit theophylline concentrations during 83 hospitalizations of 76 children, 6 to 48 months of age, who received intravenous theophylline therapy and were tested for RSV infection. Iterative linear regression analyses of all theophylline data were used to estimate apparent volume of distribution, elimination rate constant, plasma half-life, and Clp in 39 of the hospitalizations. When insufficient data were available to distinguish apparent volume of distribution and elimination rate constant (n = 44), steady-state estimates of Clp were calculated. An age-matched and percentile body weight-matched cohort design presented RSV as the primary covariate. Theophylline Clp was similar in 29 matched RSV-infected and -uninfected pairs (1.32 +/- 0.14 and 1.25 +/- 0.05 ml/kg per minute, respectively), as were other pharmacokinetic values. Unexpectedly, a significant, inverse linear relationship was found for Clp and percentile body weight. Additionally, children born prematurely and hospitalized in the neonatal intensive care unit had significantly higher theophylline Clp; this did not affect findings regarding RSV infection. Theophylline Clp was not decreased in RSV-infected children. Current theophylline dosing recommendations for young children infected with RSV should not be altered, but careful monitoring of plasma theophylline levels should be continued.

Determination of temazepam and temazepam glucuronide by reversed-phase high-performance liquid chromatography

A rapid and sensitive method for extracting temazepam from human serum and urine is presented. Free temazepam is extracted from plasma and urine samples using n-butyl chloride with nitrazepam as the internal standard. Temazepam glucuronide is analyzed as free temazepam after incubating extracts with beta-glucuronidase. Separation is achieved using a C8 reversed-phase column with a methanol-water-phosphate buffer mobile phase. An ultraviolet detector operated at 230 nm is used and a linear response is observed from 20 ng/ml to 10 micrograms/ml. The limit of detection is 15.5 ng/ml and the limit of quantitation is 46.5 ng/ml. Coefficients of variation are less than 10% for concentrations greater than 50 ng/ml. Application of the methodology is demonstrated in a pharmacokinetic study using eight healthy male subjects.