John J. Stewart

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.

Effects of Ginger on Motion Sickness Susceptibility and Gastric Function

This study was designed to evaluate the antimotion sickness activity of ginger root (Zingiber officinale) and to characterize the effects of ginger on gastric function. Twenty-eight human volunteers participated in the project. Subjects made timed head movements in a rotating chair until they reached an endpoint of motion sickness short of vomiting (malaise III or M-III). Each subject was tested with either ginger or scopolamine and a placebo. A substance was judged to possess antimotion sickness activity if it allowed a greater number of head movements compared to placebo control. Gastric emptying of a liquid was measured by nuclear medicine techniques in normal and motion sick subjects. Gastric electrical activity was monitored by cutaneous (surface) electrodes positioned over the abdominal area. Powder ginger (whole root, 500 or 1,000 mg) or fresh ginger root (1,000 mg) provided no protection against motion sickness. In contrast, subjects performed an average of 147.5 more head movements (p less than 0.01) after scopolamine (0.6 mg p.o.) than after placebo. The rate of gastric emptying was significantly (p less than 0.05) slowed when tested immediately after M-III but was inhibited less when tested 15 min after M-III. Powdered ginger (500 mg) had no effect on gastric emptying in normal or motion-sick subjects. Gastric motility was also changed during motion sickness. The frequency of the electrogastrogram (EGG) was increased after M-III (tachygastria) and the normal increase in EGG amplitude after liquid ingestion was reduced in motion sick subjects. Although powdered ginger (500 mg) partially inhibited tachygastria in motion sickness, it did not enhance the EGG amplitude in motion sick subjects. We conclude that ginger does not possess antimotion sickness activity, nor does it significantly alter gastric function during motion sickness.

Translocation of indigenous bacteria from the gastrointestinal tract of mice after oral ricinoleic acid treatment

A single dose of ricinoleic acid, the active component of castor oil, administered intragastrically to specific pathogen-free mice produced significant alterations in the proximal small intestinal mucosa. Two hours after drug administration, the duodenal villi were markedly shortened with massive exfoliation of columnar and goblet cells. This disruption of the mucosal barrier resulted in continuity between the intestinal lumen and the lamina propria of the villi. Because of the loss of the mucosal barrier, bacteria of the indigenous gastrointestinal flora translocated from the gastrointestinal lumen to the mesenteric lymph nodes, spleen, and liver. The peak incidence of bacterial translocation occurred 4 days after the ricinoleic acid treatment. Strictly anaerobic bacteria, which normally colonize the gastrointestinal tract at greater levels than aerobic or facultatively anaerobic bacteria, were translocated at a greater incidence to the mesenteric lymph nodes than were the other indigenous bacteria. The mucosa began regenerating within 4 h after the ricinoleic acid treatment and viable translocated bacteria were no longer cultured from the mesenteric lymph nodes by 7 days after treatment.

Responsiveness of genetically epilepsy-prone rats to intracerebroventricular morphine-induced convulsions.

The sensitivity to intracerebroventricular morphine-induced convulsions was determined in members of the severe seizure (GEPR-9) and moderate seizure (GEPR-3) colonies of genetically epilepsy-prone rats as well as in non-epileptic control rats. GEPR-9s were more sensitive to morphine-induced wet-dog shakes, rearing with bilateral forelimb clonus and generalized clonus than controls of GEPR-3s. GEPR-3s were less sensitive to morphine-induced wet-dog shakes and rearing with bilateral forelimb clonus than controls. Both high and extremely low doses of morphine in GEPR-9s elicited tonic extensor convulsions resembling the characteristic sound-induced convulsion of GEPR-9s. The results suggest that opiotergic systems may contribute to the pathophysiology of the seizure-prone condition in GEPR-9s. Further, differences in responsiveness of opiotergic systems in GEPR-3s and GEPR-9s may partially account for differences in seizure severity in the characteristic sound-induced seizures of these two types of GEPRs.

Habituation and Motion Sickness

The vestibular, cerebellar, and reticular systems are central in importance, in motion sickness and habituation, to the effects of motion. Nuclear medicine single photon emission computed tomography (SPECT) studies of cerebral blood flow and power spectral electroencephalographic recordings during motion sickness were used to determine alterations in the central nervous system. The rotating chair with and without visual stimulation was used to study the rate of habituation and the effect of antimotion sickness medications on this rate. An increase of theta waves over the frontal cortex indicated a decreased activation of the higher centers during motion sickness. Motion sickness also produces an increase of blood flow in the central cerebellum that has connections to the reticular system. This increase in cerebellar activity is relayed to the reticular system whereby neural recruitment builds up to trigger the vomiting center, producing motion sickness. Habituation may be a conditioned compensatory activation of the reticular neurons that prevents this disruption of normal activation. The rate of habituation when motion sickness was prevented by scopolamine was slowed, indicating that, if the central nervous system is not challenged by disruption of normal activation, it does not produce the compensatory reactions that result in habituation.

Effects of Emetic and Cathartic Agents on the Gastrointestinal Tract and the Treatment of Toxic Ingestion

Emetic drugs and saline cathartics produce direct or reflex changes in gastrointestinal motility. The changes in gastrointestinal smooth muscle function may be important in the rapid oral or rectal expulsion of gastrointestinal contents, effects which serve as a basis for emetic and cathartic drug use in the treatment of toxic ingestion. Because of difficulties in recording gastrointestinal smooth muscle contractile activity from the intact, unanesthetized animal or man, relatively few studies have attempted to characterize the changes in gastrointestinal motility preceding vomiting. Limited results from past studies and the results of more recent studies employing improved technology suggest that pharmacological activation of the emetic reflex is accompanied by characteristic movements of the stomach and small intestine. The gastric response consists of initial muscle relaxation and an expansion of gastric volume. The intestine responds with a contraction, which begins in the distal ileum and migrates orad over the entire small intestine immediately before active retching. The changes in gastric and intestinal motility may be initiated by structures in the central nervous system and may be an important component of the emetic reflex. This article urges more active research to characterize the gastrointestinal emetic response and to investigate more generally the therapeutic value of emesis in the treatment of toxic ingestion. Emphasis should be placed on the clinically important emetic drugs apomorphine and syrup of ipecac. Studies comparing the efficiency of removal of gastrointestinal contents, resultant blood levels of orally administered drugs with and without emesis, differences in the gastrointestinal emetic response between agents and the pharmacology of the gastrointestinal emetic response should be performed. Studies should also be conducted to determine the pharmacology of the emetic sensory receptors in the gastrointestinal tract and the intraluminal physical-chemical or gastrointestinal physiological factors influencing gastrointestinal emetic sensory receptor activation. The results would demonstrate the value of emesis in various poison cases and help establish criteria for use and selection of emetic drugs. No less experimental attention should be devoted to the cathartic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Effectiveness and Duration of Intramuscular Antimotion Sickness Medications

Motion sickness inhibits gastric motility, making the oral route ineffective for medications. The intramuscular route is an effective alternative. The rotating chair was used to produce the M 111 level of motion sickness on the Graybiel Symptom Scale. The intramuscular medications given 30 minutes before rotation were compared with placebo (saline, 1 mL) for effectiveness and duration in increasing the number of tolerated head movements. Average placebo number of head movements was 294. Promethazine 25 mg increased head movements by 78% (P < .05), with a duration of 12 hours. Scopolamine 0.2 mg increased head movements by 91% (P < .05), with a duration of 4 hours. The effect of caffeine 250 mg and ephedrine 25 mg was not significant. When combined with scopolamine, ephedrine produced an 32% additive effect. Scopolamine 0.08 mg, 0.1 mg, and 0.2 mg and also promethazine 12.5 mg and 25 mg were significant (P < .05). Promethazine appears to be the drug of choice for intramuscular use because of a longer duration and a high level of effectiveness. Scopolamine was of high effectiveness, but had a duration of 4 hours. It was eight times as potent by the intramuscular as by the oral route.

Effects of Motion Sickness and Antimotion Sickness Drugs on Gastric Function

This study examined the effects of motion sickness and antimotion sickness drugs on gastric emptying (GE). Drugs were tested in normal and motion sick subjects. To induce motion sickness, subjects performed head movements while seated in a rotating chair. Gastric emptying of liquid (300 mL) was determined by nuclear medicine techniques, whereas gastric electrical activity, the electrogastrogram (EGG), was monitored from surface (cutaneous) electrodes positioned over the abdominal area. Gastric emptying was severely inhibited at the peak of motion sickness symptoms, but returned to normal 15 minutes later when symptoms abated. In normal (non—motion sick) subjects intramuscular (IM) scopolamine (0.1 mg) and IM promethazine (25 mg) inhibited GE, whereas erythromycin ethylsuccinate (EES) suspension (200 mg) given orally increased GE. When administered to motion sick subjects, IM scopolamine and IM promethazine added slightly, but not significantly, to the inhibition of GE already present. Oral EES did not significantly alter GE in motion sick subjects. Although EGG frequency remained within normal limits (∼2.5–3.5 cpm) after liquid ingestion in both normal and motion sick subjects, EGG amplitude was differentially affected in the two groups. Electrogastrogram amplitude increased twofold to fourfold after liquid ingestion in normal, but not in motion sick subjects. The results suggest that (1) maximal inhibition of GE is coincident with peak motion sickness symptoms, (2) both IM scopolamine and IM promethazine inhibit GE in normal subjects, but do not add significantly to the inhibition of GE already established during motion sickness, (3) orally administered erythromycin enhances GE in normal, but not in motion sick subjects, and (4) the normal stimulatory effect of liquid ingestion on gastric motility does not occur in motion sick subjects. Both motion sickness and parenterally administered antimotion sickness drugs are potential sources of inhibited GE in space.

In vitro Adsorption of Sodium Pentobarbital by Superchar, USP and Darco G-60 Activated Charcoals

This study was designed to examine the in vitro adsorption of sodium pentobarbital by three activated charcoals. Solutions of sodium pentobarbital (20 mM) were prepared in distilled water and in 70% sorbitol (w/v). Radiolabeled (14C) sodium pentobarbital was added to each solution to serve as a concentration marker. Two ml of each drug solution was added to test tubes containing 40 mg of either Darco G-60, USP, or SuperChar activated charcoal. The drug-charcoal mixtures were incubated at 37 degrees C for O, 2.5, 5, 7.5 or 10 min. Equilibrium, indicated by a constant percentage of drug bound for two consecutive time periods, was established immediately for the aqueous mixtures and for Darco G-60 in sorbitol. The time to equilibrium was prolonged for USP (2.5 min) and SuperChar (5 min) in the presence of sorbitol. In the second series of experiments, solutions of sodium pentobarbital (1.25 to 160 mM) were prepared in either distilled water or sorbitol. Amount of drug bound by 10 to 320 mg of activated charcoal within a 10 min incubation period was determined. Scatchard analysis determined maximum binding capacity (Bmax) and dissociation constants (Kd) for each activated charcoal. In water, Bmax (mumoles/gm) was greatest for SuperChar (1141), followed by USP (580) and Darco G-60 (381), while the Kds did not differ. Sorbitol did not change the Bmax or Kd of USP or Darco G-60, but the additive significantly decreased the Bmax (717) and increased the Kd for SuperChar (3.3 to 10.1 mM). The results suggest that relative binding capacity of activated charcoal is directly proportional to surface area, and that sorbitol significantly reduces sodium pentobarbital binding to SuperChar.

Effects of Methotrexate on Intestinal Transit in Rats

A study was designed to determine the effects of methotrexate (MTX) on rat intestinal transit. Adult male rats were implanted with indwelling cannulas in the proximal duodenum 5 to 7 days prior to experimentation. After recovery from surgery, groups of animals were treated with either saline (1.0 ml/kg/day) or MTX at 0.5, 1.25, 3.125, or 7.8 mg/kg/day (ip) for 3 consecutive days (Days 1-3). On each of the next 5 consecutive days (Days 4-8) weight and intestinal transit determinations were made in animals from each test group following a 24-hr fast. Intestinal transit was determined by measuring the progression of an intraduodenally administered bolus of radioactive chromium (Na2(51)CrO4, 0.5 mu Ci) through the small intestine. When compared with saline-treated controls, intestinal transit was significantly (p less than 0.05) increased on 1 or more of the 5 test days in animals treated with doses of MTX greater than 0.5 mg/kg/day. When compared with animals treated with saline, animals treated with MTX lost a greater percentage of their initial body weight after the fast period. Plasma concentrations of MTX, determined at various time intervals after 3.125 mg/kg given daily for 1 to 3 consecutive days, peaked at 15 and 30 min after each injection and diminished to undetectable levels after 4 hr. The results indicate that 3 days of parenteral therapy with MTX significantly increases rat intestinal transit. The intestinal effects appear to be transient and are proportional to the total dose of drug administered over the 3-day period. The intestinal effects of MTX occur from 1 to several days after peak plasma concentrations of drug and are associated with a reduced ability to sustain body weight after a 24-hr fast.