Phillip C. Jobe

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.

Neurotransmitter abnormalities as determinants of seizure susceptibility and intensity in the genetic models of epilepsy

Normal subjects are not considered to be epileptic merely because they exhibit a seizure in response to an appropriate stimulus of sufficient intensity. In epileptics, a relatively weak stimulus will elicit an explosive neuronal response, whereas in a normal individual it will cause only trivial responses. Fortunately, only a few subjects in any given animal or human population are epileptic; however, most if not all epileptics are genetically predisposed to seizures. The importance of genetic determinants in human epilepsy has become established only recently [l]. Genetic factors probably control seizure susceptibility and, therefore, the likelihood of developing epilepsy [l-8]. The genetic determinant is not solely responsible for the appearance of seizures but is an important contributing component. Seizures probably do not occur in the absence of other factors such as stress, biochemical and hormonal imbalances, or other environmental or physical initiators [l]. Thus, epilepsy is a composite of the individual’s genetically controlled seizure propensity plus the presence of one or more seizure triggering factors. We believe that neurochemical studies in subjects with a genetically determined predisposition to seizures are helping establish the molecular basis of epileptogenicity. However, heretofore most investigations of epilepsy have used animal models with very high degrees of inherited seizure resistance. These are normal animals which are made “epileptic” by the use of various chemical or electrical methods. Except in the kindling model of epilepsy, these normal animals retain their relatively high innate seizure resistance. Although valuable information has been obtained on the initiation of seizures in normal animals, this approach has revealed very little about genetically determined seizure susceptibility. Genetic models of epilepsy. At least one genetic model of epilepsy is available within each of several animal species, including the rat [9, 101, mouse

Effect of Midbrain and Pontine Tegmental Lesions on Audiogenic Seizures in Genetically Epilepsy-Prone Rats

Summary: A bilateral mechanical lesion of the midbrain and pontine tegrnentum was found to abolish completely the tonic components of sound‐induced seizures in genetically epilepsy‐prone rats (GEPR) that display tonicclonic seizures. Correlations between varied lesion placements and effects on maximal audiogenic seizures provided evidence that damage to the nucleus reticularis pontis oralis (RPO) of the midbrain and pontine reticular formation (RF) was responsible for the seizure‐attenuating effects. Moreover, electrolytic lesions of the pontine RF involving the RPO nucleus were found to abolish the tonic components of the maximal audiogenic seizure. Additionally, bilateral mechanical lesions involving the RPO nucleus were found to attenuate the clonic components of sound‐induced seizures in GEPR that display only running seizures and clonus. These findings are consistent with previous studies showing that pontine tegmental lesions attenuate the tonic components of maximal electroshock‐ and pentylenetetrazol‐induced seizures, and lend further support to the hypothesis that all generalized tonic seizures share a common neural substrate. The role of the brainstem RF in tonic versus clonic convulsions is discussed in light of the present findings.

II. Noradrenergic and serotonergic determinants of seizure susceptibility and severity in genetically epilepsy-prone rats

Pharmacological studies demonstrate a reciprocal relationship between both noradrenergic and serotonergic transmission and audiogenic seizure severity and susceptibility in the genetically epilepsy-prone rat (GEPR). In contrast, drug-induced changes in the neurochemical indices of dopaminergic activity do not result in alterations in seizure severity. These pharmacological investigations led to the hypothesis that both noradrenergic and serotonergic neurons are capable of regulating seizure severity in the GEPR. Pharmacological investigations also provided evidence that monoaminergic neurons serve as determinants of seizure susceptibility in these epileptic animals. The GEPR is susceptible to environmentally-induced seizures which cannot be precipitated in neurologically normal subjects. Drug studies suggest that monoaminergic decrements serve as one set of susceptibility determinants. However, non-monoaminergic abnormalities also play important roles in the seizure predisposition which characterizes the GEPR. Pathophysiological studies have confirmed and extended the concepts generated by the pharmacological investigations. Noradrenergic and serotonergic deficits do indeed characterize the seizure naive state of the GEPR. These studies have provided a basis for tentative identification of areas of the brain in which monoaminergic abnormalities regulate seizure severity and susceptibility. Monoaminergic defects in some areas such as the thalamus may regulate both susceptibility and severity. In other areas, defects may regulate only severity or susceptibility. In the striatum, noradrenergic defects do not appear to be present and probably are not determinants of the epileptic state of the GEPR.

Abnormalities in Monoamine Levels in the Central Nervous System of the Genetically Epilepsy-Prone Rat

Summary: Norepinephrine, dopamine, and 5‐hydroxytryptamine concentrations were determined in the central nervous systems of genetically epilepsy‐prone rats (GEPR) and in control rats. Norepinephrine concentrations were abnormal in all major areas of the central nervous system of the GEPR, with decrements existing in the telencephalon, hypothalamus‐thalamus, midbrain, pons‐medulla and spinal cord. An increment in the concentration of this neurotransmitter existed in the cerebellum. Dopamine concentrations were normal in all areas of the GEPR brain. Abnormalities in 5‐hydroxytryptamine concentrations were also present in the GEPR. They were exclusively decrements and occurred in the telencephalon, hypothalamus‐thalamus, midbrain, and pons medulla. Concentrations of this neurotransmitter were normal in the cerebellum and spinal cord. Coupled with our earlier pharmacologic data, these observations support our concept that noradrenergic and/or 5‐hydroxytryptaminergic decrements are etiologically important in seizure susceptibility in the GEPR. The lack of abnormalities in brain dopamine concentrations strengthens our hypothesis that dopaminergic transmission does not regulate seizure susceptibility in this model.

Angular bundle kindling is accelerated in rats with a genetic predisposition to acoustic stimulus-induced seizures

Limbic kindling was examined in genetically epilepsy-prone (GEPR) and non-epileptic control rats. The early stage of kindling development was accelerated in both groups of GEPR rats compared to controls. Later stages of kindling were accelerated in GEPR-9 but not GEPR-3 rats. These results indicate that GEPR rats have an enhanced susceptibility to limbic kindling and suggest that limbic brain alterations may contribute to acceleration of the early stage kindling development in GEPR rats.

Indices of noradrenergic function in the central nervous system of seizure-naive genetically epilepsy-prone rats.

Summary: Norepinephrine concentrations and tyrosine hydroxylase activity were determined in the brains of moderate‐seizure and severe‐seizure genetically epilepsy‐prone rats (GEPRs) and in nonepileptic control rats. Both moderate‐seizure (GEPR‐3) and severe‐seizure (GEPR‐9) animals had widespread abnormalities in brain norepinephrine concentrations. Abnormalities in tyrosine hydroxylase activity were restricted to the midbrain. The state of abnormal seizure susceptibility, but not severity, in the GEPR may be determined by noradrenergic deficits in the hypothalamus/thalamus. Both seizure severity and susceptibility may be determined by noradrenergic deficits in the telencephalon, midbrain, and pons‐medulla. Seizure severity but not susceptibility may be determined by noradrenergic abnormalities in the cerebellum.

Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat

Norepinephrine turnover rates were estimated in the hypothalamus-thalamus, midbrain, pons-medulla and telencephalon of genetically epilepsy-prone rats (GEPR). In each of these 4 brain areas the endogenous norepinephrine levels were significantly lower in the GEPR than in control animals. In the hypothalamus-thalamus, midbrain and telencephalon the calculated norepinephrine turnover rates were also significantly lower in GEPRs than in control. These studies confirm and extend earlier observations relating seizures in the GEPR to decrements in central nervous system noradrenergic function.

Evaluation of monoaminergic receptors in the genetically epilepsy prone rat

The intensity of sound-induced convulsions in the genetically epilepsy-prone rat (GEPR) was reduced in a dose related fashion by intracerebroventricular administration of dobutamine, (β1 agonist), terbutaline (β2 agonist) or phenylephrine (α1 agonist). BHT-920 (α2 agonist) did not cause a dose-related decrease in sound-induced convulsion intensity. Binding studies showed that whole brain α and β receptor densities (Bmax) were normal while the Kd was increased for the β ligand in GEPR brain.

Cochlear Morphology of the Audiogenic-Seizure Susceptible (Ags) Or Genetically Epilepsy Prone Rat (Gepr)

The organ of Corti (OC) of the genetically epilepsy prone rat (GEPR), a strain which is highly susceptible to audiogenic seizures (AGS), was examined by means of the scanning electron microscope (SEM). Ten female GEPRs (seizure intensity score of 2 or 3) and 10 female control rats (seizure intensity score of 0) were used in this study. (Seizure intensity was scored on an ascending scale of 0-9; 0 being no seizure (Jobe et al., 1973).) Each rat was perfused with buffered glutaraldehyde and the temporal bones fixed for one week in formalin. After decalcification, staining and microdissection, the entire OC was prepared for scanning electron microscopy (SEM). The GEPR organ of Corti contained several morphological differences when compared with controls. 1) In all 10 GEPRs, the headplates forming the top of the tunnel of Corti exhibited some form of structural abnormality. 2) Five animals had some form of stereocilia aberration of the inner (IHC) and/or outer (OHC) hair cells. 3) In 4 animals, significant numbers (10-15%) of IHCs were missing in large segments of all cochlear turns. 4) In 2 GEPRs, all OHCs were absent from the middle turn to the hook. In these 2 animals, IHCs were present in the upper middle turn but became less numerous and completely absent in the basal turn and hook. 5) One set of cochleas had 1000 more OHCs than had those of control rats. Since GEPRs are genetically susceptible to seizures, the preceding cochlear abnormalities are probably genetically-induced developmental defects. It is likely that the abnormally long stereocilia, mis-shaped stereocilia and deficits in hair cell populations are a consequence of the distorted headplates. The elongated stereocilia could be a compensatory attempt to contact the tectorial membrane during development. The mis-shaped stereocilia and hair cell deficits could represent a failure of compensatory mechanisms. The cochlear abnormalities may play a role in both susceptibility and intensity of audiogenic seizures.