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Guide To Beating Hypoglycemia

New Treatment of Hypoglycemia

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"From Shih et al., 1999; Shih and McDonough, 1999. bFrom Shih and McDonough, 1999; Shih et al., 2003. N/A, information not available; sub-Q, subcutaneous.

"From Shih et al., 1999; Shih and McDonough, 1999. bFrom Shih and McDonough, 1999; Shih et al., 2003. N/A, information not available; sub-Q, subcutaneous.

Insights into Human Disorders

Organophosphates are potent and irreversible inhibitors of acetylcholine esterase (AChE), the ACh degrading enzyme. Therefore their administration increases the availability of ACh for general activation of all subtypes of the ACh receptors.

Other Drugs

This section combines several other drugs, the administration of which is associated with seizures. Although these drugs are unrelated to one another, they are worth mentioning either for their mechanisms of convulsive action or because of relevant occurrence in humans. Some of these drugs induce conditions with epileptic seizures that do not require a diagnosis of epilepsy: drug or other chemically induced seizures (Engel, 2001). However, hypoglycemia is not included in the current classification (Engel, 2001), although one might argue that this condition associated with seizures is commonly caused by excessive insulin (i.e., a drug) of exogenous or endogenous origin.

Strychnine

Methods of Generation

Strychnine (Allen, 2000) has been used for practical human toxicology for centuries. Victims of strychnine poisoning die in convulsions. Strychnine sulfate can be dissolved in normal saline (1mg/ml). Doses between 1 and 4mg/kg IP are used for 3- to 25-day-old rats. CD50 values for the same ages are between 1.8 and 0.5mg/kg and decrease with age (Kubova and Mares, 1995). Doses for adult rats are around 2 to 3mg/kg administered sub-Q (Kubova et al., 1990).

Defining Features

In very young rats at PN3-5, circling and barrel rotations are observed. A higher incidence of myoclonic twitches can be seen from PN7 onward. Tonic-clonic seizure pattern either fully developed or without the tonic phase can be recorded in all age groups, including adults. Sharp waves and spikes are the predominant features in the EEG of PN12-25 rats. In younger rats, slow waves with very poor electroclinical correlation occur (Kubova and Mares, 1994; Pylkkö and Woodbury, 1961).

Limitations

Seizures induced by strychnine are considered by some investigators as a model of therapy-resistant seizures (Löscher, 1997). However, it is difficult to fit these seizures into the classification of human seizures and epilepsy (Engel, 2001).

Insights into Human Disorders

The mechanism of the convulsant action of strychnine has been defined as a blockade of chloride channel associated with glycine receptors (Curtis et al., 1971). These inhibitory receptors can be found mostly in the spinal cord and brainstem (Young and Snyder, 1973; Zarbin et al., 1981). Therefore strychnine can serve as a model of therapy-resistant seizures arising from the lower brainstem and spinal cord.

Aminophylline

Methods of Generation

Both aminophylline (theophylline and ethylenediamine) and caffeine can induce convulsions (Chu, 1981; Stone and Javid, 1980; Walker, 1981a, b). Aminophylline can be dissolved in normal saline. Doses from 150 to 350mg/kg IP induce seizures in rats from PN7 to adulthood with CD50 values ranging between 180 and 280mg/kg IP throughout development (Mares et al., 1994).

Defining Features

Aminophylline induces dose-dependent clonic seizures, tonic-clonic seizures, and lethality throughout development.

Limitations

This is an unusual model of symptomatic seizures. Theo-phylline-induced seizures have been described in humans (Jensen et al., 1984).

Insights into Human Disorders

Theophylline acts as an antagonist of adenosine receptors. According to the classification published in 2001 (Engel, 2001), aminophylline-induced seizures are a model of conditions with epileptic seizures that do not require a diagnosis of epilepsy (drug or other chemically induced seizures).

Insulin-induced Hypoglycemia

Methods of Generation

In experimental animals, seizures can be induced by administration of insulin, leading to hypoglycemia (Urion et al., 1979). Insulin can be dissolved in distilled water at a concentration of 15 international units (IU) per milliliter. The usual dose for seizure production is 5 to 30IU/kg IP (Urion et al., 1979; Vannucci and Vannucci, 1978). After this dose, rats develop seizures within 4 hours. Our unpublished data show that the prior fasting (for 24 hours) improves the incidence and decreases the latency to onset of insulin-induced seizures. Thus, in overnight fasted rats, hypo-glycemic seizures usually fully develop within 2 to 3 hours, and their incidence is close to 100%. In our experience, it is very difficult to produce hypoglycemic seizures in the immature rats. We were able to induce seizures in PN21 and older rats (post weaning) but only extremely rarely in suckling rats (Vannucci and Vannucci, 1978), even during observation periods as long as 10 hours after insulin administration.

Defining Features

During severe hypoglycemia, a sequence of events occurs. Onset of seizures usually correlates with a peripheral glucose drop down to 20mg/100ml (1.1 mM). First, with decreasing systemic glucose, rats are hypoactive and flaccid. Individual twitches then occur. Jumps, usually restricted to the hindlimbs, are also observed. Barrel rotations are a very typical expression of hypoglycemic seizures

(see Chapter 48). Sometimes clonic and tonic seizures occur, including an opisthotonic position. All these seizures are associated with a loss of posture. EEG shows generalized spike and spike and wave activity (Figure 10). Metabolic studies demonstrate significant changes in the 2DG uptake in hypothalamic nuclei (belonging to food-intake control group) and also in the midbrain and brainstem structures, such as subthalamic nucleus, substantia nigra pars reticulata, pedunculopontine tegmental nucleus, and vestibular nuclei. The c-fos immunopositivity is especially prominent in the substantia nigra reticulata and subthalamic nucleus in rats experiencing hypoglycemic seizures. Neuronal injury has been studied in rats with 10 to 30 minutes of isoelectric EEG during severe hypoglycemia. The injury involves the neo-cortex, hippocampal CA1, and amygdala regions as well as cerebellar Purkinje cells (Auer and Siesjo, 1993; Auer et al., 1984).

Limitations

This model is not important for the studies of the mechanisms of anticonvulsant drug action. However, the mechanisms underlying hypoglycemic seizures and the brain structures responsible for excessive and synchronized firing during conditions of general metabolic shutdown of neuronal activity are still worth further exploration (Lewis et al., 1974).

Insights into Human Disorders

Hypoglycemia is frequently associated with neurologic side effects (Davis et al., 1997). From these side effects,

Adult rat, 120 min after insulin 30 IU/kg i.p

Adult rat, 120 min after insulin 30 IU/kg i.p

FIGURE 10 Discharges recorded during severe insulin-induced hypoglycemia (blood glucose <20mg/100ml) in a Sprague-Dawley rat. Arrow marks time of onset of barrel rotations. This pattern illustrates dissociation of electro-encephalographic (EEG) discharges and motor seizures induced by insulin-induced hypoglycemia. Electrocorticograms and stereo EEG from sensorimotor cortex, hippocampus, and deep midbrain/brainstem structures: SNR, substantia nigra pars reticulate; PPTG, pedunculopontine tegmental nucleus.

FIGURE 10 Discharges recorded during severe insulin-induced hypoglycemia (blood glucose <20mg/100ml) in a Sprague-Dawley rat. Arrow marks time of onset of barrel rotations. This pattern illustrates dissociation of electro-encephalographic (EEG) discharges and motor seizures induced by insulin-induced hypoglycemia. Electrocorticograms and stereo EEG from sensorimotor cortex, hippocampus, and deep midbrain/brainstem structures: SNR, substantia nigra pars reticulate; PPTG, pedunculopontine tegmental nucleus.

seizures occur most frequently (Kaufman, 1998; Pocecco and Ronfani, 1998). Hypoglycemic seizures represent a model of symptomatic seizures frequently occurring in humans, especially with type 1 diabetes mellitus or metabolic conditions affecting carbohydrate metabolism (Corn-blath and Schwartz, 1991). Treatment for these seizures is correction of blood glucose; therefore no antiepileptic drugs are required (Auer and Siesjo, 1988).

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