Tolerance and Dependence

Frey, H.‐H.

doi:10.1007/978-3-642-69518-6_11

Cited by 11 publications

(8 citation statements)

References 60 publications

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“…2, which illustrates tolerance to the anticonvulsant effects of PB and PHT after prolonged treatment of mice. Usually, acute seizure tests such as the maximal electroshock seizure (MES) or the pentylenetetrazole (PTZ) tests in mice were used for such studies (31,32). All‐or‐none responses were determined (i.e., the occurrence of tonic or clonic seizures in response to a fixed intensity of electrical or chemical stimulus as a function of different doses of an AED administered in separate groups of animals).…”

Section: Experimental Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

“…Another potentially important factor in this type of protocol is that animals do not repeatedly experience convulsive stimuli during the period of prolonged AED treatment, so that behavioral types of tolerance, which occur in animals and humans (33), are excluded. Nevertheless, by using such quantal responses of AEDs in rodent models of seizures, clear development of tolerance was demonstrated for several first‐generation AEDs, including PB, CBZ, PHT, trimethadione, and BZDs such as DZP, clonazepam (CZP) and CLB (31,32).…”

Section: Experimental Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

“…In case the drug concentration required for seizure protection increases because of the development of tolerance but remains below the achieved steady‐state concentration, epilepsy remains controlled by the dosage chosen, and tolerance remains undetected by the clinician. However, pharmacologists who are able to elicit seizures at will and to assess protection or development of tolerance at very low serum concentrations may be able to detect tolerance more often (31). This may, at least in part, explain the discrepancy between the experimental evidence that demonstrates tolerance to effect in most or all animals tested and for almost all AEDs studied, as discussed earlier, and the reports in the clinical literature in which, as will be shown, tolerance is seen in only a subgroup of responders.…”

Section: Clinical Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

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Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Löscher

Schmidt²

2006

Epilepsia

212

141

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Summary: Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most firstgeneration AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

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Section: Experimental Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

Section: Experimental Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

Section: Clinical Evidence For Tolerance To Antiepileptic Drugsmentioning

confidence: 99%

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Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Löscher

Schmidt²

2006

Epilepsia

212

141

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“…The development of tolerance was also found in the kindling model for primidone and phenobarbital (28), carbamazepine (29), phenytoin (30), abecarnil (31), and vigabatrin (32), which is consistent with chronic efficacy studies in other rodent models (c.f. 15,33,34). With some of these drugs, "learned" (or contingent) tolerance (c.f.…”

Section: Discussionmentioning

confidence: 99%

“…saline injection at the same time in the morning as during the drug treatment period. With respect to behavioral observations, particular attention was paid to alterations that might be related to a withdrawal syndrome (15).…”

Section: Chronic Drug Testing In Kindled Ratsmentioning

confidence: 99%

Development of Tolerance During Chronic Treatment of Kindled Rats With the Novel Antiepileptic Drug Levetiracetam

2000

Epilepsia

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Purpose: Levetiracetam (LEV) is an interesting novel antiepileptic drug with proven efficacy in both animal models and patients with partial epilepsy. To study whether the efficacy of the drug changes during chronic treatment, we evaluated the anticonvulsant activity of LEV during prolonged daily administration in amygdala-kindled rats.Methods: On the basis of the anticonvulsant potency and duration of action after acute doses, LEV was administered in fully kindled rats three times daily at 108 mg/kg i.p. for 3 weeks. For the study of anticonvulsant efficacy, the afterdischarge threshold was determined before, during, and after the drug treatment period. To determine whether the pharmacokinetics of the drug change during prolonged treatment, LEV levels were repeatedly determined in plasma during the treatment period.Results: LEV markedly increased the afterdischarge thresh-old and decreased the seizure severity and duration after initial dosing, but a marked loss of anticonvulsant efficacy developed during chronic treatment. This loss of efficacy was not due to alterations in drug elimination, indicating the development of functional tolerance to LEV during repeated administration. After the termination of treatment, no withdrawal signs (e.g., changes in behavior, body temperature, body weight, or seizure threshold) were observed.Conclusions: The data demonstrate that chronic administration of LEV leads to a significant reduction in anticonvulsant efficacy in the kindling model of temporal lobe epilepsy. Whether this experimental observation has clinical relevance must await monotherapy trials with long-term follow-up of patients who initially responded to LEV.

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La tolérance aux opiacés existe-t-elle dans le traitement de la douleur chronique?

Müller¹,

Sudbrack²,

Laugner³

1992

Doul. et Analg.

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Tolerance and Dependence

Cited by 11 publications

References 60 publications

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Development of Tolerance During Chronic Treatment of Kindled Rats With the Novel Antiepileptic Drug Levetiracetam

La tolérance aux opiacés existe-t-elle dans le traitement de la douleur chronique?

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