Drug-drug interactions of new active substances: mibefradil example

Krayenbühl, J. C.; Vozeh, S; Kondo-Oestreicher, M; Dayer, P.

doi:10.1007/s002280050673

Cited by 78 publications

(38 citation statements)

References 20 publications

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“…Mibefradil was approved for use in essential hypertension and stable angina pectoris until it was withdrawn from the market due to drug-drug interactions leading to irregular heart rhythms (219). Submicromolar concentrations of mibefradil, formerly Ro-40 -5967, preferentially block T-type channels, while higher concentrations are required to block cardiovascular L-type channels (282).…”

Section: A Antihypertensivesmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,521

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Section: A Antihypertensivesmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,521

1,446

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“…Studies with mibefradil, a non-DHP blocker specific for T-type Ca 2 þ channels, have implied that selective inhibition of T-type Ca 2 þ channels is advantageous in the treatment of hypertension or angina pectoris (Hermsmeyer et al, 1997;Van der Vring et al, 1999). However, mibefradil was withdrawn from the market because of serious pharmacokinetic and pharmacodynamic interactions with other drugs frequently administered to patients with cardiovascular diseases (Krayenbuhl et al, 1999). Therefore, the development of a new T-type Ca 2 þ channel blocker without adverse effects has been considered necessary for medication.…”

Section: T Furukawa Et Almentioning

confidence: 99%

Identification of R(−)‐isomer of efonidipine as a selective blocker of T‐type Ca²⁺ channels

Furukawa

Miura

Honda

et al. 2004

British J Pharmacology

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1 Efonidipine, a derivative of dihydropyridine Ca 2 þ antagonist, is known to block both L-and T-type Ca 2 þ channels. It remains to be clarified, however, whether efonidipine affects other voltagedependent Ca 2 þ channel subtypes such as N-, P/Q-and R-types, and whether the optical isomers of efonidipine have different selectivities in blocking these Ca 2 þ channels, including L-and T-types. 2 To address these issues, the effects of efonidipine and its R(À)-and S( þ )-isomers on these Ca 2 þ channel subtypes were examined electrophysiologically in the expression systems using Xenopus oocytes and baby hamster kidney cells (BHK tk-ts13). 3 Efonidipine, a mixture of R(À)-and S( þ )-isomers, exerted blocking actions on L-and T-types, but no effects on N-, P/Q-and R-type Ca 2 þ channels. 4 The selective blocking actions on L-and T-type channels were reproduced by the S( þ )-efonidipine isomer. 5 By contrast, the R(À)-efonidipine isomer preferentially blocked T-type channels. 6 The blocking actions of efonidipine and its enantiomers were dependent on holding potentials. 7 These findings indicate that the R(À)-isomer of efonidipine is a specific blocker of the T-type Ca 2 þ channel.

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“…After being marketed, however, the drug generated an unexpectedly high incidence of serious adverse reactions, such as bradyarrhythmias with ␤-blockers or rhabdomyolysis with statins, resulting from interactions. [3][4][5] It is self-evident that an adverse effect that occurs rarely (eg, once in several thousand patients) may be entirely undetected in a premarketing experience; indeed, one case of an unusual adverse effect before marketing may well go unrecognized. Nevertheless, such adverse effects, once recognized, may be so alarming as to result in the withdrawal of a drug; examples involve agents that produce hepatotoxicity 6 or marked QT prolongation and torsades de pointes.…”

Section: What Is Not Known About a Drug When It Is Marketed?mentioning

confidence: 99%

An Underrecognized Challenge in Evaluating Postmarketing Drug Safety

Roden

2005

Circulation

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he withdrawal of the cyclooxygenase (COX)-2-specific inhibitor rofecoxib (Vioxx; Merck) has generated a high-profile debate in the medical and lay press over when a signal suggesting the potential for harm from this drug was first apparent and what steps the medical community, the US Food and Drug Administration, and the pharmaceutical sponsor took and should have taken to address this issue. 1,2 This debate, however, has glossed over a fundamental problem that the withdrawal of the drug serves to highlight-not how best to deal with a potential signal once it is described, but rather how to identify such important and initially unanticipated effects after a drug is marketed.

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Drug-drug interactions of new active substances: mibefradil example

Cited by 78 publications

References 20 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Identification of R(−)‐isomer of efonidipine as a selective blocker of T‐type Ca²⁺ channels

An Underrecognized Challenge in Evaluating Postmarketing Drug Safety

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Drug-drug interactions of new active substances: mibefradil example

Cited by 78 publications

References 20 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Identification of R(−)‐isomer of efonidipine as a selective blocker of T‐type Ca2+ channels

An Underrecognized Challenge in Evaluating Postmarketing Drug Safety

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Product

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Identification of R(−)‐isomer of efonidipine as a selective blocker of T‐type Ca²⁺ channels