Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report two patients with refractory epilepsy who developed unilateral painful gynecomastia and lower extremity pain (one of them localized and the other one diffuse), shortly after receiving Pregabalin (PGB). Neither of them had previous endocrinologic problems or complaints about pain on their medical history. PGB was stopped in one patient and reduced in the other one, with complete disparition of the symptoms in the following weeks in both patients. This supports the hypothesis that gynecomastia could be a drug-induced and easy to manage secondary effect of PGB, with a higher incidence than observed on previous clinical trials.
 ...
PMID:Two cases of painful gynecomastia and lower extremity pain in association with pregabalin therapy. 1698 76

Pregabalin, ((S)-3-(aminomethyl)-5-methylhexanoic acid, also known as (S)-3-isobutyl GABA, Lyricatrade mark) is approved for treatment of certain types of peripheral neuropathic pain and as an adjunctive therapy for partial seizures of epilepsy both the EU and the USA and also for generalized anxiety disorder in the EU. Though pregabalin binds selectively to the alpha(2)-delta (alpha(2)-delta) auxiliary subunit of voltage-gated calcium channels, the cellular details of pregabalin action are unclear. The high density of alpha(2)-delta in skeletal muscle fibers raises the question of whether pregabalin alters excitation-contraction coupling. We used the mouse soleus neuromuscular junction from mice containing an artificially mutated alpha(2)-delta Type 1 protein (R217A) as a model to examine the effect of pregabalin. Pregabalin reduced nerve-evoked muscle contractions by 16% at a clinically relevant concentration of 10 muM in wildtype mice. When acetylcholine receptors were blocked with curare, pregabalin had no effect on contraction from direct stimulation of muscle, suggesting a lack of drug effects on contraction coupling. Our data are consistent with pregabalin having no effect on striated muscle L-type calcium channel function. However, in mice expressing mutant (R217A) alpha(2)-delta Type 1, there was no significant effect of pregabalin on nerve-evoked muscle contraction. We propose that pregabalin reduces presynaptic neurotransmitter release without altering postsynaptic receptors or contraction coupling and that these effects require high affinity binding to alpha(2)-delta Type 1 auxiliary subunit of presynaptic voltage-gated calcium channels.
 ...
PMID:Pregabalin action at a model synapse: binding to presynaptic calcium channel alpha2-delta subunit reduces neurotransmission in mice. 1706 82

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (alpha2-delta-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the alpha2-delta-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
 ...
PMID:Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. 1708 53

Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2-delta (alpha2-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha2-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.
 ...
PMID:Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. 1712 31

Pregabalin is a novel central nervous system (CNS) drug with no interaction at benzodiazepine or GABA receptor. Its mechanism of action is correlated with its high affinity for the alpha/delta submit of the voltage-dependant CNS calcium channel. Pregabalin is rapidly absorbed with at least 90% bioavailable irrespective of dose, does not bind to plasma proteins and is excreted virtually unchanged by the kidneys. Pharmacokinetics are linear and predictable across the therapeutic dose range (150-600 mg/ day). Pregabalin is indicated, like gabapentin, in the treatment of neuropathic pain syndromes like post-herpetic neuralgia (PHN) and diabetic polyneuropathy (DPN). Efficacy in other neuropathic pain syndromes need further investigations. This paper emphasizes advantages and disadvantages on a clinical point of view.
 ...
PMID:[Pregabalin (Lyrica) and neuropathic pain syndromes]. 1725 24

Pregabalin is an alpha(2)-delta ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain. Pregabalin is the second of only two medications that are US FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is also the third medication for the treatment of postherpetic neuralgia. Currently, there are three pivotal clinical studies documenting the efficacy and safety of pregabalin for the treatment of painful diabetic neuropathy, and three clinical studies regarding the use of pregabalin for pain associated with postherpetic neuralgia. This article will review each of these studies, as well as provide a clinical review for the use of pregabalin in the treatment of neuropathic pain.
 ...
PMID:Pregabalin for the treatment of painful neuropathy. 1714 73

Pregabalin is a new analog of the neurotransmitter gamma-aminobutyric acid (GABA). It is an alpha2-delta (alpha2-delta) ligand that has analgesic, anticonvulsant, and anxiolytic activity. Alpha2-delta is an auxiliary protein associated with voltage-gated calcium channels. Pregabalin binds potently to the alpha2-delta subunit resulting in modulation of calcium channels and reduction in the release of several neurotransmitters, including glutamate, norepinephrine, serotonin, dopamine, and substance P. This review discusses the pharmacology of this medication as well as available studies in patients.
Pain Pract 2005 Jun
PMID:Pregabalin for pain management. 1717 55

Antiepileptic drugs (AEDs) are commonly utilized for nonepileptic conditions, including various psychiatric disorders and pain syndromes. Evidence for their benefit in these nonepileptic conditions varies widely among different drugs, but there is, in general, a paucity of published multicenter randomized double-blind trials. Variable levels of evidence suggest that lamotrigine and the vagal nerve stimulator have antidepressant properties. Carbamazepine, valproate, lamotrigine, and oxcarbazepine appear to have mood stabilizing properties while gabapentin, pregabalin, and tiagabine have anxiolytic benefits. Barbiturates, topiramate, and possibly phenytoin may precipitate or exacerbate depression. Underlying depression and anxiety symptoms may be exacerbated by levetiracetam, while psychotic symptoms have rarely been reported with topiramate, levetiracetam, and zonisamide. Pregabalin, gabapentin, carbamazepine, and oxcarbazepine have been used to treat neuropathic pain such as postherpetic neuralgia, and diabetic polyneuropathy. Topiramate and divalproex sodium have utility in the prophylaxis or acute treatment of migraine. Further rigorous studies are needed to clarify the utility of AEDs in nonepileptic conditions.
 ...
PMID:Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. 1719 18

The term 'Ca2+ channel alpha2delta ligands' has recently been applied to an evolving drug class that includes gabapentin (Neurontin) and pregabalin (Lyrica), and reflects significant progress over the past decade in elucidating the mechanism of action of these drugs: a novel, specific action at one of the subunits constituting voltage-sensitive Ca2+ channels. Binding of these ligands to the alpha2delta subunit is considered to explain their usefulness in treating several clinical disorders, including epilepsy, pain from diabetic neuropathy, postherpetic neuralgia and fibromyalgia, and generalized anxiety disorder. The evidence indicates a relationship between alpha2delta subunit binding and the modulation of processes that subserve neurotransmission. This modulation is characterized by a reduction of the excessive neurotransmitter release that is observed in certain neurological and psychiatric disorders.
 ...
PMID:Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. 1722 65

Pregabalin binds to the voltage-dependent calcium channel alpha2delta subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 and L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED50 of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The alpha2delta subunit might be less involved in the CA in SIP.
 ...
PMID:Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain. 1732 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>