Pregabalin Research Articles

The Opening Effect of Pregabalin on ATP‐Sensitive Potassium Channels in Differentiated Hippocampal Neuron–derived H19‐7 Cells

Adenosine triphosphate (ATP)-sensitive K+ (KATP) channels can couple an intracellular metabolic state to an electrical activity, which is important in the control of neuronal excitability and seizure propagation. We investigated whether the newer antiepileptic drug, pregabalin (PGB), could exert effects on KATP channels in differentiated hippocampal neuron-derived H19-7 cells. The inside-out configuration of the patch-clamp technique was used to investigate KATP channel activities in H19-7 cells in the presence of PGB. Effects of various compounds known to alter KATP channel activities were compared. The activity of KATP channels in these cells was characterized. The single-channel conductance from a linear current-voltage relation was 78 +/- 2 pS (n = 8) with a reversal potential of 63 +/- 2 mV (n = 8), similar to that of KATP channels reported in pancreatic beta cells. 2,4-Dinitrophenol activated channel activity, but the further addition of glucose (20 mM) or glibenclamide (30 microM) could offset these increments. PGB significantly opened these KATP channel activities in a concentration-dependent fashion with a median effective concentration (EC50) value of 18 microM. A significant increase was noted in the mean open lifetime of KATP channels in the presence of PGB (1.71 +/- 0.04 to 5.62 +/- 0.04 ms). This study suggests that in differentiated hippocampal neuron-derived H19-7 cells, the opening effect on KATP channels could be one of the underlying mechanisms of PGB in the reduction of neuronal excitability.

Antidepressants and Antiepileptic Drugs for Chronic Non-Cancer Pain

The development of newer classes of antidepressants and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain. These drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. The actions of antidepressants and antiepileptic drugs differ in neuropathic and non-neuropathic pain, and agents within each medication class have varying degrees of efficacy. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and certain novel antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain. The analgesic effect of these drugs is independent of their antidepressant effect and appears strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is comparable; tolerability also is comparable, but safety and side effect profiles differ. Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain. Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia. Copyright © 2005 American Academy of Family Physicians.) Permission from the AAFP was granted to publish this article in the hardcopy only. Kindly refer to www.aafp.org or subscribe to the hardcopy of South African Family Practice. (SA Fam Pract 2005;47(3): 30-36)

Therapy underused despite range of options in depression

Therapy underused despite range of options in depression

Model suggests pregabalin better value that levetiracetam in Spain

Model suggests pregabalin better value that levetiracetam in Spain

Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy

Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.

Pfizer has launched pregabalin [Lyrica] capsules in Canada

Pfizer has launched pregabalin [Lyrica] capsules in Canada

Mediation of Highly Concentrative Uptake of Pregabalin by L-Type Amino Acid Transport in Chinese Hamster Ovary and Caco-2 Cells

Pregabalin (PGB) is a novel drug under development for the treatment of epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. In this study, we investigated PGB transport in rats, mammalian cell lines, and Xenopus laevis oocytes. In contrast to gabapentin (GBP), PGB absorption in rats showed unique linear pharmacokinetics. PGB entered CHO and Caco-2 cells predominately via Na(+)-independent processes. Uptake of PGB was mutually exclusive with leucine, GBP and 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid, the substrates preferential for system L. The preloaded PGB in CHO cells was exchangeable with leucine, but at a lower exchange rate than that of leucine and GBP. Dixon plots showed competitive inhibition of leucine uptake by PGB, with a K(i) value very close to the K(m) value for PGB uptake (377 versus 363 microM). At an extracellular concentration of 300 microM, the intracellular PGB concentration in CHO cells reached 1.5- and 23-fold higher than that of GBP and leucine, respectively. In contrast, at clinically relevant concentrations, PGB seemed not to interact with GABA transport in GAT1, GAT2, and GAT3 cell lines, system y(+), b(0,+), B(0,+), and B(0) transport activities in Caco-2 and NBL-1 cells, and the b(0,+)-like transport activity in rBAT cRNA-injected X. laevis oocytes. Taken together, these results suggest that L-type transport is the major transport route for PGB and GBP uptake in mammalian cells. The differential affinity of PGB and GBP at L-type system leads to more concentrative accumulation of PGB than GBP, which may facilitate PGB transmembrane absorption in vivo.

Pregabalin, Newly Approved for Pain, Also Is Effective for Epilepsy

Pregabalin, Newly Approved for Pain, Also Is Effective for Epilepsy

Simultaneous high-performance liquid chromatographic analysis of pregabalin, gabapentin and vigabatrin in human serum by precolumn derivatization with o-phtaldialdehyde and fluorescence detection

A rapid, simple and robust method is presented for the simultaneous determination of the γ-amino- n-butyric acid (GABA) derivatives pregabalin (PGB), gabapentin (GBP) and vigabatrin (VGB) in human serum by high-performance liquid chromatography (HPLC). Serum is deproteinized with trichloroacetic acid and aliquots of the supernatant are precolumn derivatized with o-phtaldialdehyde (OPA) and 3-mercaptopropionic acid. Separation is achieved on a Alltima 3C18 column using isocratic elution; the drugs are monitored using fluorescence detection. Norvaline is used as an internal standard. Within-day precision (COV; n = 10) is 1.2% for PGB (serum concentration 10.0 mg/l), 1.1% for GBP (serum concentration 15.8 mg/l) and 0.3% for VGB (serum concentration 15.5 mg/l). The method is linear up to at least 63 mg/l for PGB, 40 mg/l for GBP and 62 mg/l for VGB. Lower limits of quantitation (LOQ) are 0.13 mg/l for PGB, 0.53 mg/l for GBP and 0.06 mg/l for VGB. No interferences were found from commonly coadministered antiepileptic drugs (AEDs) and from endogenous amino acids. Experimental design in combination with statistical evaluation (ANOVA) was used to study the robustness of chromatography and sample preparation. The method is very suitable for routine therapeutic drug monitoring and for pharmacokinetic studies.

Pregabalin: Insights from Randomized Trials

Pregabalin: Insights from Randomized Trials

Efficacy of Pregabalin in Social Anxiety Disorder

The novel compound pregabalin is clinically related to gabapentin, although the compounds have pharmacologic differences. In recent studies, pregabalin

Novel therapeutic agents: Pregabalin in the management of chronic neuropathic pain (NeP): A novel evaluation of flexible and fixed dosing

This 12-week, randomized, double-blind, placebo-controlled study in 338 patients with chronic NeP due to diabetic peripheral neuropathy (DPN, N=249) or postherpetic neuralgia (PHN, N=89) evaluated fixed dose pregabalin (PGB) (BID, 300 mg/day for 1 week and 600 mg/day thereafter) and flexible dose PGB (BID, 150 - 600 mg/day with weekly adjustments based on individual response and tolerability [median dose=457 mg/day]) versus placebo. Of the 338 patients enrolled, 65 (19.2%), 141 (41.7%) and 132 (39%) were randomized to placebo, PGB flexible dose and fixed dose groups respectively. Patients completed daily pain and sleep diaries, rating pain and sleep interference every morning upon awakening. The primary efficacy parameter was mean pain score at endpoint (mean of the last 7 diary entries). Response to treatment (>50% reduction in pain score), weekly mean pain score and sleep interference were also evaluated. Intent-to-treat analysis showed that both flexible and fixed dose PGB significantly reduced mean pain score at endpoint versus placebo (P=0.002 and P<0.001, respectively). Response to treatment was noted for 48% and 52% of patients in the PGB flexible and fixed dose treatment groups, respectively, versus 24% for placebo (P<0.001 in each case). Both PGB treatment groups were significantly superior to placebo in improving sleep interference (p<0.001). The most common adverse events (AEs) for PGB-treated patients were dizziness, weight gain (not affecting diabetes control), peripheral edema (non CV/renal origin) and somnolence. Fifty patients discontinued due to treatment-related AEs (5 placebo, 17 flexible dose PGB, and 28 fixed dose PGB). These results are consistent with previous studies and further support the efficacy, tolerability and safety of PGB for treatment of chronic NeP pain due to DPN or PHN. PGB dosing aimed at an optimal balance of efficacy and tolerability provides significant pain relief and may reduce the risk for AEs and therapy discontinuation.

S.13.04 Pregabalin: A mechanistically and therapeutically novel anxiolytic

S.13.04 Pregabalin: A mechanistically and therapeutically novel anxiolytic

Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat.

To determine whether a pharmacologic treatment could delay or prevent the epileptogenesis induced by status epilepticus (SE) through the protection of some brain areas, we studied the effects of the long-term exposure to pregabalin (PGB) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. SE was induced in adult and 21-day-old (P21) rats. At 20 min after pilocarpine, rats received 50 mg/kg PGB (pilo-preg) or saline (pilo-saline). PGB treatment was given daily at the dose of 50 mg/kg for 7 days after SE and at 10 mg/kg from day 8 until killing. Neuronal damage was assessed in hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from adult and P21 animals killed 6 days after SE. The number of glial fibrillary acidic protein (GFAP)-reactive astrocytes was tested by immunohistochemistry in sections adjacent to those used for cell counting. The latency to spontaneous seizures was controlled by visual observation and EEG recording. PGB induced neuroprotection in layer II of piriform cortex and layers III-IV of ventral entorhinal cortex of adult rats, whereas no hippocampal region was protected. In P21 rats, damage was limited to the hilus and similar in pilo-preg and pilo-saline animals. The number of GFAP-positive astrocytes was higher in pilocarpine- than in saline-treated rats. It was decreased in pilo-preg compared with pilo-saline rats in layer II of the piriform cortex. Adult pilo-preg rats became epileptic after a longer latency (39 days) than did pilo-saline rats (22 days). These data underline the antiepileptogenic consequences of long-term PGB treatment, possibly mediated by the protection of piriform and entorhinal cortices in the lithium-pilocarpine model of epilepsy.

Health of prisoners admitted to and discharged from Bedford Prison.

The age, smoking and drinking habits, active health problems, and occupational fitness of prisoners entering Bedford prison, and the health and willingness of prisoners being discharged from prison to take a letter to their general practitioner were surveyed. This group of men had a high level of illness, neglected their health, and had a high alcohol intake. Fewer problems were found than in a survey in New York City. Many prisoners with active medical problems on discharge from prison were unwilling to take a letter to their own general practitioner.