Primidone

Primidone

Effect of Primidone on Dentate Nucleus gamma-Aminobutyric Acid Concentration in Patients With Essential Tremor.[Pubmed:26757316]

Clin Neuropharmacol. 2016 Jan-Feb;39(1):24-8.

OBJECTIVES: It is not known whether current use of the medication Primidone affects brain gamma-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking Primidone versus 26 ET patients not taking Primidone. METHODS: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus. RESULTS: The right dentate GABA concentration was similar in the 2 groups (2.21 +/- 0.46 [on Primidone] vs 1.93 +/- 0.39 [not on Primidone], P = 0.15), as was the left dentate GABA concentration (1.61 +/- 0.35 [on Primidone] vs 1.67 +/- 0.34 [not on Primidone], P = 0.72). The daily Primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively). CONCLUSIONS: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily Primidone and 26 ET patients not taking Primidone. Furthermore, there was no association between daily Primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on Primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, Primidone usage would not confound interpretation of the results.

Photochemical degradation of atenolol, carbamazepine, meprobamate, phenytoin and primidone in wastewater effluents.[Pubmed:24798495]

J Hazard Mater. 2015 Jan 23;282:216-23.

The photochemical degradation of five pharmaceuticals was examined in two secondary wastewater effluents. The compounds, which included atenolol, carbamazepine, meprobamate, phenytoin and Primidone, were evaluated for both direct and sensitized photolysis. In the two wastewaters, direct photolysis did not lead to significant compound degradation; however, sensitized photolysis was an important removal pathway for the five pharmaceuticals. Upon solar irradiation, hydroxyl radical (HO) was quantified using the hydroxylation of benzene and singlet oxygen ((1)O2) formation was monitored following the degradation of furfuryl alcohol. Degradation via sensitized photolysis was observed following five-day exposures for atenolol (69-91%), carbamazepine (67-98%), meprobamate (16-52%), phenytoin (44-85%), and Primidone (34-88%). Varying removal is likely a result of the differences in reactivity with transient oxidants. Averaged steady state HO concentrations ranged from 1.2 to 4.0x10(-16)M, whereas the concentrations of (1)O2 were 6.0-7.6x10(-14)M. Partial removal due to presence of HO indicates it was not the major sink for most compounds examined. Other transient oxidants, such as (1)O2 and triplet state effluent organic matter, are likely to play important roles in fates of these compounds.

Primidone inhibits TRPM3 and attenuates thermal nociception in vivo.[Pubmed:28106668]

Pain. 2017 May;158(5):856-867.

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant Primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 muM and marked specificity for TRPM3. Most prominently, Primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of Primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

Primidone Therapy for Essential Vocal Tremor.[Pubmed:26660910]

JAMA Otolaryngol Head Neck Surg. 2016 Feb;142(2):117-21.

IMPORTANCE: Essential vocal tremor is difficult to treat. An effective pharmacologic treatment could allow patients to avoid or decrease the frequency or dosage of botulinum neurotoxin injections. OBJECTIVE: To evaluate the efficacy of Primidone in the treatment of essential vocal tremor. DESIGN, SETTING, AND PARTICIPANTS: Medical records of all patients with a primary or secondary diagnosis of laryngeal spasm or essential tremor treated with Primidone between June 1, 2012, and March 21, 2014, at a tertiary care medical center were reviewed. Data analysis occurred in April 2014. MAIN OUTCOMES AND MEASURES: Duration of therapy, improvement of symptoms, and whether the patient subsequently initiated botulinum neurotoxin therapy. RESULTS: All 30 patients were female (mean [SD] age, 71.9 [11.8] years). Mean (SD) therapy duration was 5.25 (7.22) months. Nine patients (30%) had other vocal conditions (4 had coexisting spasmodic dysphonia, 4 had laryngopharyngeal reflux disease, and 1 had muscle tension dysphonia). Twelve (40%) had previously undergone treatment. Fourteen of 26 patients (54%) reported an improvement in their vocal symptoms, and 16 of 29 (55%) did not discontinue Primidone therapy. Twenty-two of 30 patients (73%) experienced adverse effects. Therapy was discontinued by 11 of 21 patients (52%) who experienced adverse effects and 2 of 8 patients (25%) who did not report adverse effects (P = .24) (1 patient who had adverse effects was missing data on discontinuation of therapy). Sixteen patients (53%) subsequently initiated botulinum toxin therapy, including 5 of 14 patients (36%) who reported clinical improvement with Primidone therapy and 7 of 12 patients (58%) who did not report improvement (P = .43). CONCLUSIONS AND RELEVANCE: Primidone therapy was an effective pharmacologic treatment for essential vocal tremor in 14 of 26 patients in this case series, providing an alternative to botulinum neurotoxin therapy.

Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdala-kindled rats.[Pubmed:2721568]

Eur J Pharmacol. 1989 Mar 21;162(2):309-22.

In amygdala-kindled rats, single-dose administration of Primidone did not reduced seizure activity 2 h after i.p. injection, i.e. when plasma levels of the drug were highest, but significant anticonvulsant effects were found 24 h after administration, when the drug was almost completely eliminated. During chronic treatment with Primidone, marked anticonvulsant efficacy was determined after 3-15 days of three times daily treatment with 50 mg/kg i.p., indicating that this effect was due to the accumulation of metabolites, especially phenobarbital. Maximum anticonvulsant activity attained during chronic Primidone medication was almost equal to that found during chronic treatment of kindled rats with phenobarbital, 30 mg/kg once daily. However, drug plasma level determinations during both treatments showed that on days when both treatments were about equieffective, levels of metabolically derived phenobarbital in the Primidone group were significantly lower than levels in rats treated with phenobarbital alone, thus indicating that Primidone potentiated the anticonvulsant effect of metabolically derived phenobarbital. Additional evidence for potentiation of the anticonvulsant effect of phenobarbital by Primidone was found in single dose experiments with combined injection of both drugs, whereas side-effects, such as ataxia and muscle relaxation, induced by phenobarbital were not increased by combined treatment with Primidone. Accordingly, side-effects occurring during chronic Primidone treatment were less pronounced than side-effects found during chronic phenobarbital medication. In both treatment groups, tolerance to the anticonvulsant effect developed during the 2nd week of administration, while attenuation of side-effects took place already in the first week. Following cessation of treatment, signs of physical dependence, such as withdrawal hyperexcitability and weight loss, were observed. The data indicate that, at least in kindled rats, the anticonvulsant activity of Primidone during chronic treatment is due to the combined and possibly synergistic actions of Primidone and metabolically derived phenobarbital.