Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma
Л К МошетоваM.M. SoshinaК.I. TurkinaЕ. А. ГришинаZhannet A. SozaevaА. А. КачановаК. А. АкмаловаDmitriy V. IvashchenkoМихаил Сергеевич ЗастрожинВладимир Петрович ФисенкоД. А. Сычев
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Abstract Objectives Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). Methods 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). Results The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). Conclusions CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.Cite
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Effects of D-timolol and L-timolol on IOP were compared with two rabbit models. When the drug solution was injected into vortex vein, 1% D-timolol produced ocular hypotension just like 0.5% L-timolol except D-timolol was less potent than L-timolol to lower the IOP. On the other hand, when 0.5% of D-timolol and L-timolol were instilled into the rabbit eye on IOP recovery model both agents showed equipotency to delayed the IOP recovery. Effects of D-timolol and L-timolol on ocular blood flow were also studied with two rabbit models. D-Timolol at 0.5% did not affect the ocular pulsatile blood flow measured with Langham's pneumatonometer whereas 0.5% L-timolol significantly suppressed it. D-Timolol (0.5%) was found to increase retinal and choroidal blood flows measured with laser Doppler method whereas L-timolol suppressed it. These results indicate that D-timolol though less potent than L-timolol to lower IOP, is superior over L-timolol to improve the blood flow in retina and choroid.
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It is assumed that S-timolol can produce more severe systemic adverse reactions than R-timolol. The aim of this study was to estimate the intraocular pressure-lowering effect of RS-timolol in comparison to R-timolol and S-timolol in water-loaded rabbits.Ocular hypertension was provoked in rabbits by orogastric water loading. Topical administration of one of three timolol solutions: 0.85%, RS-timolol, or 3% R-timolol, or 0.5% S-timolol was performed to the right eyes 40 min before starting the water loading procedure. Left eyes served as a control group. Intraocular pressure was measured before and 30, 60, 90, 120 min after the water loading.Intraocular pressure-lowering effect of all three timolol solutions was comparable.RS-timolol can be effective for lowering intraocular pressure in rabbits.
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Pharmacogenetic tests that allow the clinician to individualize dosage to the patient according to the activity of their metabolism are described. Pharmacogenetic aspects of the oxidative phase of antipsychotic biotransformation are reviewed. Depending on the rate of metabolism and enzyme activity of cytochrome (CYP) family (especially, CYP1 A2, CYP2D6 and CYP3A4) people can be divided into three groups: poor, rapid and ultrarapid metabolizers. Pharmacogenetic testing before the administration of therapy can be useful for choosing the optimal drug and its effective and acceptable dose for the individual patient. Along with the advantages and possibilities of pharmacogenetic testing, its difficulties and pitfalls are discussed. The authors emphasized that the investigation of cytochrome-based metabolism is only one of the components of individualized medicine.
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Purpose Ophthalmic timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% timolol in patients scheduled for a cataract operation. Results The concentration in the aqueous humor was 210 ± 175 ng/ml (mean ± SD) two hours after administration of timolol 0.1% hydrogel and 538 ± 304 ng/ml after aqueous 0.5% timolol. In the aqueous 0.5% timolol group more patients had unnecessarily high concentrations of timolol in the aqueous humor. Beta 1-receptors and Beta 2-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of timolol in the aqeuous 0.5% timolol group. A similar correlation was observed between age and concentration of timolol in the aqeuous 0.5% timolol group. Conclusion In contrast to the conventional aqueous 0.5% timolol, 0.1% timolol hydrogel caused only slight inter-individual variation in timolol concentration in the aqueous humor.
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Genetic variants in pharmacokinetic genes can alter the effectiveness and increase the risks of using analgesics to treat pain. The purpose of this retrospective study is to describe the clinical experiences that led to pharmacogenetic testing of pediatric pain management program patients for alterations in the CYP2D6, CYP2C19, and CYP2C9 genes and correlate the analgesic efficacy and adverse analgesic effects with the gene-specific findings and Metabolic Reserve (MR) index.Nineteen patients were referred for pharmacogenetic testing between February 2010 and December 2013 due to analgesic ineffectiveness or adverse analgesic effects. CYP2D6, CYP2C19, and CYP2C9 functional status was inferred from genotyping; and MR calculated. Data from the available inpatient and outpatient medical records from January 2007 to May 2014 for these patients were reviewed and extracted to characterize patient analgesic response phenotype.Significant CYP2D6 genetic variants were identified in 16 of the 19 (84%) patients: 4 were ultra-rapid metabolizers, 8 were deficient, 3 were poor metabolizers, and 1 was CYP2D6 null metabolizer. Of the 3 patients with functional CYP2D6 status, 2 were CYP2C19 null metabolizers. The MR scores ranged from 3.0 to 7.0, with a bimodal distribution with high frequencies corresponding to 4.0/4.5 and 7.0.Clinical evaluation of analgesic ineffectiveness and adverse effects led to the high likelihood of identifying patients with CYP2D6, CYP2C19, and CYP2C9 alleles associated with alterations in analgesic metabolism. Further research is needed to integrate pharmacogenetic and clinical information into anticipatory guidance for pharmacogenetic testing and analgesic prescribing to children with pain.
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Abstract: Propranolol has become the treatment of choice of large and complicated infantile hemangiomas. There is a controversy concerning the safety of systemic propranolol. Here we show that topical use of the beta‐blocker timolol can also inhibit the growth and promote regression of infantile hemangiomas. In this case series we treated 11 infantile hemangiomas in nine children including six preterm babies with the nonselective betablocker timolol. A timolol containing gel was manufactured from an ophthalmic formulation of timolol 0.5% eyedrops. This gel was applied using a standardized occlusive dressing (Finn‐Chambers) containing approximately 0.25 mg of timolol. In all infants topical timolol was associated with growth arrest, a reduction in redness and thickness within the first 2 weeks. Seven hemangiomas showed almost complete resolution, and four became much paler and thinner. No data are available on the transdermal absorption of timolol. Even supposing complete absorption of timolol from the occlusive dressing, a maximum dose of 0.25 mg of timolol would result per day and hemangioma. Regression of infantile hemangiomas treated using 0.5% timolol gel in this case series occurred earlier than spontaneous regression which is generally not observed before the age of 9–12 months. The promising results need to be verified in prospective randomized trials on topical beta blocker administration for infantile hemangiomas which should address dose, duration, and mode of application.
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This case report highlights the importance of pharmacogenetic testing in the treatment of attention deficit hyperactive disorder (ADHD). A 6-year-old boy diagnosed with ADHD was prescribed methylphenidate 5 mg twice daily (7 am and noon) and the family was compliant with administration of this medication. On the first day of treatment, the patient had an adverse reaction, becoming disobedient, more mischievous, erratic, resistant to discipline, would not go to sleep until midnight, and had a poor appetite. The All-In-One PGX (All-In-One Pharmacogenetics for Antipsychotics test for CYP2D6, CYP2C19, and CYP2C9) was performed using microarray-based and real-time polymerase chain reaction techniques. The genotype of our patient was identified to be CYP2D6*2/*10, with isoforms of the enzyme consistent with a predicted cytochrome P450 2D6 intermediate metabolizer phenotype. Consequently, the physician adjusted the methylphenidate dose to 2.5 mg once daily in the morning. At this dosage, the patient had a good response without any further adverse reactions. Pharmacogenetic testing should be included in the management plan for ADHD. In this case, cooperation between the medical team and the patients' relatives was key to successful treatment.
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