Journal of clinical pharmacology
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Randomized Controlled Trial Multicenter Study
Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.
Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. ⋯ Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.
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Heart failure (HF) impacts an estimated 5.7 million Americans, and its prevalence is projected to increase to more than 8 million Americans in the next 15 years. Key clinical trials have established an evidence-based foundation for treatment of heart failure with reduced ejection fraction (HFrEF). Ivabradine and sacubitril/valsartan, which inhibit the f-channel and the angiotensin receptor and neprilysin, respectively, were recently approved by the Food and Drug Administration for HFrEF. ⋯ The place of therapy with ivabradine and sacubitril/valsartan is defined by these trials and their interplay with guideline-directed medical therapy. Ivabradine and sacubitril/valsartan increase pharmacotherapy options for the treatment of HFrEF but are not yet first-line agents. Clinical application will be better defined in the coming years as practitioners increase their familiarity with ivabradine and sacubitril/valsartan.
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Clinical Trial
Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics.
The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. ⋯ Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine.
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Meta Analysis Comparative Study
Comparison of dexmedetomidine and clonidine as adjuvants to local anesthetics for intrathecal anesthesia: A meta-analysis of randomized controlled trials.
The authors performed a meta-analysis to compare the characteristics of clonidine and dexmedetomidine as adjuvants to local anesthetic in intravertebral anesthesia. Four investigators independently searched electronic databases for randomized trials comparing the characteristics of clonidine vs dexmedetomidine as adjuvants to local anesthetic on adults. The endpoints were onset of analgesia, sensory and motor block, and duration of analgesia. ⋯ The duration of stable sensory block, duration of overall sensory block, and the time before the need for analgesic requirements were significantly extended, 10.8 minutes, 22.3 minutes, and 38.6 minutes, respectively, when dexmedetomidine was used as an adjuvant to local anesthetics (bupivacaine or ropivacaine). No significant differences were detected in the motor block characteristics and the time to achieve peak sensory level between dexmedetomidine and clonidine as adjuvants to local anesthetics. Compared to clonidine, the addition of dexmedetomidine as an adjuvant to local anesthetics is associated with earlier, prolonged sensory block characteristics and later need for analgesic requirements.
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X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. ⋯ A PK-PD model with a maximum effect (Emax ) and a time-varying effective concentration to reach 50% of Emax (EC50,t ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.