Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.
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PMID:Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion. 1809 17

Intravenous prostanoids are the backbone of therapy for advanced pulmonary arterial hypertension (PAH) and have improved long-term outcome and quality of life. Currently, two prostanoids are approved by the US Food and Drug administration for parenteral administration: epoprostenol (Flolan) and treprostinil (Remodulin). Chronic intravenous therapy presents considerable challenges for patients and caregivers who must learn sterile preparation of the medication, operation of the pump, and care of the central venous catheter. Patients are routinely counseled and advised regarding the risks of CR-BSIs and catheter care before central line insertion. Central line infections as well as bacteremia are well documented risks of chronic intravenous therapy and may significantly contribute to morbidity and mortality. Recent reports have suggested a possible increase in CR-BSI; therefore, the Scientific Leadership Council of the Pulmonary Hypertension Association decided to provide guidelines for good clinical practice regarding catheter care. Although data exits regarding patients with central venous catheters and the risk of blood stream infections in patients with cancer or other disorders, there is little data regarding the special needs of patients with pulmonary arterial hypertension requiring central venous access. These guidelines are extrapolated from the diverse body of literature regarding central venous catheter care.
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PMID:Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension. 1863 70

For some years drugs of several different classes have been available in Germany for the treatment of pulmonary arterial hypertension (PHT): prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors. To-date all relevant studies have consistently shown improvement in the 6-minute walking test (Iloprost, Treprostinil, Bosentan, Sitaxentan, Ambrisentan, Sildenafil). Results have not been consistent when the end-point has been an improvement in New York Heart Association (NYHA) class III or in the time to clinical worsening. Despite the good safety data for all drugs approved in Germany in the treatment of PHT, there are some clinically relevant interactions and significant contraindications. The availability of several options demands a detailed knowledge of studies to optimize safety and success in the treatment of PHT. Placebo-control mortality studies are not available for ethical reasons for those drugs that have been approved in Germany. But cohort analyses using historical survival rates have demonstrated a impressive improvement in survival of patients with PHT. Although there has been great progress in the treatment of PHT, a cure of this grave disease is not yet possible.
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PMID:[Specific drugs for the treatment of pulmonary arterial hypertension - current status]. 1881 92

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.
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PMID:Treprostinil for pulmonary hypertension. 1882 1

Treprostinil is a prostacyclin analog and has been used on idiopathic pulmonary arterial hypertension (PAH). There is only limited clinical experience using treprostinil to manage PAH in patients with end-stage liver disease (ESLD). We report three ESLD patients with PAH, who were treated with continuous intravenous treprostinil. A 59-year-old woman with ESLD secondary to alcoholic hepatitis had portopulmonary hypertension with mean pulmonary arterial pressure (mPAP) of 44 mmHg and transpulmonary gradient (TPG) of 23 mmHg. Treprostinil at 45 ng/kg/min for 6 months decreased mPAP to 23 (TPG to 8). A 53-year-old man had ESLD secondary to alcoholic hepatitis with PAH caused by multiple pulmonary embolisms (mPAP of 32 and TPG of 23). Treprostinil at 36 ng/kg/min for 3 months decreased mPAP to 23 and TPG to 14. Both patients underwent uneventful liver transplantation. A 48-year-old man had ESLD secondary to hepatitis C and portopulmonary hypertension with mPAP of 60 and TPG of 44. Two years after intravenous treprostinil at 106 ng/kg/min, his mPAP decreased to 44 and TPG to 30. These results demonstrate that for a selected group of ESLD patients with PAH, a continuous intravenous infusion of treprostinil appears to be safe and effective.
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PMID:Initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease. 1917 41

Treprostinil diethanolamine is an oral prostacyclin analog currently being evaluated for the treatment of pulmonary arterial hypertension (PAH). Treprostinil is metabolized primarily by cytochrome P450 (CYP) 2C8 with minor contribution from CYP2C9. It is expected that oral treprostinil will be administered with bosentan, approved for the treatment of PAH and known to induce CYP2C9 and 3A4. This study evaluated whether a drug interaction exists between oral treprostinil, bosentan, and its active metabolite Ro 48-5033 during co-administration. Twenty-four participants were randomized in a 3-way crossover study to oral treprostinil 1 mg twice daily, bosentan 125 mg twice daily, and oral treprostinil 1 mg twice daily and bosentan 125 mg twice daily. Treprostinil geometric mean ratios (GMRs) (90% confidence interval [CIs]) for steady-state AUC(0-12) and C(max) (combination/treprostinil) were 0.92 (0.83, 1.03) and 0.96 (0.83, 1.11), respectively, whereas bosentan GMRs (combination/bosentan) were 1.02 (0.95, 1.10) and 1.04 (0.94, 1.15), respectively, and Ro 48-5033 GMRs were 0.99 (0.93, 1.06) and 1.03 (0.94, 1.13). In conclusion, because the GMR and 90% CI are within the equivalence interval of 0.8 to 1.25, co-administration of oral treprostinil and bosentan did not result in a pharmacokinetic interaction for either agent.
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PMID:Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. 2013 11

Treprostinil, which is available for subcutaneous (SC) and intravenous (IV) administration, has demonstrated efficacy in increasing exercise capacity, reducing signs and symptoms of pulmonary arterial hypertension (PAH), and improving cardiopulmonary hemodynamics in patients with PAH; however, the infusion site pain commonly experienced with SC treprostinil has limited its use. Prospective and observational clinical studies have shown that the dose of SC treprostinil can be escalated at a higher rate than described in early clinical trials to achieve symptom relief, in part because of favorable tolerability of treatment and the apparent dose independence of site pain. In addition, pain management protocols that include non-pharmacologic and pharmacologic (i.e., topical and systemic) approaches provide analgesic relief from infusion site pain. With experience, physicians and patients have recognized that some infusion sites are better than others, and the frequency of site rotation can be reduced to improve tolerability. Dosing to achieve rapid onset of efficacy and proactively managing infusion site pain enhance the likelihood for a patient with PAH to maintain and derive benefit from SC treprostinil therapy.
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PMID:Subcutaneous treprostinil in pulmonary arterial hypertension: Practical considerations. 2085 20

Treprostinil is a prostacyclin derivative approved for the treatment of pulmonary arterial hypertension by intravenous, subcutaneous and inhalational administration. Unlike its precursor epoprostenol, treprostinil is chemically stable at room temperature and neutral pH, and its plasma half-life is longer. In addition to promoting smooth muscle relaxation in the pulmonary vasculature, treprostinil has suppressive effects on platelet aggregation, smooth muscle proliferation and inflammation. A Phase III study, investigating the addition of inhaled treprostinil to oral bosentan or sildenafil, confirmed significant improvements in exercise capacity and quality of life. This review examines the pharmacodynamics, pharmacokinetics, clinical efficacy and safety of inhaled treprostinil for use in pulmonary arterial hypertension.
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PMID:Inhaled treprostinil for the treatment of pulmonary arterial hypertension. 2278 40

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.
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PMID:Differential effects of Selexipag [corrected] and prostacyclin analogs in rat pulmonary artery. 2291 43

Treprostinil diolamine sustained release (UT-15C SR) is being evaluated as an oral therapy for pulmonary arterial hypertension. This study evaluated the pharmacokinetics (PKs) of treprostinil following administration of UT-15C SR in subjects with end-stage renal disease (ESRD) compared with healthy subjects with normal renal function (NRF) and the effect of hemodialysis on the PK parameters of treprostinil. Eight ESRD subjects (requiring dialysis, mean creatinine clearance = 11.5 mL/min) received 2 single doses of 1 mg of UT-15C SR (separated by 2 weeks), with the first dose given immediately after dialysis and the second given 4 hours before the start of dialysis. Eight NRF subjects received a single dose of 1 mg of UT-15C SR. The median Cmax, AUC0-inf, and t1/2 of treprostinil were 680 pg/mL, 3240 hours pg/mL, and 2.35 hours, respectively, in ESRD subjects dosed after dialysis and were 551 pg/mL, 3152 hours pg/mL, and 2.05 hours, respectively, in ESRD subjects dosed before dialysis. In comparison, corresponding values were 730 pg/mL, 3726 hours pg/mL, and 3.54 hours, respectively, in NRF subjects. UT-15C SR of 1 mg was well tolerated by NRF and ESRD subjects. The most frequent adverse event was headache and nausea. There was no substantial difference in treprostinil PKs between ESRD and NRF subjects following administration of UT-15C SR tablets. Hemodialysis did not have clinically important effect on treprostinil PK in ESRD subjects.
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PMID:Pharmacokinetics of treprostinil diolamine in subjects with end-stage renal disease on or off dialysis. 2318 23


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