Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other respiratory system products, ATC code R07AX01.
Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular -monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation.
Mixture NO 800 ppm in Nitrogen appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, mixture can improve oxygenation (as indicated by significant increases in PaO2).

The efficacy of Mixture NO 800 ppm in Nitrogen has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of aetiologies.

In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 % O2 with (n=114) or without (n=121) nitric oxide most with an initial concentration of 20 ppm with weaning as possible to lower doses with a median duration of exposure of 40 hours. The objective of this double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO). Neonates with less than a full response at 20 ppm were evaluated for a response to 80 ppm nitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (the prospectively defined primary endpoint) showed a significant advantage for the nitric oxide treated group (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher dose of nitric oxide. The adverse events collected occurred at similar incidence rates in both groups.
Follow-up exams at 18-24 months of age were similar between the two groups with respect to mental, motor, audiologic, and neurologic evaluations.

In the CINRGI trial, 186 term- and near-term neonates with hypoxic respiratory failure and without lung hypoplasia were randomised to receive either Mixture NO 800 ppm in Nitrogen (n=97) or nitrogen gas (placebo; n=89) with an initial dose of 20 ppm weaning to 5 ppm in 4 to 24 hours with median duration of exposure of 44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewer neonates in the Mixture NO 800 ppm in Nitrogen group required ECMO compared to the control group (31 % vs. 57 %, p<0.001). The Mixture NO 800 ppm in Nitrogen group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with Mixture NO 800 ppm in Nitrogen, 2(2 %) were withdrawn from study drug due to methaemoglobin levels >4 %. The frequency and number of adverse events were similar in the two study groups.

In patients undergoing heart surgery, an increase in pulmonary artery pressure due to pulmonary vasoconstriction is frequently seen. Inhaled nitric oxide has been shown to selectively reduce pulmonary vascular resistance and reduce the increased pulmonary artery pressure. This may increase the right ventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenation in the pulmonary circulation.

In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure were randomised to receive either Mixture NO (n=395) in a dose of 5 ppm or nitrogen (placebo n=400), beginning within the first 24 hours of life and treated for at least 7 days, up to 21 days. The primary outcome, of the combined efficacy endpoints of death or BPD at 36 weeks GA, was not significantly different between groups, even with adjustment for gestational age as a covariate (p = 0.40), or with birth weight as a covariate (p = 0.41). The overall occurrence of intraventricular haemorrhage was 114
(28.9 %) among the Mixture NO treated as compared to 91 (22.9 %) among the control neonates. The overall number of death at week 36 was slightly higher in the NO group; 53/395 (13.4 %) as compared to control 42/397 (10.6 %). The INOT25 trial, studying the effects of NO in hypoxic preterm neonates, did not show improvement in alive without BPD. No difference in the incidence of IVH or death was however observed in this study. The BALLR1 study, also evaluating the effects of Mixture NO in preterm neonates, but initiating mixture NO at 7 days and in a dose of 20 ppm, found a significant increase in neonates alive without BPD at gestational week 36, 121 (45 % vs. 95 (35.4 %) p<0.028. No signs of any increase adverse effects were noted in this study.

Nitric oxide chemically reacts with oxygen to form nitrogen dioxide.

Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric oxide may form peroxynitrite with superoxide (O2 -), an unstable compound which may cause tissue damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and may also react with SH- groups in protein forming nitrosyl compounds. The clinical significance of the chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits pulmonary pharmacodynamic effects at intra- airway concentrations as low as 1 ppm.

The European Medicines Agency has waived the obligation to submit the results of studies with Mixture NO 800 ppm in Nitrogen in all subsets of the paediatric population in persistent pulmonary hypertension and other pulmonary heart disease. See section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin that is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate.
Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in the placebo group and in the 5 ppm and 20 ppm NO groups, but reached approximately 5 % in the 80 ppm NO group. Methaemoglobin levels > 7 % were attained only in patients receiving 80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until 40 hours.
Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.