Pulmonary hypertension - riociguat
Pulmonary hypertension (PH) is a serious condition in which the blood pressure in the pulmonary artery is too high - typically 25mmHg compared with a normal pressure closer to 12mmHg. This leads to damage to the endothelial cells lining the capillaries in the lung, with the result that the muscles in the arterial wall tighten up, narrowing the arteries.
Pulmonary hypertension (PH) is a serious condition in which the blood pressure in the pulmonary artery is too high - typically 25mmHg compared with a normal pressure closer to 12mmHg. This leads to damage to the endothelial cells lining the capillaries in the lung, with the result that the muscles in the arterial wall tighten up, narrowing the arteries.
Small blood clots can also form, blocking the smaller arteries, and the scar tissue that forms if the arterial walls thicken also narrows the arteries. This means that the heart has to work harder to pump blood through the lungs, thus the most common cause of death in patients with PH is heart failure. Standard antihypertensive drugs are ineffective, and treatment options are limited, and available for only one form of the condition: pulmonary arterial hypertension.
A new drug being developed for PH is Bayer's riociguat.1 It works in a different way from existing drugs: it stimulates soluble guanylate cyclase, which is the receptor for nitric oxide. PH is associated with an impaired production of the endogenous vasodilator NO, and the drug both increases the receptors" sensitivity to NO, and stimulates it directly when there is little or no NO around.
In a clinical trial, following an initial dose finding study in four subjects, 15 patients with moderate to severe PH were given doses of 2.5 or 1.0mg of the drug, and it had a favourable safety profile at these levels.2 The drug was given after an overnight fast and after a washout period of at least 12 hours for patients who were taking acute vasodilating drugs such as calcium channel blockers. It gave a dose dependent significant improvement in pulmonary haemodynamic parameters to a greater extent than was achieved with inhaled NO. The drug has systemic effects and no pulmonary selectivity, the mean systolic blood pressure was not adversely affected, remaining above 110mmHg. It was generally well tolerated.
Phase II and III trials are under way in patients with different forms of pulmonary hypertension.
Reference:
1. J. Mittendorf et al. Chem. Med. Chem. 2009, 4, 853
2. F. Grimminger et al. Eur Respir J. 2009, 33, 785