Antihypertensive Effect of Different Doses of Rostafuroxin in Comparison With Losartan
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 2

Summary: 
      The principal aim of the study is to demonstrate that Rostafuroxin is able to induce a more
      pronounced reduction of arterial blood pressure respect to Losartan, in hypertensive patients
      carrying at least one of the pre-specified gene mutations. In previous studies has been
      demonstrated that these mutations are able to induce specific alterations inducing an
      increase of sodium (Na) reabsorption at renal tubular level and an increase of arterial blood
      pressure. Pilot studies have demonstrated that Rostafuroxin is able to reduce the impact of
      these alterations, and so directly reverse the increase in blood pressure.
    

Detailed description: 
      About 30% of the world adult population is affected by hypertension in industrialised
      countries. Elevated arterial pressure is the major cause of cardiovascular mortality and
      international guidelines emphasise the benefits of reducing blood pressure. The current
      antihypertensive strategies may reduce by 20-30% the cardiovascular risk of hypertensive
      patients when this efficacy is measured in clinical trials in comparison with placebo. A
      precise world-wide estimation of this efficacy both in term of patient burden and healthcare
      costs is not available; however, a recent analysis suggests that the world-wide cost of
      hypertension associated cardiovascular complications is around 1,000 billions dollars.
      Therefore, effective improvement in the diagnosis and treatment of hypertension can provide
      the most significant contribution to the decrease of cardiovascular mortality and reduction
      of the world-wide costs associated to treatment of hypertension complications.

      Most of clinical trials, performed with the aim to show a reduction of the systolic blood
      pressure in hypertensive patients, show that reduction of systolic blood pressure is
      independent from the class of tested drugs as diuretics, β blockers, Ca channel blockers or
      inhibitors of RAS seem to have roughly the same efficacy. These findings have been used as an
      argument to support the notion that the antihypertensive therapy efficacy in reducing
      cardiovascular risk depends on the magnitude of the blood pressure fall rather than on the
      mechanism of action of the drug. This view contrasts with the well established notion that
      the secondary prevention capacity in other cardiovascular diseases differs among these
      classes of drugs with minor difference on the prevention of heart failure or stroke between
      the Ca antagonist and the other classes of drugs.

      Furthermore, the recent findings on genetic of hypertension taken together with the previous
      data on pathophysiology of hypertension and its cardiovascular complications are consistent
      with the notion that a variety of heterogeneous genetic-molecular mechanisms concur to
      develop the rather uniform clinical picture of primary hypertension. Drugs are small
      molecules that produce their effects by interacting with larger molecules (proteins) whose
      function or reactivity may vary from one patient to another because the variations within the
      gene encoding them. Therefore, it is logical to postulate that the consequence of this
      different interaction either in term of blood pressure reduction or cardiovascular risk
      prevention may vary from a patient to another according to the peculiar function of the
      proteins involved in a given patient.

      Rostafuroxin was selected during a research program aimed to synthesizing and selecting new
      antihypertensive compounds able to interfere with abnormalities in Na tubular reabsorption
      due to humoral and/or genetic mechanisms leading to essential (or genetic) hypertension. Many
      studies performed on the Milan hypertensive strain of rats (MHS), bearing a primary renal
      alteration in the ability to excrete sodium and increased blood pressure levels, showed a
      clear capacity of Rostafuroxin to revert these alteration, reducing systemic blood pressure.

      Rostafuroxin selectively interferes with the Na-K pump correcting its functional
      abnormalities without interfering with other receptors involved in blood pressure regulation
      or hormonal homeostasis. At nanomolar concentration, rostafuroxin reduces the Na-K pump
      hyperactivation induced in renal cell cultures by either incubation with nanomolar ouabain
      concentrations or cell transfection with the 'hypertensive' variant of adducin.

      Similarly, less than 1 μg/kg os of rostafuroxin is able to completely normalize both blood
      pressure and the increased renal Na-K pump activity in rats made hypertensive by a chronic
      infusion of low-dose ouabain. The antihypertensive effect of rostafuroxin is long-lasting
      since it is still present 24 hours after oral administration. It is not associated with
      changes in heart rate. Moreover, the long-term antihypertensive activity of rostafuroxin is
      not associated with alterations of plasma potassium, RAAS, insulin resistance, plasma lipid
      profile and uricemia. These findings indicate that the normalization of renal sodium handling
      brought about by this compound is not accompanied by the typical side effects of diuretics,
      such as: hypokaliemia, increased plasma levels of renin, aldosterone, triglycerides and uric
      acid, or insulin resistance.

      Increased levels of EO and the mutated adducin are both associated with the organ
      complications related to hypertension, namely cardiac hypertrophy and progression toward
      renal insufficiency. Cardiac and renal hypertrophy is induced in rats by chronic ouabain
      infusion. Rostafuroxin prevents the ouabain-induced organ hypertrophy.

      Rostafuroxin has shown a high safety ratio in toxicological studies and was well tolerated in
      previous clinical trials.

      Patients with mutated adducin and increased EO plasma levels share many functional, hormonal
      and biochemical characteristics with MHS rats, therefore Rostafuroxin could become a first
      choice treatment in such patients bearing specific gene mutations and presenting high
      arterial blood pressure levels.

      Preliminary proof of concept studies have shown ability of Rostafuroxin to reduce arterial
      blood pressure levels in such a patients.
    

Intervention name(s): Rostafuroxin; Losartan
Intervention type(s): Drug; Drug
Intervention description(s): This is a potent, selective and safe inhibitor of this altered mechanism and has been proved to be effective in reducing blood pressure levels in Adducin mutated rat strains and in chronic Ouabain infused rat model.; COZAAR (losartan potassium) is an angiotensin II receptor (type AT1) antagonist. Losartan potassium, a nonpeptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole- 5-methanol monopotassium salt.
Other intervention name(s): Rosta
Intervention MeSH terms: Losartan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment