Evaluating MED2005 & Nitrostat Bioavailability
Condition: Erectile Dysfunction
MeSH terms: Erectile Dysfunction
Study type: Interventional
Phase: Phase 1

Summary: 
      Futura Medical Developments Ltd (FMD) are developing a gel formulation of GTN (MED2005) as a
      topical treatment for ED delivered using DermaSys®, a versatile and bespoke technology.
      Treatment requires the application of a small quantity of gel (approx 300 mg), containing a
      fixed dose of GTN, to the glans of the penis. Pharmacokinetic studies in healthy volunteers
      indicate rapid absorption of the drug and low systemic exposure, reducing the risk of adverse
      events (such as headache) commonly associated with GTN therapy.

      The purpose of this study is to demonstrate similar or lower bioavailability of GTN from
      MED2005 (test IMP) with that from Nitrostat (reference IMP).

      The study will be conducted in two parts (Part 1 and 2). Part 1 will be conducted in 30
      subjects and Part 2 will be conducted in 10 subjects. Part 1 will compose of a pre-study
      screen, followed by six treatment periods and a post-study follow-up.

      Part 2 will compose of a pre-study screen, followed by two treatment periods and a post-study
      follow-up. Subjects can only participate in either Part 1 or 2 of the study (not both).
    

Detailed description: 
      GTN is a well-established vasodilatory therapeutic agent with a long, documented history of
      use and comprehensive safety profile. In Europe, licensed indications for GTN include the
      treatment and prophylaxis of angina pectoris and the relief of pain associated with chronic
      anal fissure. Other indications for prescription only parenteral products include use during
      cardiac surgery and for emergency reduction of blood pressure.

      GTN's vasodilatory action is thought to result from the release of nitric oxide (NO) in
      vascular smooth muscle. NO stimulates guanylate cyclase, the enzyme responsible for
      production of cGMP, whose action is to lower intracellular calcium resulting in smooth muscle
      relaxation and vasodilation.

      In the case of erectile dysfunction, GTN works locally by penetrating the glans/penile skin
      and directly targeting penile blood vessels. Nitrates appear to have a direct, local effect
      on penile haemodynamics. The most likely mechanism for the erectile effect of nitrates
      involves nitrate induced dilation of the cavernous and helicine arteries, thereby increasing
      blood flow to the lacunar spaces, coupled with nitrate-induced relaxation of trabecular
      smooth muscle.

      Nitroglycerin (Nitrostat) is indicated for the acute relief of an attack or acute prophylaxis
      of angina pectoris due to coronary artery disease.

      The principal pharmacological action of nitroglycerin is relaxation of vascular smooth
      muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related
      manner, dilation of both arterial and venous beds. Dilation of postcapillary vessels,
      including large veins, promotes peripheral pooling of blood, decreases venous return to the
      heart, and reduces left ventricular end-diastolic pressure (preload). Nitroglycerin also
      produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial
      pressure (afterload), and dilates large epicardial coronary arteries; however, the extent to
      which this latter effect contributes to the relief of exertional angina is unclear.

      Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase,
      resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and
      other tissues. These events lead to dephosphorylation of myosin light chains, which regulate
      the contractile state in smooth muscle, and result in vasodilatation.
    

Intervention name(s): MED2005; Nitrostat 0.6Mg Sublingual Tablet; Nitro Pohl
Intervention type(s): Drug; Drug; Drug
Intervention description(s): (Day -1 to Day 1): Subjects will undergo six treatment periods, each separated by at least a two day washout. Each treatment period will be approximately 1 day in duration from the afternoon of Day -1 to the afternoon of Day 1 at 6 hours (h) post-dose. In each of the treatment periods, the subject will receive one of the six administrations over 6 treatment periods (1/period) and will return approximately two days later for the next treatment period.; Active comparator to be used for Part 1 of the study. Nitrostat will be dosed in two treatment periods and 3 x 0.6 mg tablets will be required to make up the 1.8 mg dose.; to be dosed intravenously in Part 2 of the study
Other intervention name(s): glyceryl trinitrate; Nitroglycerin 0.6 mg; Nitroglycerin
Intervention MeSH terms: Nitroglycerin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic