Evaluation of Anti-anginal Drugs

Eval of antianginals:

1. Limitations of present drugs:
   1. Affect hemodynamic parameters.
   1. Do not protect the heart against stress induced adrenergic effects.
   1. Tolerance develops.
   1. Beneficial effects are short-lived.

In-vitro methods:

1. Isolated heart (Langendorff) technique
2. Isolated heart-lung preparation
3. Calcium antagonism in isolated rabbit aorta
4. Relaxation of bovine coronary artery
5. Coronary artery ligation in isolated rat heart
6. Plastic casts from coronary vasculature in dogs

Isolated heart (Langendorff) preparation

• Principle: heart is perfused in a retrograde direction from aorta which closes aortic valves. So the perfusate enters coronary circulation. 

• Procedure for excision of heart à Anaesthesia à Heart is excised along with aorta à Cannulation of aorta à Perfusion fluid à Assessment of contractile function

Indices measured

1. Morphology of heart
2. Biochemistry
3. Cardiac rhythm and electrophysiology
4. Contractile function of heart
5. Coronary flow
6. Pharmacology
7. Arrhythmias
8. K⁺ levels
9. Calcium antagonism
10. EDRF release from coronary bed
11. Electrophysiological evaluation of CV agents

Advantages

• Highly reproducible, low cost and large numbers can be studied
• Broad spectrum parameters can be measured
• Absence of confounding factors (neurohormonal)
• Allows induction of regional or global ischemia
• Hypoxia can be imposed
• Ischemia-reperfusion and arrhythmia studies

Disadvantage

• Constantly deteriorating preparation

Isolated heart-lung preparation

Isolated rabbit aorta:

Rabbit sacrificed à

Abdominal aorta isolated, cut into small rings and mounted in tissue bath containing Krebs buffer à

Addition of Kcl or NE induces contraction in the aortic rings.

Relaxation of bovine arteries:

• Coronary artery ligation:

• Plastic casts:

• In-vivo methods:
  • Occlusion of coronary artery
  • Microspheres-induced acute ischemia
  • Isoproterenol-induced myocardial necrosis
  • Stenosis-induced coronary thrombosis model
  • Electrical stimulation-induced coronary thrombosis
  • Myocardial ischemic preconditioning model

• Occlusion of coronary artery in dogs:

Using Barium sulphate coronary arteriograms are made and infarcted area measured using X ray.

P-Nitro blue tetrazolium is used to visualize infarcted area. These are compared between test and control.

• Microsphere induced acute ischemia:
  • Dog anesthetized.
  • Micro-spheres are injected into the LCA to induce ischemia.
  • Test/control administered.
  • Parameters measured: Systolic and Diastolic pressure, LVEDP, HR, Pulmonary capillary pressure, PAP, COP between test and control.

• Isoproterenol induced Myocardial necrosis:

• Parameters measured: Systolic and Diastolic pressure, LVEDP, HR, Pulmonary capillary pressure, PAP, COP and compared between test and control.

Ischemic preconditioning model:

• Rationale is that preconditioning decreases the damage caused by ischemia-reperfusion injury and this model tests those drugs that help in up-regulating the ischemic preconditioning. 
• Rabbit are anesthetized.
• The LCA is ligated for 5 min and then released for 10 min.
• Test/control or vehicle is administered.  
• This is f/b again ligating the LCA for 30 minutes and then re-perfusing.
• The hemodynamic parameters are compared b/w test and control.

Measurement of coronary blood flow:

1. Electromagnetic flowmeter
2. Inert gas technique
3. Radioactive technique
4. Radioactive microsphere technique
5. Thermodilution technique
6. Coronary arteriography

• Electromagnetic flow-meter: Two opposite magnetic poles are placed on either side of a coronary vessel. Distally two chromium-vanadium electrodes are placed adhering to the coronary vessel. The magnetic field perpendicular to blood flow generates a voltage which is picked up by electrodes and recorded.

• Clinical evaluation:
• Criteria (Parameters) of efficacy:
• Exercise capacity (total exercise time, maximum MET[metabolic equivalent of task] level achieved, maximum workload achieved, maximum heart rate and the double product.)
• ECG characters: Time to onset of angina, time to ST depression (by 1 mm), magnitude of ST, time taken for normalization after ST depression, exercise induced ventricular arrhythmias
• Coronary diameter
• Frequency of anginal pain/need to consume short acting nitrates
• HRQOL
• Morbidity and mortality (since the target of anti-anginal therapy is essentially symptoms control, at present, there is no requirement to prove beneficial effect on these variables in terms of efficacy)

• Phase 1:
• Subjects:
• Patients with stable angina pectoris for preceding 4 weeks without any change.
• Patients with stable angina, 6 months after revascularization
• Patients with stable angina 30 days after MI
• Stable means last <20 minutes and relieved immediately by rest.

• Parameters:
• Pharmacodynamic: hemodynamic effects at rest and during exercise (can be documented by MRI or myocardial perfusion imaging). EXERCISE PARAMETERS, EFFECT ON RENAL FUNCTION, PULMONARY FUNCTION, PLAETLET FUNCTION, GLUCOSE AND LIPID METAB.
• PK: Cmax, Tmax, t1/2, AUC
• Interactions: Pharmacokinetic and pharmacodynamic interactions should be investigated primarily with other frequently coadministered drugs in the target population.

• Phase 2:
• Subjects: Same as phase 1
• Parameters: CRITERIA FOR EFFICACY EXPLAINED ABOVE
• Design: randomized, placebo-controlled and double-blinded
• Wash-out: Withdrawal of ongoing anti-anginal meds
• Placebo run-in: 2 weeks atleast. Short acting nitrates for exacerbations are allowed in this period.
• Dosing interval: atleast 6 weeks to establish clinically useful dose range. Atleast 3 doses should be used.

• Phase 3:
• Subjects: Same as phase 1
• Parameters: CRITERIA FOR EFFICACY EXPLAINED ABOVE
• Design: randomized, active-controlled and double-blinded. Dose from phase 2 should be chosen. Should be of atleast 12 weeks.
• Studies where the new drug is administered as both monotherapy and add-on therapy should be carried out.