THERAPEUTIC SCIENCE (HEALTH MANTEINANCE)

PREVENTION
NUTRITION EXERCISE VACCINATION

DIAGNOSIS

TREATMENT

THERAPEUTICAL SOURCES
NUTRITIONAL BIOLOGICAL
obesity, diabetes mellitus, hypertension, peptic ulcer and osteoporosis. Blood and blood cells , Plasma, Transplantation. Haematopoietic growth factors, Biological response modifiers, Hormones. Drugs

BIO/PHARCEUTICAL

SURGICAL RADIATION AND OTHER NON-INVASIVE THERAPIES PSYCHOTHERAPY

HIERARCHY OF THE THERAPEUTICAL PROCESS

Therapeutic action Organ physiological response Modification of a physiological function Modification of a biochemical function Pharmaceutical interaction with receptor Clinical effects Organ physiologicql level

Tissular level

Cellular level

Molecular level

Captopril

Losartan

SOURCES FOR THERAPEUTIC AGENTS

PLANT EXTRACTS

BACTERIAL BROTHS

ANIMAL VENOMS

SMALL MOLECULE DRUGS MIMICS BIOLOGICAL MOLECULES

PHARMACEUTICALS

BIOPHARMACEUTICALS

TURNING ACTIVE COMPOUNDS INTO MEDICINES

PHARMACEUTICAL

MEDICATION

GALENIC FORMULATION + EXCIPIENTS

History of therapeutic agents

Ancient remedies Regulation Regulation Medicinal Chemistry (1950) Regulation Natural products (first half s XX)

Biotechnology (1982)

HISTORY OF THERAPEUTICS
724 s XIII S XIX 1906 1920 1938 Drug stores: Arabian pharmacists in Bhagdag First pharmacopeas Drug stores converted into larger pharmaceutical companies FDA creation (misbranded foods and drugs) Insulin, Penicillin were mass manufactured and distributed Toxicity studies were required

1950

Numerous drugs: the pill, cortisone, blood pressure drugs, MAO inhibitors, Thorazine, Haloperidol or Diazepam.

HISTORY OF THERAPEUTICS
1960 1962 1970 1978 1980 1982 Thalidomide Proof of efficacy was required Cancer drugs First production in India without protection Small biotech companies Rcombinant Insulin

OBJECT OF REGULATIONS
REDUCE TOXICOLOGICAL EFFECTS (1938, FDA)
Elixir Sulfanilamide

(sulfanimamide solved in ethylen glycol) 100 deaths

PROOF OF EFFICACY (1962, FDA)

SULFANILAMIDE

Thalidomide 10,000 children in Africa and Europe were born with severe malformities

THALIDOMIDE

R+D OF NEW PHARMACEUTICALS

LEAD COMPOUND (New Chemcial Entity (NCE) BIO/PHARMACEUTICAL FORMULATION Investigational new drug (IND)

PRECLINICAL STUDIES

CLINICAL STUDIES

DEVELOPMENT

NDA TO FDA ; EMEA;TGA

The life of a polemic drug

Only a year after its release, the first study showed that cast doubt on the cardiovascular safety of COX-2.

Rofecoxib

This has not stopped at this time, Merck 'superaspirin' became one of the top-selling drugs. In the last 2000 global sales exceeded 2,000 million euros. 1999 Goes on sale in the U.S.
JANUARY 2000 Reaches the Spanish market. MARCH 2000 A clinical trial sponsored by Merck (which compares Vioxx with a classic antiinflammatory 8000 patients) revealed that those who take Vioxx have fewer gastrointestinal problems but four times more cardiovascular risk.

AUGUST 2001 An extensive review in the journal JAMA 'challenges the cardiovascular safety of COX-2. SEPTEMBER 2001 The FDA warns Merck for failing to warn the medical advertising to coronary risk of Vioxx. APRIL 2002 The FDA mandates that change in the labeling of Vioxx. They allow to talk about their gastrointestinal benefits, but must include a warning about cardiovascular risks. JULY 2002 The Spanish Ministry of Health introduced supervision requirements for all prescriptions for COX-2. AUGUST 2004 Present data from a study conducted by the FDA: people who consume the highest dose of rofecoxib triple their cardiac risk. Rheumatologists warn Americans that are measured heart risks of COX-2 before prescribing. SEPTEMBER 2004 Merck withdrew the drug to confirm an increased risk of heart problems. Its shares fell by 27%

3-4 years

Revenue of the first drug into the market

WHO model list of essential medicines

http://www.who.int/medicines/publications/EML15.pdf

ANAESTHETICS ANALGESICS ANTIDOTES ANTI-INFECTIVE MEDICINES ANTI-MIGRAINE MEDICINES ANTINEOPLASTIC AND IMMUNODEPRESSIVES ANTIPARKINSON MEDICINES MEDICIENS AFFETING THE BLOOD BLOOD PRODUCTS AND PLASMA SUBSTITUTES CARDIOVASCULAR MEDICINES DERMATOLOGICAL MEDICINES

WHO model list of essential medicines

DIAGNOSTIC AGENTS DESINFECTANTS AND ANTISEPTICS DIURETICS GASTROINTESTITAL MEDICINES HORMONES IMMUNOLOGICALS MUSCLE RELAXANTS OPHTALMIOLOGICAL PREPARATIONS OXYTOCICS PERITONEAL DIALYSIS SOLUTION PSYCHOTHERAPEUTIC MEDICINES

WHO model list of essential medicines

MEDICINES ACTING ON THE RESPIRATORY TRACT SOLUTIONS CORRECTING WATER, ELECTROLYTE AND ACID-BASE DISTURBANCES VITAMINS AND MINERALS

BLOCKBUSTERS
Category Cholesterol reducers Antiulcer compounds Antidepressants Non streroideal antiinflammatory drugs sales 2003 M$ 26.1 24.3 19.5 12.4 % increase 2002 14 9 10 6

Antipsychotic drugs
Calcium antagonists Eryhropoietine Antieplyleptic Oral anti diabetics Cephalosporines

12.2
10.8 10.1 9.4 9.0 8.3

20
2 16 22 10 10

SOURCES FOR THERAPEUTIC AGENTS

PLANT EXTRACTS

BACTERIAL BROTHS

ANIMAL VENOMS

SMALL MOLECULE DRUGS MIMICS BIOLOGICAL MOLECULES

PHARMACEUTICALS

BIOPHARMACEUTICALS

BIOPHARMACEUTICALS
Hormones: insulin, growth hormone Thrombolytic agents Blood factors: factor VIII, factor IX Haematopietic growth: Interferons Interleukin based products Monoclonal antibodies Antisense therapy

(PHARMACOLOGY: apply scientifc priciples to make medicines more effective and less dangerous) PHARMACEUTICAL ADMINISTRATION (FORMULATION)
DISSOLUTION

THERAPEUTIC ACTION OF PHARMACEUTICALS

BODY ACTS ON A PHARMACEUTICAL (PHARMACOKINETICS)

ADME

PHARMACEUTICAL ACTS ON THE BODY (PHARMACODYNAMICS)

BIOCHEMICAL ACTION

THERAPEUTIC ACTION OF PHARMACEUTICALS (PHARMACODYNAMICS)

Paradigm: Biological Actions are receptor mediated

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R+D OF NEW PHARMACEUTICALS PRECLINICAL STUDIES

TARGET IDENTIFICATION FIND A LEAD COMPOUND IMPROVE AFFINITY IMPROVE ADME REDUCE TOXIOLOGICAL EFFECTS REDUCE SECONDARY EFFECTS FORMULATION IND BIO/PHARMACEUTICAL

R+D OF NEW PHARMACEUTICALS CLINICAL TRIALS

Phase 0 (introduced in 2006)
Phase I
First test on humans at smaller dosis 20-80 healthy subjects to assess safety, tolerability, pharmacokinetics and pharmacodynamics

Phase II

20-300 individuals in one center. Assess toxicity and eficacy

Phase III 300-3000 multicenter