Capítulo 1: Fundamentación Teórica
1.3 Tecnologías
1.3.4 Identificación basado en el iris/retina
The ultimate long-term goal of medicinal chemistry is to design a “useful drug”. A use-ful drug is more than a molecule that is safe and efficacious. It is more than a compound that produces papers in scholarly journals. A useful drug is a drug molecule that is not only safe and efficacious, but also one that can pass government regulations, pass through multiple levels of human clinical trials, be economically produced in large quantities, be successfully marketed, and can ultimately help people with disease.
Successfully treating humans with disease is the “bottom line” in drug design.
Perhaps the greatest hurdle along the pathway of a molecule becoming a useful drug is the need to sequentially pass clinical trials. However, before a drug can be evaluated in human clinical trials, it must first successfully negotiate preclinical test-ing. This frequently involves five or six types of test, and is completed in non-human animals:
1. Acute toxicity — acute dose that is lethal in 50% of animals; usually two species, usually two routes of administration
2. Subacute toxicity — physiology, histology, autopsy studies; two species, sometimes with dosings over a 6 month time period
3. Chronic toxicity — detailed organ evaluation; two species, sometimes studied for 1–2 years
4. Mutagenic potential — effects on genetic stability of bacteria (Ames test) of mammalian cells in culture
5. Carcinogenic potential — required if drug is to be administered for prolonged periods of time
6. Reproductive performance effects — effects on animal progeny, production of birth defects
Once a molecule successfully passes the preclinical testing, it is ready for human clin-ical trials. There are four phases of human clinclin-ical trial.
Phase 1 — the effects of the drug as a function of dose are measured in a small number (25–45) of healthy volunteers who do not have the disease under study;
safety is primarily evaluated.
Phase 2 — the drug is studied in a small number of people (20–150) who have the disease under study; both safety and efficacy are evaluated.
Figure 3.10 The drug development process. The timeline for drug discovery and development is long, adding to the high cost of drug development. Computational methods have helped to shorten this timeline.
Phase 3 — the drug is studied in a large number of people (hundreds to thousands) who have the disease under study, typically using a multi-center, double-blind, placebo–controlled, randomized clinical trial (RCT) protocol.
Phase 4 — once the drug has been approved for market, vigilant post-marketing sur-veillance is done to ascertain the possible appearance of previously undetected tox-icities or problems.
The drug development process is long, as is shown in figure 3.10. During the drug development phases, toxicity is one of the most important hurdles to the success of a drug molecule. Toxicity can affect the person who is taking the medication (causing skin rashes, liver problems, bone marrow failure, etc.) or, in the case of women, can affect their developing fetus if they are pregnant. Table 3.2 lists some of the drugs
Table 3.2 Drugs Producing Adverse Effects on the Fetus
Drug Effect
ACE inhibitors Kidney damage
Amphetamines Abnormal developmental patterns
Androgens Masculinization of female
Busulfan Congenital malformations
Carbamazepine Neural tube defects affecting brain formation
Cocaine Stroke in fetus
Cyclophosphamide Congenital malformations
Cytarabine Congenital malformations
Diethylstilbestrol Vaginal adenocarcinoma in child
Ethanol Risk of fetal alcohol syndrome
Etretinate High risk of multiple congenital malformations
Iodine Congenital goiter, hypothyroidism
Isotretinoin High risk of face, ear, and other malformations
Methotrexate Multiple congenital abnormalities
Methylthiouracil Hypothyroidism in child
Metronidazole May be mutagenic (animal studies show no evidence for mutagenic or teratogenic effects in humans)
Penicillamine Congenital skin malformations
Phenytoin Fetal hydantoin syndrome
Propylthiouracil Congenital goiter
Streptomycin Eighth nerve toxicity (deafness) in child
Tamoxifen Increased risk of spontaneous abortion or fetal damage Tetracycline Discoloration and defects of teeth and altered
bone growth
Thalidomide Phocomelia (shortened bones of the limbs)
Trimethadione Multiple congenital abnormalities
Valproic acid Neural tube defects of the brain
that produce an adverse effect on the fetus. Toxicity problems have resulted in many drugs being withdrawn from the market, as shown in table 3.3. As shown in figure 3.11, toxicity problems are a major cause of drug rejection during the develop-ment process.
Successful completion of the four phases of human clinical trials enables a drug to be widely distributed for the treatment of human disease. However, a simple reality of drug discovery is that drugs are developed by industry. The lead compound may have been identified in an academic university-based laboratory, but the clinical trials are invariably completed by the industrial sector. Academic institutions, governments, or international organizations (e.g., the World Health Organization, WHO) do not develop drugs. Because of this, drug molecules tend to be developed only if they have a good prospect for being profitable. In order to be profitable, a drug molecule should be patented so that the vendor can enjoy exclusive rights to its marketing. Although a discussion of the criteria for patentability is beyond the scope of this book, the drug Table 3.3 Approved Drugs Withdrawn Because of Toxicity
Drug Year Adverse reaction
Astemizole 1998 Interactions (e.g., with grapefruit juice)
Benoxaprofen 1982 Liver damage
Centoxin 1993 Increased mortality
Cerivastatin 2001 Muscle breakdown
Cisapride 2000 Cardiac arrhythmias
Clioquinol 1975 Optic neuropathy (eye problem)
Dexfenfluramine 1997 Cardiac valve abnormalities
Fenfluamine 1997 Cardiac valve abnormalities
Flosequinan 1993 Increased mortality
Indoprofen 1984 Gastrointestinal bleeding/perforation
Metipranolol 0.6% eyedrops 1990 Anterior uveitis (eye problem)
Mibefradil 1998 Many drug interactions
Temafloxacin 1992 Various serious adverse effects
Terodiline 1991 Cardiac arrhythmias
molecule should be chemically unique, without evidence of previous pharmacological development.
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APPENDIX 3.1: BASIC REACTIONS FOR DRUG