343
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
to the market. Then a prospective, multicenter, randomized, placebo-controlled,
double-blind clinical trial APPROV (Adenomatous Polyp Prevention on VIOXX)
was performed. Its purpose was to evaluate the effectiveness for prevention of colon
polyps in patients with colorectal adenomatous polyps in the medical history. An increasing risk of cardiovascular events such as myocardial infarction and stroke was
found. Therefore, clinical trials (APPROV) were terminated and the drug Vioxx
was withdrawn from the market [43].
Along with these critical side effects, like VIOXXa, there are less serious side effects, such as nausea, dizziness, dry mouth, skin rash, etc. They are significant only
with the long-term usage of drug compounds. Table 11.9 shows the most frequent
adverse effects of therapeutic compounds [44].
Traditionally, the drug development process starts with definition of the target
protein. An interaction of the drug with this target leads to the manifestation of a
therapeutic effect. It is also well known, that drugs in most cases interact with different additional targets (off-targets). Availability of these additional mechanisms
of action provides the emergence of side effects. The proteins which led to the appearance of side effects are known as antitargets. The list of antitargets associated
with the cardiovascular system was published by Whitebread with co-authors [44].
The antitarget interactions predicted by GUSAR Online web-service [http://www.
way2drug.com/GUSAR] and associated with the toxic and side effects are shown
in Table 11.10.
Table 11.9 The most frequent side effects of drugs
Localization
Effect
Gastrointestinal tract
Hepatitis and/or hepatocellular damage; Constipation; Diarrhea;
Nausea and/or vomiting; Ulceration; Pancreatitis; Dry mouth
Blood
Agranulocytosis; Hemolytic anemia; Pancytopenia; Thrombocytopenia; Megaloblastic anemia; Clotting and/or bleeding;
Eosinophilia
Cardiovascular system
Arrhythmias; Hypotension; Hypertension; Congestive heart failure;
Angina and/or chest pain; Pericarditis; Cardiomyopathy
Integuments
Erythemas; Hyperpigmentation; Photodermatitis; Eczema; Urticaria; Acne; Alopecia
Metabolism
Hyperglycemia; Hypoglycemia; Hyperkalemia; Hypokalemia;
Metabolic acidosis; Hyperuricemia; Hyponatremia
Respiratory System
Airway obstruction; Pulmonary infiltrates; Pulmonary edema;
Respiratory depression; Nasal congestion
Musculoskeletal system
Myalgia and/or myopathy; Rhabdomyolysis; Osteoporosis
Urogenital System
Nephritis; Nephrosis; Tubular necrosis; Renal dysfunction; Bladder
dysfunction; Nephrolythiasis
Endocrine system
Thyroid dysfunction; Sexual disfunction; Gynecomastia; Addison
syndrome; Galactorrhea
Nervous system
Seizures; Tremor; Sleep disorders; Peripheral neuropathy; Headache; Extrapyramidal effects
Central nervous system
Delirium, confusion; Depression; Hallucination; Drowsiness;
Schizophrenic and/or paranoid reactions; Sleep disturbances
Eye
Disturbed color vision; Cataract; Optic neuritis; Retinopathy; Glaucoma; Corneal opacity
Hearing
Deafness; Vestibular disorders
11 Computational Toxicology in Drug Discovery: Opportunities and Limitations
to the market. Then a prospective, multicenter, randomized, placebo-controlled,
double-blind clinical trial APPROV (Adenomatous Polyp Prevention on VIOXX)
was performed. Its purpose was to evaluate the effectiveness for prevention of colon
polyps in patients with colorectal adenomatous polyps in the medical history. An increasing risk of cardiovascular events such as myocardial infarction and stroke was
found. Therefore, clinical trials (APPROV) were terminated and the drug Vioxx
was withdrawn from the market [43].
Along with these critical side effects, like VIOXXa, there are less serious side effects, such as nausea, dizziness, dry mouth, skin rash, etc. They are significant only
with the long-term usage of drug compounds. Table 11.9 shows the most frequent
adverse effects of therapeutic compounds [44].
Traditionally, the drug development process starts with definition of the target
protein. An interaction of the drug with this target leads to the manifestation of a
therapeutic effect. It is also well known, that drugs in most cases interact with different additional targets (off-targets). Availability of these additional mechanisms
of action provides the emergence of side effects. The proteins which led to the appearance of side effects are known as antitargets. The list of antitargets associated
with the cardiovascular system was published by Whitebread with co-authors [44].
The antitarget interactions predicted by GUSAR Online web-service [http://www.
way2drug.com/GUSAR] and associated with the toxic and side effects are shown
in Table 11.10.
Table 11.9 The most frequent side effects of drugs
Localization
Effect
Gastrointestinal tract
Hepatitis and/or hepatocellular damage; Constipation; Diarrhea;
Nausea and/or vomiting; Ulceration; Pancreatitis; Dry mouth
Blood
Agranulocytosis; Hemolytic anemia; Pancytopenia; Thrombocytopenia; Megaloblastic anemia; Clotting and/or bleeding;
Eosinophilia
Cardiovascular system
Arrhythmias; Hypotension; Hypertension; Congestive heart failure;
Angina and/or chest pain; Pericarditis; Cardiomyopathy
Integuments
Erythemas; Hyperpigmentation; Photodermatitis; Eczema; Urticaria; Acne; Alopecia
Metabolism
Hyperglycemia; Hypoglycemia; Hyperkalemia; Hypokalemia;
Metabolic acidosis; Hyperuricemia; Hyponatremia
Respiratory System
Airway obstruction; Pulmonary infiltrates; Pulmonary edema;
Respiratory depression; Nasal congestion
Musculoskeletal system
Myalgia and/or myopathy; Rhabdomyolysis; Osteoporosis
Urogenital System
Nephritis; Nephrosis; Tubular necrosis; Renal dysfunction; Bladder
dysfunction; Nephrolythiasis
Endocrine system
Thyroid dysfunction; Sexual disfunction; Gynecomastia; Addison
syndrome; Galactorrhea
Nervous system
Seizures; Tremor; Sleep disorders; Peripheral neuropathy; Headache; Extrapyramidal effects
Central nervous system
Delirium, confusion; Depression; Hallucination; Drowsiness;
Schizophrenic and/or paranoid reactions; Sleep disturbances
Eye
Disturbed color vision; Cataract; Optic neuritis; Retinopathy; Glaucoma; Corneal opacity
Hearing
Deafness; Vestibular disorders