Pharmaceutical industry - Drug discovery and development | index-art.info
Keywords: Antihypertensive drugs, metabolism, computational approaches. Unlike the quantitative structure-activity relationships (QSARs), quantitative structure .. The identified metabolites indicate that metabolism occurs on the butyl side. I Aspects of centrally acting antihypertensive agents are reviewed with an 3 The pharmacological basis of side effects, including withdrawal phenomena and drug interactions . study the structure-activity relationship in this class of centrally. In therapy, the lavorotatory isomer, (L)-(–)-methyldopa is used; [o]#: 25° to ° Studies of the structure-activity relationship” indicated that relatively very few Elongation of the side chain by even one carbon atom completely abolishes the.
Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.
A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed.
Some patients develop angioedema due to increased bradykinin levels. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy of the kidney. A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain. Patients should be advised to report symptoms such as sore throat or fever to their physician. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks .
Bradykinins have been implicated in cell proliferation and migration in gastric cancers and bradykinin antagonists have been investigated as anti-cancer agents .
ACE inhibitor - Wikipedia
Overdose[ edit ] Symptoms and Treatment: Chemicals that interact with drug targets in desirable ways become known as leads and are subjected to further developmental tests. Also, additional chemicals with slightly altered structures may be synthesized if the lead compound does not appear to be ideal. Once a lead chemical is identified, it will undergo several years of animal studies in pharmacology and toxicology to predict future human safety and efficacy.SAR of phenylethanolamine /SAR of sympathomimetics
Lead compounds from natural products Another very important way to find new drugs is to isolate chemicals from natural products. Digitalisephedrineatropinequininecolchicineand cocaine were purified from plants. Thyroid hormonecortisoland insulin originally were isolated from animals, whereas penicillin and other antibiotics were derived from microbes. In most cases these indigenous peoples learned which plants had medicinal value the same way they learned which plants were safe to eat—trial and error.
Ethnopharmacology is a branch of medical science in which the medicinal products used by isolated or primitive people are investigated using modern scientific techniques. In some cases chemicals with desirable pharmacological properties are isolated and eventually become drugs with properties recognizable in the natural product.
In other cases chemicals with unique or unusual chemical structures are identified in the natural product. These new chemical structures are then subjected to drug screens to determine if they have potential pharmacological or medicinal value. There are many cases where such chemical structures and their synthetic analogs are developed as drugs with uses unlike those of the natural product.
One such compound is the important anticancer drug taxol, which was isolated from the Pacific yew Taxus brevifolia. Taxol and the Pacific yew As a member of the yew family, Taxaceaethe Pacific yew Taxus brevifolia has flat, evergreen needles and produces red, berrylike fruits.
The toxicity of members of the yew family was described in ancient Greek literature. Indeed, the genus name Taxus derives from the Greek word toxon, which can be translated as toxin or poison. Pliny the Elder described people who died after drinking wine that had been stored in containers made from yew wood. Julius Caesar described how one of his enemies, Catuvolcus, poisoned himself using a yew plant. The early Japanese used yew plant parts to induce abortion and to treat diabetesand Native Americans used yew to treat arthritis and fever.
In part because of widespread historical accounts of the pronounced biological effects inherent in members of the yew family, samples of the Pacific yew were included in screens for potential anticancer drugs. Extracts from the Pacific yew were tested against two cancer cell lines in and found to have promising effects. After a sufficient quantity of the extract was prepared, the active compound, taxol, was isolated in In NCI-supported clinical trials with taxol were begun, and by NCI-supported clinical researchers at Johns Hopkins University reported very positive effects in the treatment of ovarian cancer.
Also in the NCI reached an agreement with Bristol-Myers Squibb to increase production, supplies, and marketing of taxol. Taxol marketing for the treatment of ovarian cancer began in Taxol; cancerWatch the subtle disruptive effect that the widely used anticancer drug Taxol has inside a cell.
Displayed by permission of The Regents of the University of California. Initially, the sole source of taxol was the bark of the Pacific yew, native to the old-growth forests along the northwest coast of the United States and in British Columbia.
This led to considerable public controversy. Environmental groups feared that harvesting of the yew would endanger its survival. It took the bark of between three and ten year-old plants to make enough drug to treat one patient. There were also fears that harvesting the yew would lead to environmental damage to the area and could potentially destroy much of the habitat for the endangered spotted owl.
After several years of controversy, Bristol-Myers Squibb adopted a semisynthetic process for making taxol. This process uses a precursorwhich is chemically converted to taxol. The precursor is extracted from the needles renewable biomass of Taxus baccata, which is grown in the Himalayas and in Europe.
Although there were some political controversies surrounding the discovery and development of taxol, the story of its development and marketing provides another example of how public and private enterprise can cooperate in the development of new discoveries and new drugs.
Strategies for drug design and production Structure-activity relationship The term structure-activity relationship SAR is now used to describe the process used by Ehrlich to develop arsphenamine, the first successful treatment for syphilis.
In essence, Ehrlich synthesized a series of structurally related chemical compounds and tested each one to determine its pharmacological activity. In subsequent years many drugs were developed using the SAR approach. Once a series of chemical compounds had been synthesized and tested, medicinal chemists began to understand which chemical substitutions would produce agonists and which would produce antagonists.
Additionally, substitutions that would cause metabolic enzyme blockade and increase the gastrointestinal absorption or duration of action began to be understood. Three-dimensional molecular models of agonists and antagonists that fit the drug receptor allowed scientists to gain important information about the three-dimensional structure of the drug receptor site.
By the s SAR had been further refined by creating mathematical relationships between chemical structure and biological activity. This refinement, which became known as quantitative structure-activity relationship, simplified the search for chemical structures that could activate or block various drug receptors.
Computer-aided design of drugs A further refinement of new drug design and production was provided by the process of computer-aided design CAD.
With the availability of powerful computers and sophisticated graphics software, it is possible for the medicinal chemist to design new molecules and evaluate their potential interaction with a receptor or an enzyme before they are synthesized.
This means that the chemist may be able to synthesize and test only the most promising compounds, thus allowing potential new drugs to be synthesized more efficiently and cheaply. Combinatorial chemistry Combinatorial chemistry was a development of the s.
It originated in the field of peptide chemistry but has since become an important tool of the medicinal chemist. Traditional organic synthesis is essentially a linear process with molecular building blocks being assembled in a series of individual steps.
Quantitative structure-activity relationships of antihypertensive agents.
Part A of the new molecule is joined to part B to form part AB. This step-wise construction is continued until the new molecule is complete. Using this approach, a medicinal chemist can, on average, synthesize about 25 new compounds per year. In combinatorial chemistry, one might start with five compounds A1—A5.
These five compounds would be reacted with building blocks B1—B5 and building blocks C1—C5.
Each one of these combinations would also combine with each of the C1—C5 building blocks, so that compounds would be synthesized. Using robotic synthesis and combinatorial chemistry, hundreds of thousands of compounds can be synthesized in much less time than would have been required to synthesize a few compounds in the past.
This marketing approval was an important advancement because it represented the first time a clinically important, synthetic human protein had been made into a pharmaceutical product. Again, the venture was successful because of cooperative efforts between physicians and scientists working in research institutions, universities, hospitals, and the pharmaceutical industry.
Human insulin is a small protein composed of 51 amino acids and has a molecular weight of 5, daltons units of atomic mass. Indeed, the synthesis of sheep insulin had been reported in and human insulin in It took almost another 20 years to bring synthetic human insulin to market because a synthetic process capable of producing the quantities necessary to supply market needs had not been developed.
In a new pharmaceutical firm, Genentech Inc. Since the amino acid sequence and chemical structure of human insulin were known, the sequence of DNA that coded for synthesis of insulin could be reproduced in the laboratory. The DNA sequence coding for insulin production was synthesized and incorporated into a laboratory strain of the bacteria Escherichia coli.
In other words, genes made in a laboratory were designed to direct the synthesis of insulin in bacteria.
Regulatory approval for marketing human insulin came just six years after Genentech was founded. In some ways, the production of human growth hormone by recombinant DNA technology, first approved for use inwas more important than the synthesis of insulin. Prior to the availability of human insulin, most people with diabetes could be treated with the bovine or porcine insulin products, which had been available for 50 years see above Isolation of insulin.
Unlike insulin, the effects imparted by growth hormone are different for every species. Therefore, prior to the synthesis of human growth hormone, the only source of the human hormone was from cadaver pituitaries. However, there are now a number of recombinant preparations of human growth hormone and other human peptides and proteins on the market.
Drug regulation and approval Regulation by government agencies Concerns related to the efficacy and safety of drugs have caused most governments to develop regulatory agencies to oversee development and marketing of drug products and medical devices.
Use of any drug carries with it some degree of risk of an adverse event. Some authors have challenged thiazides as first line treatment. Subsequently, if dual therapy is required to use ACE-inhibitor in combination with either a calcium channel blocker or a thiazide diuretic.
Triple therapy is then of all three groups and should the need arise then to add in a fourth agent, to consider either a further diuretic e. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive. Age can affect the choice of medications. Current UK guidelines suggest starting patients over the age of 55 years first on calcium channel blockers or thiazide diuretics.
Quantitative structure-activity relationships of antihypertensive agents.
Anxiety may be improved with the use of beta blockers. Asthmatics have been reported to have worsening symptoms when using beta blockers. Benign prostatic hyperplasia may be improved with the use of an alpha blocker.
ACE inhibitors or ARBs should be included in the treatment plan to improve kidney outcomes regardless of race or diabetic status.