Side effects biologies

Let us outline one of our approaches with the following simple example. Suppose we have a dataset of compounds and two experimental biological activities, of which one is a target activity (TA) and the other is an undesirable side effect (USE). Naturally, those with high TA and low USE form the first subclass, those with low TA and high USE the second, and the rest go into the third, intermediate subclass. 

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Biological characterization includes toxicological studies, dose relationships, routes of adininistration, identification of side effects, and absorption, distribution, metaboHsm, and excretion patterns. If the results are stiU acceptable, product formulation and dosage form are developed. The product should be pleasing to the patient and thus may contain flavoring and colorants. 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

The natural prostanoids have myriad biological effects and held great promise as potential therapeutic agents in numerous diseases. The natural prostanoids, however, also have three notable drawbacks which medicinal chemists have tried to overcome by molecular modification in order to produce acceptable dmg candidates. These drawbacks are rapid metaboHsm which results in lack of activity if taken orally and a short duration of action, numerous side effects due to their multiplicity of biological activities, and poor chemical stabiUty, a characteristic especially pronounced in PGE, -D, and -I stmctures. 

In 1959 Clinton and coworkers reported the first synthesis of some pyrazole fused androstane derivatives and described their biological activity (B-76MI40404). Stanazolol (695) or 17-methyl-2iT-5o -androst-2-eno[3,2-c]pyrazol-17/3-ol was 10 times as active as 17a -methyltestosterone in improving nitrogen retention in rats (B-80MI40406), and its myotrophic activity was only twice that of 17a-methyltestosterone. It is used as an anabolic steroid with no lasting adverse side effects. 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

In some cases the unwanted enantiomer can perturb other biological processes and cause catastrophic side effects. The use of enantiomerically pure compounds thus permits more specific drug action and the reduction in the amount of drug administered. Even in the cases where the other enantiomer is inactive, the work involved in its metabolism before secretion can be avoided. 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Cytokines and biological response modifiers represent a broad class of therapeutic agents that modify the hosts response to cancer or cancer therapies. The enormous body information about their clinical uses and their side effects is beyond the scope of this essay that can only give illustrative examples. For an up-to-date information the reader can resort to reference [5]. As many as 33 different interleukins are known and the list continues to grow IL-2 used in the treatment of kidney cancer is one example. Interferon alpha is used for chronic myelogenous leukeia, hairy cell leukaemia and Kaposi s sarcoma. Interferons are also used in the treatment of chronic infections such as viral hepatitis. Tumor necrosis factor (alpha), G/GM/M-CSF, and several other cellular factors are used in treatment of various cancers. Many of these cytokines produce serious side effects that limit their use. 

A foil discussion of each of the above categories of biological medicines and related agents covered by each of the categories is beyond the scope of this brief essay. However, ImmunoFacts is the most current and comprehensive collection of immunologic and vaccine information and is continuously updated for clinical application, including side effects [5]. 

Recombinant human DL-1 receptor antagonist (Anakinra, Kineret ) blocks the biological activity of interleukin-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. Thereby it reduces the pro-inflammatory activities of IL-1 including cartilage destiuction and bone resorption. Side effects include an increased risk of infections and neutropenia. 

In the case of chiral molecules that are biologically active the desired activity almost always resides in only one of the enantiomers. The other enantiomer constitutes isomeric ballast that does not contribute towards the desired activity and may even exhibit unwanted side effects. Hence, there is a marked trend in pharmaceuticals, agrochemicals and flavours and fragrances towards the marketing of products as enantiomerically pure compounds. This, in turn, has generated a demand for economical methods for the synthesis of pure enantiomers (Sheldon, 1993a). 

Within the area of biological treatments it is especially important to analyze the non-pharmacological factors of psychopharmacology, which include the fact that prescription patterns vary from one ethnic group to another colored patients in the United States receive greater doses of neuroleptic drugs and injectable or depot forms are more frequent than oral medication (Alarcon, 2005) how side effects are perceived and reported are strongly affected by the patient s (culturally... 

Biological factors that may influence pharmacological response and side effects include pharmacokinetics such as protein binding, distribution, metabolism, or... 

Biological Psychopathology Illness-related neurocognitive impairment Current and past experience with medication therapeutic and side effects... 

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