Clinical importance

M.p. 83-5 - C. Does not occur naturally, but has been obtained synthetically. It is the basic hydrocarbon skeleton of biologically and clinically important steroids. 

Luminescence has been used in conjunction with flow cells to detect electro-generated intennediates downstream of the electrode. The teclmique lends itself especially to the investigation of photoelectrochemical processes, since it can yield mfonnation about excited states of reactive species and their lifetimes. It has become an attractive detection method for various organic and inorganic compounds, and highly sensitive assays for several clinically important analytes such as oxalate, NADH, amino acids and various aliphatic and cyclic amines have been developed. It has also found use in microelectrode fundamental studies in low-dielectric-constant organic solvents. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Description of Method. Creatine is an organic acid found in muscle tissue that supplies energy for muscle contractions. One of its metabolic products is creatinine, which is excreted in urine. Because the concentration of creatinine in urine and serum is an important indication of renal function, rapid methods for its analysis are clinically important. In this method the rate of reaction between creatinine and picrate in an alkaline medium is used to determine the concentration of creatinine in urine. Under the conditions of the analysis, the reaction is first-order in picrate, creatinine, and hydroxide. 

Bioluminescence can also be used as the basis for immunoassay. For example, bacterial luciferase has been used in a co-immobilized system to detect and quantify progesterone using a competitive immunoassay format (34), and other luciferase-based immunoassays have been used to quantify insulin, digoxin, biotin, and other clinically important analytes (35). 

Chemiluminescence has been studied extensively (2) for several reasons (/) chemiexcitation relates to fundamental molecular interactions and transformations and its study provides access to basic elements of reaction mechanisms and molecular properties (2) efficient chemiluminescence can provide an emergency or portable light source (J) chemiluminescence provides means to detect and measure trace elements and pollutants for environmental control, or clinically important substances (eg, metaboHtes, specific proteins, cancer markers, hormones, DNA) and (4) classification of the hioluminescent relationship between different organisms defines their biological relationship and pattern of evolution. 

Clinical Analysis. A wide range of clinically important substances can be detected and quantitated using chemiluminescence or bioluminescence methods. Coupled enzyme assay protocols permit the measurement of kinase, dehydrogenase, and oxidases or the substrates of these enzymes as exemplified by reactions of glucose, creatine phosphate, and bile acid in the following ... 

Table 3. Clinically Important Substances Detected Using Coupled Enzyme Reactions...

New impetus was given to photomedicine by development of lasers that are compatible with the clinical environment. These include HeNe, Ar ion, mby, and tunable dye lasers operating in the continuous wave (cw) mode. Prior to the advent of lasers in medicine, only the treatment of newborn jaundice, and the appHcation of long wavelength uv irradiation in conjunction with adininistration (or topical appHcation) of psoralen class sensitizers to treatment of skin diseases (86), principally psoriasis, were clinically important phototherapies. 

Ansamacrolides. Antibiotics ia the ansamacroHde family ate also referred to as ansamycias. They are benzenoid or naphthalenoid aromatic compounds ia which nonadjacent positions are bridged by an aliphatic chain to form a cycHc stmcture. One of the aliphatic—aromatic junctions is always an amide bond. Rifampin is a semisyntheticaHy derived member of this family and has clinical importance. It has selective antibacterial activity and inhibits RNA polymerase. 

In the 1950s, meprobamate, a propandiole, and methaqualone, a quiQa2oline, achieved limited clinical importance. Piperidindiones including glutethimide and methyprylon were also used. 

C QHyN O SNa, as a potentially useful P-lactamase inhibitor capable of potentiating the activity of a number of clinically important P-lactam antibiotics against resistant strains (153). 

Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important P-lactamases (10—14,57,58) including penases, and Richmond-Sykes types 11, 111, IV, V, VI ([Bacteroides). Type I Cephases are poorly inhibited. Clavulanic acid synergizes the activity of many penicillins and cephalosporins against resistant strains. The chemistry (59—63), microbiology (64,65), stmcture activity relationships (10,13,60—62,66), biosynthesis (67—69), and mechanism of action (6,26,27,67) have been reviewed. 

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Proetz, A. W. (1951). Air currents in the upper respiratory tract and their clinical importance. Ann. Otol. Rhinol. Laryngol. 60, 439-467. 

Biotechnology and synthetic chemistry as routes to clinically important compounds, in particular terpenolactones 99PAC1025. 

Preparation of clinically important natural products using plant cell culture and synthetic chemistry 97G293. 

Combined biotechnological and synthetic methods for preparation of polycyclic y-lactones, clinically important compounds 98PAC2093. 

The oldest effective drug for the treatment of this disease is indisputably quinine. Although the antipyretic activity of cinchona bark was known to the Incas, it remained for the Jesuit missionaries to uncover its antimalarial properties in the early seventeenth century. The advance of organic chemistry led to the isolation and identification of the alkaloid, quinine, as the active compound at the turn of this century. The emerging clinical importance of this drug led up to the establishment of cinchona plantations in the Dutch East Indies. This very circum-... 

Buscher, R., Hermann, V., and Insel, P. A. (1999). Human adrenoceptor polymorphisms Evolving recognition of clinical importance. Trends Pharmacol. Sci. 20 94-99. 

Table 11.1. Clinically important antibiotics and the producing microorganism3...

Capecitabine is used for the treatment of colorectal and breast cancers. It is contraindicated in patients with known hypersensitivity to capecitabine or any of its components or to 5-fluorouracil and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. The use of capecitabine is restricted in patients with severe renal impairment. The drag can induce diarrhea, sometimes severe. Other side effects include anemia, hand-foot syndrome, hyperbilirubinemia, nausea, stomatitis, pyrexia, edema, constipation, dyspnea, neutropenia, back pain, and headache. Cardiotoxicity has been observed with capecitabine. A clinically important drag interaction between capecitabine and warfarin has been demonstrated. Care should be exercised when the drag is co-administered with CYP2X9 substrates. 

Autoimmune diseases may inflict on each organ or cell. Manifestations range from affecting a single cell type and its specific function (such as the (3-cell of the islands in the pancreas) to systemic diseases which have a detrimental effect on an entire organ system (e.g. the vasculature) of even many different organs. Table 1 summarizes some clinically important diseases. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

Drug Interactions. Table 1 Examples of clinically important drug interactions due to enzyme inhibition... 

Dtug interactions can cause serious problems in clinical practice especially when the affected dmg has the potential to be highly toxic. Furthermore, pharmacokinetic interactions are clinically important if the affected dmg has a narrow therapeutic range (i.e. small difference between the minimum effective concentration and the toxic concentration Fig. 1) and a steep concentration-response curve (i.e. significant alterations in pharmacological and/or adverse effects caused by small changes in blood concentration). 

O-phosphotransferases that modify macrolides are produced by highly macrolide resistant E. coli isolates. However, these enzymes have no clinical importance for macrolide resistance in gram-positive bacteria, and gram-negative ones are regarded as naturally resistant [2]. 

SWS/SWA, in particular, may play an important role in somatic and cognitive restoration, including the consolidation of certain forms of procedural and declarative memory. A substantial diminution in the amount of SWS/SWA occurs across the human lifespan. This decline is beginning already in adolescence and middle-aged adults have only 25% of the SWS observed in young adults, whereas the elderly have almost none. While the clinical importance of these phenomena is unknown, it is reasonable to speculate that they may be related to the increase of sleep complaints associated with aging. 

Onset, peak, and duration are three properties of insulin diat are of clinical importance... 

Several groups of drugs that bind to tubulin at different sites interfere with its polymerization into microtubules. These drugs are of experimental and clinical importance (Bershadsky and Vasiliev, 1988). For example, colchicine, an alkaloid derived from the meadow saffron plant Colchicum autumnale or Colchicum speciosum), is the oldest and most widely studied of these drugs. It forms a molecular complex with tubulin in the cytosol pool and prevents its polymerization into microtubules. Other substances such as colcemid, podophyllotoxin, and noco-dazole bind to the tubulin molecule at the same site as colchicine and produce a similar effect, albeit with some kinetic differences. Mature ciliary microtubules are resistant to colchicine, whereas those of the mitotic spindle are very sensitive. Colchicine and colcemid block cell division in metaphase and are widely used in cytogenetic studies of cultured cells to enhance the yield of metaphase plate chromosomes. 

A variety of other clinically important infections, such as brucellosis, listeriosis, salmonellosis, and various Mycobacterium infections, are of interest as these are often localized in organs rich in MPS cells. Liposome encapsulation has been demonstrated to improve therapeutic indices of several drugs in a number of infectious models. The natural avidity of macrophages for liposomes can also be exploited in the application of the vesicles as carriers of immunomodulators to activate these cells to an microbicidal, antiviral, or tumoricidal state. These studies were recently reviewed by Emmen and Storm (1987), Popescu et al. (1987), and Alving (1988). In addition to the treatment of "old" infectious diseases, the concept of MPS-directed drug delivery is of considerable interest for the therapy AIDS, possibly enabling control of human immunodeficiency virus replication in human macrophages. 

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

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