Clinical uses

The predominant clinical use of corticosteroids is a result of their associated antiinflammatory properties. These are commonly used as topicals for the suppression of symptoms, including inflammation, occurring in a particular disease state these compounds are rarely considered curative in their usage. Many other disease states do, however, respond well symptomatically to treatment with corticosteroid therapy. Some of these (11) are Hsted below. 

Although the compounds were isolated in quantities of only a few milligrams per kilogram of cmde plant leaves, extensive work on a variety of animal tumor systems led to eventual clinical use of these bases, first alone and later in conjunction with other materials, in the treatment of Hodgkin s disease and acute lymphoblastic leukemia. Their main effect appears to be binding tightly to tubuHn, the basic component of microtubules found in eukaryotic cells, thus interfering with its polymerization and hence the formation of microtubules required for tumor proliferation (82). 

W. I. Taylor and N. R. Famswortli, eds., The Catharanthus Alkaloids, Botanj, Chemist, Pharmacology and Clinical Uses, Marcel Dekker, New York, 1973 W. I. Taylor and N. R. Famswortli, eds.. The Uinca Alkaloids, Botanj, Chemistry and Pharmacology, Marcel Dekker, New York, 1973. 

A method for the fractionation of plasma, allowing albumin, y-globulin, and fibrinogen to become available for clinical use, was developed during World War II (see also Fractionation, blood-plasma fractionation). A stainless steel blood cell separation bowl, developed in the early 1950s, was the earhest blood cell separator. A disposable polycarbonate version of the separation device, now known as the Haemonetics Latham bowl for its inventor, was first used to collect platelets from a blood donor in 1971. Another cell separation rotor was developed to faciUtate white cell collections. This donut-shaped rotor has evolved to the advanced separation chamber of the COBE Spectra apheresis machine. 

The clinical use of plasma products varies widely between countries (Table 8) with commercial products being imported in some instances to meet demand. In the United States, the market for plasma products increased from 250,000,000 in 1980 to over 850,000,000 in 1991. This expansion resulted from a 60% increase in the use of albumin, a 70% increase in the use of Eactor X concentrate, and the introduction of intravenous immunoglobulin (IgG iv). The 1987 quantity of IgG iv was 10.7 kg per million population by 1991 this usage had increased approximately 220%. The introduction of highly... 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

U.S.A., in lactating dairy cattie to increase milk production. EH Lilly and Company, The Upjohn Company, and American Cyanamid Company also have interests in the commercial appHcation of recombinant bovine GH. Recombinant porcine GH [9061-23-8] preparations from several companies, eg. The Upjohn Company, Smith Kline Beecham Animal Health, Pitman-Moore, Inc., Monsanto Company, and American Cyanamid Company, are being evaluated for commercial use. Recombinant human GH for clinical use is marketed under such names as Protropin (Genentech), Umatrope (EH Lilly), Genotropin (Sumitomo), and Somatonorm (Kabi-Vitmm) by a variety of pharmaceutical companies. A listing of additional suppHers is available (2). 

For the purposes of this article, antiestrogens are compounds that counteract the biological activity of estrogens at the receptor level. In the late 1970s, there were no steroidal antiestrogens in widespread clinical use. Clomiphene [911 -45-5]( ) and tamoxifen/7(954(9-25 -/7(9) were nonsteroidal antiestrogens that had been employed for the treatment of female infertility and breast cancer, respectively. 

There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

Biomedical and Biotechnology. The use of mictocapsules for a variety of biomedical and biological appHcations has been promoted for many years (50,51). Several biomedical mictocapsule appHcations ate in clinical use or have approached clinical use. One appHcation is the use of air-fiUed human albumin mictocapsules as ultrasound contrast agents. Such mictocapsules, caUed mictobubbles, ate formed by ultrasonicating 5% albumin solutions to produce 4—10-)J.m diameter air-fiUed capsules (52). When injected the capsules act as a useful transpulmonary echo contrast agent (53) that has been approved for use in humans by the U.S. FDA. 

NO synthons, including the vasodilators sodium nitropmsside (SNP) (261) and nitroglycerin (262), have been in clinical use since the 1970s. Newer synthons include molsidomine (263) and the NONOates, prodmg dimers of NO. 

Einahy, all data, including the results of the clinical investigation, ate collected in a New Dmg Apphcation (NDA) and sent to the EDA. Once approved, the new dmg goes into production. After manufacturing begins, the new dmg products must be monitored in clinical use in the marketplace for reports of untoward reactions. This amounts to post-approval surveillance known as Phase IV. All such reports must be submitted to the EDA in a timely manner. 

The primary site of action is postulated to be the Hpid matrix of cell membranes. The Hpid properties which are said to be altered vary from theory to theory and include enhancing membrane fluidity volume expansion melting of gel phases increasing membrane thickness, surface tension, and lateral surface pressure and encouraging the formation of polar dislocations (10,11). Most theories postulate that changes in the Hpids influence the activities of cmcial membrane proteins such as ion channels. The Hpid theories suffer from an important drawback at clinically used concentrations, the effects of inhalational anesthetics on Hpid bilayers are very small and essentially undetectable (6,12,13). 

Propanidid. Propanidid [1421-14-3] (Epontol), C gH2yNO, (7) a derivative of the propyl ester of homo vanillic acid, has been in clinical use in Europe for a number of years. Its main advantage is rapid onset of action and a fast recovery which, like etomidate, is because of rapid metaboHsm by esterases rather than redistribution (108). Excretion is rapid 75 to 90% of the dmg is eliminated as metaboUtes within two hours. Propanidid side effects include hypotension, tachycardia, and hyperventilation followed by apnea, as well as excitatory side effects such as tremor and involuntary muscle movement (109). 

Approved for clinical use in 1986, alfentani [71195-58-9] (Alfenta, Rapifen), is about one fourth... 

The rate of removal of the local anesthetic from the site of injection also affects its profile. AH local anesthetic agents possess some vasodilatory activity at clinically useful concentrations. Agents which are more potent in this regard tend to be absorbed more rapidly by the vasculature. They are less potent anesthetics and have shorter durations than those having lower vasodilatory activity. A comparison of potency, onset, and duration as a function of physiochemical properties is presented in Table 4. 

Specific Local Anesthetic Agents. Clinically used local anesthetics and the methods of appHcation are summarized in Table 5. Procaine hydrochloride [51-05-8] (Novocain), introduced in 1905, is a relatively weak anesthetic having along onset and short duration of action. Its primary use is in infiltration anesthesia and differential spinal blocks. The low potency and low systemic toxicity result from rapid hydrolysis. The 4-arninobenzoic acid... 

Table 5. Clinically Used Local Anesthetic Agents...

B. G. Coviao and H. G. VasaHo, Local Anesthetics Mechanism of Action and Clinical Use, Grune and Stratton, New York, 1976. 

NitrofuraZone. 2-[5-Nitro-2-furanyl)methylene]hydrazinecarboximide, the first nitrofiiran to be employed clinically, is prepared from 5-nitro-2-furancarboxaldehyde and semicarbazide (19). This product has seen clinical use topically as an antibacterial, for systemic appHcation for bacterial infections in poultry and swine, and also has been employed as a food additive. In rats, nitrofurazone is hydroxylated at the 4 position of the furan moiety (27). The involvement of nitrenium ions has also been postulated in the mechanism of action of nitrofurazone (38). 

Additional discussions are available in the General References concerning the properties of several nitrofiirans. This includes further coverage of the chemotherapeutic and physical properties antimicrobial activity bacterial resistance absorption, distribution, and excretion clinical use and safety studies, of this interesting class of antiinfective compounds. 

The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

Clinical Use. Vancomycin and teicoplanin as fomiulated dmgs are lyophilized powders to be reconstituted with sterile water for injection. Vancomycin hydrochloride [1404-93-9] is presented in vials of 500 mg that give 100—200 mL solution of pH 2.5—4.2. It is administered by slow (60 min) infusion at a dose of 500 mg every 6 h or 1 g every 12 h/d. The teicoplanin contains the five factors (87%) plus 13% of the pseudoaglycone T-A3-1. It is presented in vials containing 200 mg of lyophili ed power that after dissolution with 3 mL of solvent gives a solution at pH 7.5. The dose regimen is 200—800 mg/d by iv bolus adrninistration. 

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