Clinical evaluation

Hydrazine sulfate [10034-93-2] N2H4 H2SO4, originally advanced by the Syracuse Cancer Research Institute for treatment of cancerous cachexia and tumor inhibition (221), now has Investigational New Dmg (IND) status in the United States. Clinical evaluations are under way at various institutions such as Harbor-UCLA Medical Center (222) and the Mayo Clinic. After extensive trials, hydrazine sulfate has been approved as an anticancer dmg in Russia (223). Chemical stmctures for estabUshed dmgs in the United States may be found in Reference 224. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

Heptylphysostigmine (eptastigmine) (17) has been shown to be as active as physostigmine in AChE inhibition, but superior to physostigmine in terms of oral bioavadabihty and half-life (118—120). However, further clinical evaluation of this compound has been halted because of dmg-related hematological toxicity. 

Metrifonate [52-68-6] (24) is itself not an AChE inhibitor, but is none2ymaticaIly converted into an active irreversible inhibitor of the en2yme. The compound is relatively specific for AChE over butyrylcholinesterase (135) and the irreversible nature of its inhibition gives rise to an extended duration of action. Some clinical experience has been gained through its use to treat schistosomiasis (136,137) and it is undergoing clinical evaluation for AD. 

Apphcation for discovery and product patents must be made early in the process. Appropriate labels ate designed and the product is submitted to the FDA for approval to begin human testing in the form of an Investigational New Dmg Apphcation (INDA). When such approval is granted, the clinical evaluation is developed as follows. 

This drug also is reported to activate macrophages, to iaduce polyclonal B-ceU activation as well as enhance specific antibody production m vivo, and to iaduce the synthesis of iaterferon and interleukin 1 (52). The iaduction of these important cytokiaes (and others) largely accounts for the profile of biological activity displayed by the pyrimidinones. Bropirimine is currentiy ia clinical evaluation for cancer, arthritis, and immunorestoration ia AIDS patients. 

The -NH(CH2)3N(CH2)2 amide of teicoplanin factor A2-2, coded MPT. 62,873 [122173-74-4] was also prepared. The combined effect of a moderate basicity and a slightly increased lipophilicity at neutral pH probably led to a better penetration through the cell wall. MDL 62,873 was consistentiy more active than teicoplanin against CNS clinical isolates (119,120). No semisynthetic dalbaheptide is under clinical evaluation at this writing. 

Clinical evaluation is underway to test transvenous electrodes. Transvenous leads permit pacemakers to be implanted under local anesthesia while the patient is awake, greatly reducing recovery time and risk. As of 1996, the generation of implantable defibrillators requires a thoracotomy, a surgical opening of the chest, in order to attach electrodes to the outside of the heart. Transvenous electrodes would allow cardiologists to perform pacemaker procedures without a hospital or the use of general anesthesia. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

The stmctures of selected cephalosporins on the U.S. market, or in the final stages of development, are shown in Tables 4—8 (see also 78, 87). For every cephalosporin which has made it to the marketplace, HteraHy thousands of analogues were synthesized in order to estabUsh the stmcture-activity profile and allow selection of a clinical candidate. In addition to these compounds, there is a tremendous number of cephalosporin compounds currendy at various stages of development. A more extensive listing of the newer cephalosporins under preclinical or clinical evaluation may be found in a number of reviews (79,88). 

Macchiarini, R, Wain, J., Almy, S. and Dartevell, R, Experimental and clinical evaluation of a new synthetic, absorbable sealant to reduce air leaks in thoracic operations. J. Thorac. Cardiovasc. Surg., 117, 751-758 (1999). 

Given the routine use of mast cell stabilizers in the clinic, for example in the setting of asthma treatment, these preclinical results may stimulate clinical evaluation in humans. 

In addition to those described above, some of the newest compounds emerging in SERM development are ER 3-selective ligands and pathway-selective modulators that target the interaction of the ERs with the transcription factor NFkB. While such compounds are in the early stages of clinical evaluation, thus far they demonstrate great potential for use in the treatment of inflammatory disorders such as arthritis, inflammatory bowel disease, and like other SERMs, cancer [4]. 

The role of standards Clinical evaluations Summary technical files... 

STB The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Immunotoxicology Studies... 

El 4 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Pharmacogenomics... 

As medical researchers continue to explore the therapeutic properties of interferons, chemical engineers will continue to provide the expertise needed to make available the quantities of these molecules necessary for clinical evaluation. 

National Research Council Clinical evaluation of naltrexone treatment of opiate-dependent individuals report of the National Research Council Committee on Clinical Evaluation of Narcotic Antagonists. Arch Gen Psychiatry 35 335—340, 1978... 

Clinical Evaluation of Patients With Inhalant Use Disorders... 

Kono J, Miyata H, Ushijima S, et al Nicotine, alcohol, methamphetamine, and inhalant dependence a comparison of clinical features with the use of a new clinical evaluation form. Alcohol 24 99-106, 2001... 

IFN-)il exhibits dose- and time-dependent inhibition of HCV rephcation in various models, independently of type I and IIIFN receptors and induced pathways (Marcello et al. 2006). A pegylated form of IFN-A, will soon enter clinical evaluation. 

The accumulated cells do not carry an HIV provirns (Egelhofer et al. 2004). This peptide has been clinically evaluated as described later. 

Layton AM, Henderson CA, Cunliffe WJ (1994) A clinical evaluation of acne scarring and its incidence. Clin Exp Dermatol 19 303-308... 

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