Immunomodulator additives

Other Immunomodulating Agents Plus WR-2721/Thiols. Combining WR-2721 (200 mg/kg ip 30-min preirradiation) and BV (25 mg/kg ip 24-h preirradiation) demonstrates at least additive radioprotection in the ( 54). Protection is optimal when WR-2721 is given 30... 

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. 

The sterols and sterolins in rice bran are potent immunomodulators. The best response was obtained with a 100 1 sterol/sterolin mixture that demonstrated T-cell proliferation from 20% to 920% and active cell antigens after four weeks in human subjects (Bouic et al, 1996). Another in vitro experimental study with sterol/sterolins, demonstrated a significant increase in cytokinines, interleukin-2 and y-interferon between 17% and 41 % in addition to an increase in natural killer cell activity. These experiments (Bouic et al, 1996) prove that sterol/sterolins are potent immunomodulators with important implications for the treatment of immune dysfunction. Rice bran products are excellent dietary supplements for the improvement of immune function. It is probable that the effects of rice bran on diabetes, CVD and cancer all result from improved immune function. 

Cells of the T cell lineage appear to be more sensitive to the immunomodulatory effects of Pb compared to other lymphoid populations. In addition, there are considerable differences in sensitivity across various T cell subpopulations [38 41], This differential sensitivity has become another major hallmark of Pb-induced immunotoxicity, although most data implicate T cells as indirect targets of Pb immunotoxicity. Both in vivo and in vitro observations of T-dependent immune responses in the presence of Pb suggest that T helper function and Th-dependent cytokines are skewed preferentially toward Th2 reactivities. Smith and Lawrence [42] found that Pb inhibited antigen presentation and stimulated a T cell clone of the Thl phenotype. McCabe and Lawrence [38] were the first to show that Pb inhibited Thl stimulation while it promoted presentation to Th2 clones. Heo and colleagues [39 41] provided both in vitro and in vivo results supporting this immunomodulation by Pb. 

This book will be of interest to toxicologists, immunologists, clinicians, risk assessors, and others with an interest in accidental or deliberate immunomodulation. Although few of the chapters are written on an introductory level, background information and citations for review articles are included in most chapters that will provide a starting point for individuals seeking additional information. 

In addition to antineoplastic, cytotoxic agents, there are cancer therapeutic or preventative drugs that are intended to be given on a chronic basis. This includes chemopreventatives, hormonal agents, immunomodulators, and so on. The toxicity assessment studies on these will more closely resemble those of more traditional pharmaceutical agents. Chronic toxicity, carcinogenicity, and Ml developmental toxicity (ICH A-B, C-D, E-F) assessments will be required. For a more complete review, the reader is referred to DeGeorge et al. (1998). 

Encapsulation of immunomodulators, e.g. muramyl tripeptide analogues, into liposomes has been designed to stimulate host immunity [108] and can be used in combination with other treatment modalities. The systemic activation of macrophages provides an additional therapeutic modality for the eradication of cancer and cancer metastases. 

The other limitation of the CFU assay in either format is that it remains an in vitro environment where distant interactions, like liver metabolism (either detoxifying the compounds or producing toxic metabolites) or immunomodulation, are absent. Investigating the meciianism of toxicity in animals for some carefully chosen compounds after being ciiaracTerized in the two previous assays, can provide valuable information for the whole series, allow further refinement of the in vitro assays (e.g., addition of S9 for metabolism) and give an early indication of which biomarkers could be used in later GLP studies. 

The ecteinascidins constitute a group of very complex alkaloid tris(tetrahydroisoquinolines) with potent in vivo antitumor activity and were isolated from the colonian Caribbean tunicate Ecteinascidia turbinata. The compounds are abbreviated as Et followed by a number that represents the value of the highest mass ion observed in the (+)-FABMS. Reports of the potent in vivo activity of extracts of that tunicate date back to 1969, when it was reported that such extracts gave T/C values of up to 272 vs P388, with four of six cures in one experiment, and they were also found to be powerful immunomodulators [72]. After a decade of effort, two research groups reported at the same time the structures of four [Et 743 (1), Et 729 (63), Et 745 (64), and Et 770 (66)] [72] and two [Et 743 (1), Et 729(63)] [73] ecteinascidins, respectively. The development of an isolation process that was efficient on a large scale allowed Rinehart s group to obtain additional ecteinascidins, Et 743 V2-oxide (67), Et 722... 

The synthesis of diaryl-thiazolotriazepines 62 from the reaction of l,2,4-triazepine-3-thiones 63 (1.8 mmol) with 2-haloketones 64 (6.25 mmol) in ethanol under reflux for 2h was described <1999T5909> with the goal of creating new immunomodulating agents (Scheme 5). The starting triazepines were prepared by the addition of thiocyanic acid 65 to the chalcones 66 according to an already known method, followed by reaction of the intermediate 67 with hydrazine. 

Such events show how the immune, endocrine and central nervous systems are integrated in their responses to any form of stress. It is well established that physical or psychosocial stress causes increased secretions of prolactin, growth hormones, thyroid, and gonadal hormones, in addition to ACTH. Endogenous opioids are secreted under such conditions and function as immunomodulators, while also elevating the pain threshold. Receptors for such hormones exist on immunocompetent cells, along with receptors for catecholamines, serotonin and acetylcholine. 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

THIAZIDES IMMUNOMODULATING DRUGS-CICLOSPORIN Risk of nephrotoxicity Additive effect Monitor renal function weekly... 

MAOIs ANTICANCER AND IMMUNOMODULATING DRUGS-PROCARBAZINE Concurrent therapy t risk of hypertensive crisis and severe seizures Additive effect on inhibiting MAO Concurrent treatment should not be started on an outpatient basis. 14 days should elapse before starting these medications after procarbazine treatment... 

BUSPIRONE ANTICANCER AND IMMUNOMODULATING DRUGS - PROCARBAZINE Risk of elevation of blood pressure Additive effect buspirone acts at serotonin receptors procarbazine inhibits the breakdown of sympathomimetics Avoid concurrent use... 

CARMUSTINE ANTICANCER AND IMMUNOMODULATING DRUGS-ETOPOSIDE (HIGH DOSE) t risk of liver toxicity, which usually occurs after 1 -2 months after initiating treatment without an improvement in tumour response Possible additive hepatotoxic effects Avoid co-administration... 

IDARUBICIN ANTICANCER AND IMMUNOMODULATING DRUGS -TRASTUZUMAB t risk of cardiotoxicity Additive cardiotoxic effects Avoid co-administration except in clinical trials... 

PORFIMER I. ACE INHIBITORS -enalapril 2. ANALGESICS -celecoxib, ibuprofen, ketoprofen, naproxen 3. ANTIARRHYTHMICS — amiodarone 4. ANTIBIOTICS -ciprofloxacin, dapsone, sulphonamides, tetracyclines 5. ANTICANCER AND IMMUNOMODULATING DRUGS -fluorouracil (topical and oral) 6. ANTIDIABETIC DRUGS-glipizide 7. ANTIMALARIALS -hydroxychloroquine, quinine 8. ANTIPSYCHOTICS -chlorpromazine, fluphenazine 9. CALCIUM CHANNEL BLOCKERS - diltiazem 10. DIURETICS -bumetanide, furosemide, hydrochlorothiazide II. PARA-AMINOBENZOIC ACID (TOPICAL) 12. RETINOIDS-acitretin, isotretinoin 13. SALICYLATES (TOPICAL) t risk of photosensitivity reactions Attributed to additive effects Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy... 

ANAKINRA ANTICANCER AND IMMUNOMODULATING DRUGS-ADALIMUMAB, ETANERCEPT, INFLIXIMAB t risk of bone marrow suppression Additive effect Avoid co-administration... 

BACLOFEN, TIZANIDINE 1. ANAESTHETICS - general 2. ANTICANCER AND IMMUNOMODULATING DRUGS - IL-2 3. ANTIDEPRESSANTS - MAOIs 4. ANTI HYPERTENSIVES AND HEART FAILURE DRUGS 5. ANTI-PSYCHOTICS 6. ANXIOLYTICS AND HYPNOTICS 7. BETA-BLOCKERS 8. CALCIUM CHANNEL BLOCKERS 9. DIURETICS 10. NITRATES 11. PERIPHERAL VASODILATORS-moxisylyte (thymoxamine) 12. POTASSIUM CHANNEL ACTIVATORS t hypotensive effect Additive hypotensive effect. Tizanidine also has a negative chronotropic effect and may cause additive bradycardia with beta-blockers and calcium channel blockers Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)... 

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