XENOBIOTICS ACTING ON THE BLOOD

Table of contents :



In many ways, erythrocytes would make an ideal agent for drug delivery. They are the most abundant cellular constituent in blood, and on average travel hundreds of kilometres in the vasculature during their lifespan (100–120 days). If they could be converted into carriers, they could, in theory, prolong the circulation and improve the bioavailability of drugs that act in the bloodstream. Loading therapeutic agents into erythrocytes is of limited value, as many drugs diffuse poorly across the erythrocyte membrane. However, coupling agents to the erythrocyte surface could overcome this problem.

Hematopoiesis-stimulating agents :

  • Erythropoiesis stimulating agents (ESA) :
  • EPO-R agonists
  • haemopoietic cell phosphatase inhibitors extend the phosphorylation of JAK2 and STAT5ref1, ref2
  • HIF-1a stabilisers : moderate genetic overxpression of HIF causes premature mortality related to cerebrovascular events and peripheral thrombosisref
  • HIF-1a prolyl 4-hydroxylase (HPH) inhibitorref1, ref2 (Urquilla P, Fong A, Oksanen S, et al. Upregulation of endogenous EPO in healthy subjects by ihibition of HIF-PH. J Am Soc Nephrol 2004;14;546A; Wiecek A, Piecha G, Ignacy W, et al. Pharmacological stabilization of HIF increases hemoglobin concentration in anemic patients with chronic kidney disease. Nephrol Dial Transplant 2005;20(suppl.6) v195))
  • Procoagulants / styptics Anticoagulants (therapy of thrombosis) Antithrombotics (anti-thrombosis)ref
    Thrombolytics / fibrinolytics
     

    dosage
    duration
    thromboselectivity
    disadvantages
    Serratia peptidase / serrapeptase (Danzen©)

    selective
    alteplase / r-tPA (Activase®, Actilyse® (cloned in CHO cells; source : Genentech Inc, USA)) began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s 100 mg 4 hours selective high cost
    amediplase is a chimeric protein which combines part of the tissue plasminogen activator (tPA) and part of the single-chain urokinase plasminogen activator (sc-UPA). Administration in a bolus injection, which constitutes an advantage over the standard thrombolytic treatments. Currently it is in Phase III clinical trial. 80 mg in 1 hour 7 hours selective high cost
    reteplase / deletion mutant r-tPA (Rapilysin® (cloned in Escherichia coli; source : Boehringer Mannheim, T/A Roche Diagnostics, Germany), Retavase©) has been reported to restore patency to CVCs in 30 minutes; it is used for the treatment of ischaemic stroke within 3 hours of symptom onset

    selective
    tenecteplase / 3 mutations r-tPA (Metalyse® (cloned in CHO cells; source : Genentech Inc, USA), TNKase®)

    selective
    desmoteplase / recombinant Desmodus rotundus salivary plasminogen activator (DSPA alpha-1) (source : PAION GmbH, under license from Schering AG) is currently undergoing phase II clinical trial for treatment of acute ischaemic stroke. DSPA, unlike tPA, does not promote kainate- or NMDA-mediated neurotoxicity in vivo. The distinguishing characteristic of vampire bat salivary plasminogen activators (DSPAs) is their strict requirement for fibrin as a cofactor. DSPAs consist of structural modules known from u-PA and t-PA such as finger (F), epidermal growth factor (E), kringle (K), and protease (P), combining to 4 genetically and biochemically distinct isoenzymes, exhibiting the formulas FEKP (DSPA alpha 1 and alpha 2) and EKP and KP (DSPA beta and DSPA gamma). Only DSPA alpha 1 and alpha 2 bind to fibrin. All DSPAs are single-chain molecules, displaying substantial amidolytic activity. In a plasminogen activation assay, all 4 DSPAs are almost inactive in the absence of fibrin but strongly stimulated by fibrin addition. The catalytic efficiency (kcat/Km) of DSPA alpha 1 increases 105-fold, whereas the corresponding value of t-PA is only 550. The ratio of the bimolecular rate constants of plasminogen activation in the presence of fibrin versus fibrinogen (fibrin selectivity) of DSPA alpha 1, alpha 2, beta, gamma, and t-PA was found to be 13,000, 6500, 250, 90, and 72, respectively. Whereas all DSPAs are therefore more fibrin dependent and fibrin selective than t-PA, the extent depends on the respective presence of the various domains. The introduction of a plasmin-sensitive cleavage site in a position akin to the one in t-PA partially obliterates fibrin cofactor requirement. Fibrin dependence and fibrin selectivity of DSPAs are accordingly mediated by fibrin binding, which involves the F domain, as yet undefined determinants within the K and P domains, and by the absence of a plasmin-sensitive activation site. These findings transcend the current understanding of fibrin-mediated stimulation of plasminogen activation: in addition to fibrin binding, specific protein-protein interactions come into play, which stabilize the enzyme in its active conformationref.

    selective tPA upregulates MMP-9 via LRP, causing degradation of neurovascular matrix integrity when given to stroke patients
    alfimeprase (3–203 Fibrolase [3-Ser]), a recombinant fibrinolytic enzyme derived from fibrolase, with 3 disulfide bonds (Cys-116/196, Cys-156 /180, and Cys-158/163). Soluble alfimeprase is secreted by Pichia pastoris and a series of chromatography steps has been developed to generate pure material at Amgen. Alfimeprase differs from fibrolase in the amino-terminal region, where the amino-terminal three residues of fibrolase (Glu-Gln-Arg) were replaced with a single serine residue. The truncated analog was designed to prevent the formation of cyclized glutamine (pyroglutamic acid). Fibrolase and alfimeprase are similar with respect to thrombolytic activityref and are irreversibly bound by a2-macroglubulinref. The enzymes exhibit direct fibrinolytic activity without the activation of plasminogen, thus little hemorrhagic activity is observedref1, ref2. Because of their thrombolytic activity, low hemorrhagic response, and a2-macroglubulin binding, these enzymes have a high therapeutic potential for treating thrombotic disease. Alfimeprase is in a clinical trial for the treatment of peripheral arterial occlusionref.

    selective
    streptokinase (Streptase®) : it cleaves Arg560 on free plasminogen molecules to form free plasmin 1,500,000 IU in 60 seconds 18-24 hours nonselective allergic phenomena, systemic arterial hypotension
    anistreplase / anisoylated plasminogen streptokinase activator complex (APSAC) (Eminase®) : Lys-plasminogen acylated at its catalytic-site Ser complexed to streptokinase 30-60 IU in bolus 110 hours poorly selective allergic phenomena
    prourokinase / saruplase (Rescupase®) (single-chain)

    nonselective
    urokinase (Abbokinase®) (two-chain) 2,000,000 IU in 15 seconds 18 hours poorly selective high cost
    heparin bound to dimeric FGF-2 / bFGF (dFGF2) leads to the dimerization of FGFR1 and activation of receptor tyrosine kinase : if given within 24 hours of a stroke, can limit the amount of brain tissue that is damaged. If given after 24 hours, it can substantially improve the patient’s rate of functional recovery, which the current treatment does not. Because dFGF2 can be given in small doses, it also reduces serious side effects, such as extreme weight loss, which patients have experienced in previous clinical studiesref

    nonselective
    ancrod, a natural defibrinogenating agent from snake venom, has proved to have a favourable effect when given within 3 h after an acute ischaemic strokeref



    Side effects : hemorrhages, treated with antithrombolytics : Antiplatelet drugs Anti-dyslipidemia xenobiotics
    drug class 
    agents and daily doses lipid/lipoprotein effects side effects contraindications
    HMG-CoA reductase inhibitors (statins)
    high binding to plasma protein, plasma peak within 0.6-4 hours, hepatic catabolism. Around 7% of the population carry 2 SNPs that may alter the amount of HMG-CoA reductase that is made, so that statins cannot work so well.
  • lovastatin (20-80 mg)
  • pravastatin (20-40 mg)
  • simvastatin (20-80 mg)
  • fluvastatin (20-80 mg)
  • atorvastatin (10-80 mg)
  • cerivastatin (0.4-0.8 mg)
  • inhibit synthesis and allows depletion of cholesterol storages
  • up-regulate LDLR => increased clearance of LDL => decreased plasma LDL-Ch by 18-55% (50-60% if combined with ion exchange resin or nicotinic acid; 70% if combined to ion exchange resin and nicotinic acid);
  • inhibit production of VLDL and alter their composition => reduction of TG by 10-30%;
  • reduces HDL-Ch by 5-15%; tolerance induces up-regulation of HMG-CoA reductase.
  • TG -7-30%
  • see also nonmetabolic effects
  • rhabdomyolysis if assumed with cyclosporine A, erythromycin,HM74 agonists, or PPAR-a agonists => prerenal acute renal failure
  • tendinopathyref
  • fetal toxicity
  • transaminitis if assumed with ethanol : lupus-like syndromeref1, ref2, ref3, ref4, ref5 or severe acute hepatitis : risks and benefits of statins in lupus erythematosusref
  • Guillain-Barre-like syndromeref 
  • lactic acidosisref
  • absolute: active or chronic liver disease
  • relative: concomitant use of cyclosporine, macrolide, various anti-fungal agents, and cytochrome P-450 inhibitors (fibrates and niacin should be used with appropriate caution monitoring serum CPK levels)
  • bile acid sequestrants / ion exchange resins : when in bowel lumen, biliary acids are exchanged with Cl-, preventing their enterohepatic recirculation
  • cholestyramine (Questran®, Questran Light®, Locholest Light®, Prevalite®) (hydrophobic) (4-16 g) 
  • colestipol chlorhydrate (Colestid®, Flavored Colestid®) (hydrophilic) (5-20 g) 
  • colesevelam (Welchol®) (2.6-3.8 g)
  • up-regulation of LDL-R => increased clearance => decrease of plasma LDL-C -15-30%
  • HDL-C -3-5%
  • TG : no change or increase
  • gastrointestinal distress (constipation, meteorism)
  • decreased absorption and recirculation of T4, Digitalis glycosides, oral anticoagulants, thiazide diuretics, furosemide, and tetracyclines if administered within 1 hour before and 4 hours later the ion exchange resin.
  • increased TG
  • absolute:
  • dysb-lipoproteinemia
  • TG >400 mg/dL

  • relative:
  • TG >200 mg/dL
  • nicotinic acid / HM74 agonists (half-life is very short and high doses are needed : 2-6 g/die)
    immediate release (crystalline) nicotinic acid (1.5-3 gm), extended release nicotinic acid (Niaspan®) (1-2 g), sustained release nicotinic acid (1-2 g) inhibition of lipolysis => decrease of FFA => decreased synthesis of TG => decreased VLDL => activation of LPL
    decreased Lp(a)
    LDL-C -5-25%
    HDL-C -15-35%
    TG -20-50%
  • facial flushing
  • hyperglycemia
  • hyperuricemia (or gout)
  • upper GI distress : dyspepsia, vomiting, diarrhoea (assume during meals), cholelithiasis, liver failure
  • cutaneous symptoms : skin dryness, itching on upper body (aspirin-responsive)
  • cystoid macular edemaref1, ref2, ref3. identical to that seen after cataract extractionref. It is usually seen in men between the ages of 30 and 60 yearsref. and usually resolves when niacin therapy is stoppedref. Prompt recognition of the association of visual loss with niacin in patients taking this drug is critical. 
  • absolute:
  • chronic liver disease
  • severe gout

  • relative:
  • diabetes mellitus
  • hyperuricemia
  • peptic ulcer disease
  • fibric acids / PPAR-a agonists > 90% is absorbed, peak after 2-4 hours, 95% bound to plasma proteins, 60-90% renal excretion. Don't adminster during pregnancy or in patients with renal and/or hepatic failure.
    Clofibrate is used to treat secondary dysb-lipoproteinemia.
    Gemfibrozil and fenofibrate are used to treat familial dysb-lipoproteinemia and familial combined hypertriglyceridemia.
    gemfibrozil (600 mg BID)
    fenofibrate (200 mg) 
    clofibrate (1000 mg BID)
    LDL-Ch -5-20% (may be increased in patients with high TG)
    HDL-Ch -10-20%
    TG -20-50%
  • rhabdomyolysis if assumed with cyclosporine A, erythromycin, clarithromycin, HM74 agonists, or PPAR-a agonists => prerenal acute renal failure
  • dyspepsia
  • cardiopathies
  • optical maculopathy
  • increase of LDL (if hypertriglyceridemia occurred)
  • decrease of platelet aggregation
  • cholelithiasis
  • gastro-intestinal tract disorders
  • increased risk of fractures in female 
  • absolute:
  • severe renal disease 
  • severe liver disease
  • inhibitors of NPCL1 expressed in the brush border membrane of enterocytes, which mediates dietary and biliary cholesterol absorptionref)
  • SCH 58235 / ezetimibe (Ezetrol®, Zetia®; Vytorin® or Inegy® in combination with simvastatin; source : Merck/Schering-Plough)
  • SCH 48461
  • SCH 58053
  • SCH354909, a fluorescent derivative



  • probucole : antioxidant drug of second/third choice due to unpredictable side effects. Used in homozygous FH. Continue use for 2-3 months causes accumulation in fat tissue and release for up to 6 months after suspension. Vehicled by LDLs. 500 mg / bis die PO. Biliary excretion.

    don't affect LDL-R
    decreased LDL
    decreased HDL 20-30%
  • diarrhea
  • QT tract lengthening (don't associate to class I or class III antiarrhythmic drugs, tricyclic antidepressants, phenothiazines)
  • MTP inhibitors
    lomitapide


    ACAT-1 inhibitors




    ACAT-2 inhibitors




    CETP inhibitors

    HDL-Ch +50-100%ref1, ref2, ref3

  • phytosterols (PS) / sterolins
    • b-sitosterol (BSS)
    • campesterol
    • stigmasterol
    ... interfer with the solubilisation of the cholesterol in the intestinal micelles and, thus, absorption is reduced : 1.5-3 g/day reduce LDL-cholesterol by 8-15%. The only side effect is that they can interfere with the absorption of carotenoids, but this can be compensated for in the diet or by adding these compounds in appropriate carriers. It has also been reported that phytosterols have anticancer properties and act as immunomodulators.





    How to raise low HDL-Ch levelsref : Anti-hyperuricemia drugs : Anti-amyloid drugs :
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