ALT-711 (Alagebrium Chloride)

A Promising Advanced Glycation Endproduct (AGE) Crosslink Breaker
Currently in Clinical Trials

Below we present a summary of the major research results for this chemical (which has recently been given the generic name "alagebrium chloride"), taken from published studies in the peer-reviewed literature. For the latest information on the progress of this drug towards establishment acceptance as a therapeutic modality for recognized diseases, see Alteon Inc. - ALT-711 In its bromide form, ALT-711 has also been called DMPTB [N-phenacyl-4,5-dimethylthiazolium bromide] or PMTB and an earlier unmethylated form was called PTB.

Safety and Interactions

  1. In a trial of 93 humans, aged >= 50 years and with evidence of vascular stiffening, given an oral dosage of 210 mg of ALT-711 daily for 56 daysR1, R2:
  2. In an experiment with six male normotensive, nondiabetic rhesus monkeys, aged 21 3.6 years, ALT-711 was administered once every other day over a 3-week period as 11 intramuscular injections, each 1.0 mg per kg of body weight. The monkeys were studied for a total of 39 weeks and showed no apparent harm from ALT-711.R
  3. In an experiment in which 8 aged, but healthy, male mongrel dogs (10.6 0.7 years) received ALT-711 as a gelatin capsule at a single oral daily dose of 1 mg/kg for 4 weeks, there were no changes in fasting blood glucose, hemoglobin A1C, hemoglobin, and creatinine (tested) nor any observable deficits.R
  4. Treatment of rats having streptozotocin-induced diabetes with ALT-711 (1.0 mg/kg per day i.p. for 1-3 weeks) did not result in significant weight or blood glucose level changes.R

Proven Benefits

  1. "OBJECTIVES: Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats....
    RESULTS: Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels.
    CONCLUSIONS: These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED."R
  2. "Sixteen weeks of treatment [of 21 patients, mean age 71 years, with stable DHF (diastolic heart failure)] with the glucose crosslink breaker, alagebrium [at 420 mg per day], resulted in a decrease in left ventricular mass and improvements in left ventricular diastolic filling and quality of life in patients with DHF."R
  3. "Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha [protein kinase C] as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor [VEGF] and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711."R
  4. "Diabetic [mice] received no treatment or treatment with the inhibitor of AGE formation aminoguanidine (1 g/kg per d) or the cross-link breaker [4,5-dimethyl-3-(2-oxo2-phenylethyl)-thiazolium chloride] ALT-711, which cleaves preformed AGE (20 mg/kg per d) for 20 wk.... The two treatments, which attenuated renal AGE accumulation in a disparate manner, were associated with less albuminuria, structural injury, macrophage infiltration, TGF-beta1, and collagen expression."R
  5. "in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice... ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice."R
  6. "SUMMARY: The results of experimental studies and one clinical trial have clearly established the usefulness of ALT-711 in the therapy of the cardiovascular and renal disorders associated with aging, diabetes, and hypertension. Thus, breaking advanced glycation end-products-related collagen crosslinks has emerged as a new approach to cardiovascular therapy."R
  7. "Therapy with ALT-711 exerted beneficial cardiovascular and renal effects in aged SHR [spontaneously hypertensive rats], improving systolic pressure, left ventricular mass, geometry, and hydroxyproline content while reducing urinary protein excretion."R
  8. "It has also been recognized that the increased cardiac and vascular stiffness may be due to increased collagen cross-linking due to the formation of advanced glycosylation end-products (AGEs). In agreement with this notion is the finding that an inhibitor of AGEs formation improves vascular stiffness in diabetic rats. More recently, cross-link breakers have been developed, and the beneficial effects of one such agent (ALT-711) have been shown in experimental and clinical settings. This report briefly summarizes age related changes in cardiovascular structure and function and describes results of experimental and clinical studies involving collagen cross-link breakers."R
  9. "This study [in STZ diabetic rats] demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress."R
  10. "in 12 dogs, 9-12 yr old....ALT-711 restored LV [left ventricular] ejection fraction, reduced aortic stiffness and LV mass with no reduction in blood glucose level (199 +/- 17 mg/dl), and reversed the upregulation of collagen type I and type III. Myocardial LV collagen solubility (%) increased significantly after treatment with ALT-711. These data suggest that an AGE cross-link breaker may have a therapeutic role in aged patients with DM [diabetes mellitus]."R
  11. In Sprague-Dawley rats in which streptozotocin diabetes was induced for 32 weeks and treatment with ALT-711 (10 mg/kg) initiated at week 16, "ALT-711 treatment restored LV [left ventricular] collagen solubility and cardiac BNP [brain natriuretic peptide expression] in association with reduced cardiac AGE levels and abrogated the increase in RAGE [AGE receptor], AGE-R3, CTGF [connective tissue growth factor], and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes."R
  12. "DMPTB was shown to cleave a major portion of the cross-links formed in vivo in diabetic human lenses which suggests that lens protein cross-links in human lenses are formed mostly from AGEs."R
  13. Improvement of total arterial compliance in aged humans with vascular stiffening.R1,R2,R3
  14. Therapeutic approach for isolated systolic hypertension in humans.R1,R2
  15. Reduction of arterial PP (pulse pressure) in aged humans with vascular stiffening.R1,R2
  16. In diabetic rats, ALT 711 was associated with reduced renal AGE accumulation and reduced transdifferentiation of epithelial cells to form myofibroblasts in association with this reduced tubular AGE, cause by a reduction of RAGE (AGE receptor) induced expression of TGF-.R
  17. In vitro, "The AGE-breakers PTB (Phenacylthiazolium bromide) and PMTB (phenacyldimethylthiazolium bromide) were among the most potent inhibitors of copper-catalyzed oxidation of ascorbate, and the hydrolysis products of these compounds exhibited even stronger chelating activity. ... it is also possible that the hydrolysis products may have carbonyl trapping activity. The chelating properties of AGE-breakers is sufficiently strong that they may also have some lathyrogenic activity, inhibiting the enzymatic cross-linking of collagen, possibly leading to decreased cross-linking and greater elasticity of newly synthesized collagen."R
  18. "Vascular and/or myocardial stiffness is a major problem in ageing, diabetes, hypertension and heart failure. The development of the stiffness is partly due to the formation of glucose-dependent cross-links in the collagen. ALT-711 cleaves these cross-links. In aged-rhesus monkeys, ALT-711 decreases vascular stiffness and this effect is reversible. ALT-711 also decreases myocardial stiffness in the monkeys but this effect is not reversible in 39 weeks."R
  19. "the authors have developed a new class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC) [ALT-711], which can chemically break already-formed AGE protein-protein crosslinks. These agents are based on a new theory of AGE crosslinking that postulates that alpha-dicarbonyl structures are present in AGE protein-protein crosslinks. In studies in aged animals, DPTC [ALT-711] has been shown to be capable of reverting indices of vascular compliance to levels seen in younger animals."R
  20. Increased cardiovascular compliance accompanied by increased cardiac output in aged monkeys, dogs and rats.R1,R2,R3
  21. Increased venous return into the heart and ejection of blood from the LV (left ventricle), thus augmenting overall tissue perfusion in the resting state without changing heart rate or blood pressure in healthy aged monkeys.R
  22. EDV-EDP (end diastolic volume, pressure) relationship in both basal and volume-expanded states in 8 aged, but healthy, male mongrel dogs (10.6 0.7 years) receiving ALT-711 moved toward that of young dogs, consistent with an increase in distensibility.R
  23. "Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. Phenylacylthiazolium bromide (PTB) protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG."R
  24. Treatment of rats with streptozotocin-induced diabetes with ALT-711 (1.0 mg/kg per day i.p. for 1-3 weeks) reversed the diabetes-induced increase of large artery stiffness as measured by systemic arterial compliance, aortic impedance, and carotid artery compliance and distensibility.R
  25. The increase in collagen crosslinking as a consequence of diabetes-induced AGE accumulation resulted in a marked decrease in the susceptibility of tail tendon collagen to pepsin digestion. By contrast, pepsin solubility of collagen, obtained from ALT-711 treated diabetes-induced rats, was not different from that observed in nondiabetic controls.R
  26. ALT-711 decreases IgG crosslinked to the RBC surface after 1 week of chronic dosing in a dose-dependent manner with EC50 of only 0.06 mg/kg and the decrease remains for at least 10 weeks.R

Potential Benefits

  1. "Potential as a therapeutic agent in cardiovascular diseases in the older population."R
  2. "A combination therapy, involving an inhibitor and a breaker, in concert with antihyperglycaemic agents, could prove to be an effective therapeutic approach for the pathological conditions resulting from advanced glycosylation."R
  3. "ALT-711 has potential in the treatment of the stiffness associated with diabetes, hypertension and heart failure."R
  4. "Intervention [with ALT-711] targeted at AGE cross-links in vivo offers a way to interfere with age-related changes of tissues."R

Negative Results and Limitations

  1. "LPA [alpha-lipoic acid] was the sole treatment to prevent both PIV [Pressure-induced vasodilation] and ACh [acetylcholine] vasodilation alterations, with a significant reduction of oxidative stress in diabetic mice. Both PIV and ACh-vasodilation were abolished in LPA-treated diabetic mice following injection of Nomega-nitro-L-arginine (p<0.05). In contrast, alagebrium and sorbinil prevented neither diabetes-induced PIV abolition nor endothelial alteration."R
  2. This study used N-phenacylthiazolium bromide which is a weaker forerunner of ALT-711 and yet the authors mistakenly called it "ALT-711". The study was mainly for the purpose of assessing "the use of differential scanning calorimetry (DSC) for the determination of these cross-links and the effects of an AGE inhibitor and breaker. Treatment with N-phenacylthiazolium bromide of diabetic rats with 2 months duration of diabetes normalized large artery stiffness, assessed by characteristic input impedance and systemic arterial compliance, but with the use of DSC, no statistical difference in cross-linking between control and treated animals could be measured."R
  3. ALT-711 reduced neither plasma glucose nor the Amadori product HbA1c in diabetic rats.R

Reviews and Additional Reading

  1. "Several approaches have been used to inhibit tissue accumulation of AGEs in diabetes, including inhibitors of AGE formation such as aminoguanidine, ALT 946, and pyridoxamine-or putative cross-link breakers such as ALT 711. Alternative interventions have also included the administration of a soluble receptor for RAGE, sRAGE, thus capturing circulating AGEs and preventing them from binding to the cell-bound full-length receptor RAGE, thereby inhibiting the proinflammatory and profibrotic response following AGE-RAGE binding. In this review we summarize the evidence for such antiglycation therapies in retarding or delaying the development and progression of diabetes-associated atherosclerosis and renal disease while focusing on interventional strategies inhibiting AGE accumulation. In summary, all approaches have been shown to confer some degree of antiatherosclerotic and renoprotective effects, albeit to different degrees and by different mechanisms."R
  2. "novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90."R
  3. "The development of the novel compound dimethyl-3-phenacylthiazolium chloride (alagebrium chloride), which chemically breaks AGE cross-links, led to several preclinical animal studies that showed an attenuation or reversal of disease processes of the heart and kidney. In diabetes, AGE not only structurally stiffen structural collagen backbones but also act as agonists to AGE receptors (RAGE) on various cell types, which stimulate the release of profibrotic growth factors, promote collagen deposition, increase inflammation, and ultimately lead to tissue fibrosis. In the heart, large vessels, and kidney, these reactions produce diastolic dysfunction, atherosclerosis, and renal fibrosis. Administration of the cross-link breaker alagebrium chloride in these diabetic animals attenuates these pathologic phenomena, restoring functionality to the heart, vasculature, and kidney."R
  4. "Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress."R
  5. "This review presents the pre-clinical and clinical studies using ALT-711, a highly potent AGE-crosslink breaker that has the ability to reverse already-formed AGE-crosslinks. Oral administration of ALT-711 has resulted in a rapid improvement in the elasticity of stiffened myocardium in experimental animals. Topical administration of ALT-711 was effective in improving the skin hydration of aged rats. The therapeutic potential of crosslink breakers for cardiovascular complications and dermatological alterations associated with aging and diabetes is discussed."R
  6. "This review summarizes the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy."R
  7. Scientific American 2000: "AGE Breakers. Rupturing the body's sugar-protein bonds might turn back the clock."R
  8. Nature 1996: "An agent cleaving glucose-derived protein crosslinks in vitro and in vivo."R

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