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Radiation Syndromes and Their Modifications
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
The route of injection markedly influences the protective action of a compound, because the rates of absorption, distribution, and excretion of the compound vary depending upon the route of administration. Generally, the drugs are injected intraperitoneally (i.p.) because this technique is easiest to use with small animals. However, the rates of absorption, distribution, and excretion are most rapid when drugs are injected intravenously (i.v.), and least rapid when injected orally. The route of administration also affects the toxicity of the compound; 2-mercaptoethylamine (cysteamine) and its oxidation product, bis-(2-mercaptoethyl) disulfide (cystamine), are equally effective after an i.p. injection. However, cystamine is also effective when given orally, whereas cysteamine is not. The protective concentration of cystamine, when injected i.v., produces a fall in blood pressure that is generally fatal to mice.
Immunomodulatory Drugs in Type I Diabetes
Published in George S. Eisenbarth, Immunotherapy of Diabetes and Selected Autoimmune Diseases, 2019
Kolb Hubert, Schmidt Michael, Kiesel Ulrich
In the low-dose streptozotocin diabetes model several different radical scavengers have been tried (I. Flechner, U. Kiesel, H. Kolb, manuscript in preparation47. Care was taken to start administration only after the last streptozotocin injection in order to avoid interaction with the beta cell toxin. Neither cysteamine (two trials with 45 and 150 mg/kg), benzamidine (50 mg/kg) nor butylated hydroxytoluene (120 mg/kg) affected the course of the disease.
The thiols glutathione, cysteine, and homocysteine in human immunodeficiency virus (HIV) infection
Published in Ronald R. Watson, NUTRIENTS and FOODS in AIDS, 2017
F. Müller, P. Aukrust, A.M. Svardal, R.K. Berge, P.M. Ueland, S.S. Frøland
Another thiol compound, cystamine, has been shown to inhibit HIV replication both in lymphocytes and macrophages in vitro.163,201 Cystamine can increase GSH.169 In addition, cystamine inhibits HIV replication by interference with two steps of the viral life cycle, namely inhibition of proviral DNA formation and assembly of HIV virions, causing the production of defective viral particles.163 Interestingly, cystamine also inhibited lipopolysaccharide (LPS)-induced TNFα production in macrophages.201 However, cystamine has not been used in humans while the structurally related form, cysteamine, has a low toxicity in man.202 In a recent study, cysteamine was found to be a potent inhibitor of HIV replication in vitro at similar concentrations to those obtained by oral administration for the treatment of cystinosis, an inherited disorder.203
Carbon Black Tinted Contact Lenses for Reduction of Photophobia in Cystinosis Patients
Published in Current Eye Research, 2019
One of the symptoms commonly experienced by cystinosis patients in the cornea is photophobia or extreme light sensitivity.16 This sensitivity is caused by the cystine crystals reaching a high enough concentration in the cornea, which occurs within the first decade of life.12 Years of squinting to reduce light exposure can lead to some patients developing intractable blepharospasm.17,18 The cystine crystals are treated with cysteamine eye drops.19–22 Cysteamine will react with cystine to create a new dimer which can exit the lysosomal membrane. Dissolution of the crystals by cysteamine will reduce photophobia, but symptoms will persist throughout the years required to reach full dissolution. The current solution is for patients to wear sunglasses while outside.
Novel cystamine-core dendrimer-formulation rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection by augmenting autophagy
Published in Expert Opinion on Drug Delivery, 2019
Janine Faraj, Manish Bodas, Garrett Pehote, Doug Swanson, Ajit Sharma, Neeraj Vij
Hence, in the present study, our laboratory designed and developed the novel cystamine-core dendrimers that get reduced to cysteamine in vivo, as an autophagy-inducing drug of choice based on our recently published studies [22,26]. Briefly, cysteamine, a reduced form of cystamine, is an FDA-approved drug used to treat cystinosis. It is also currently the focus of a pilot clinical trial, in combination with the drug epigallocatechin gallate, conducted on homozygous ΔF508-CFTR CF patients [23]. Cysteamine holds considerable therapeutic potential in CF due to its known autophagy-inducing properties, as well as to its established mucolytic and bactericidal activity [7]. Lynovex®, an oral cysteamine formulation, has demonstrated promising therapeutic potential in phase II clinical trials by reducing acute CF aggravations in human subjects [39]. In light of cysteamine’s numerous therapeutic benefits, we designed a novel mixed-surface dendrimer from a core consisting of two cysteamine units linked by a disulfide (forming cystamine), to address the unique physiochemical obstacles that hinder the delivery of CF drugs to lung epithelium. Despite the ease of oral administration, we believe an inhaled drug such as our novel cystamine dendrimer capable of penetrating the copious mucus that overlies CF respiratory epithelia would be of greater therapeutic benefit as it tackles multiple major causes of morbidity and mortality seen in CF patients, such as impaired autophagy, chronic lung inflammation, and chronic Pa growth and inflammation [14,22,40–42].
ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease
Published in Expert Opinion on Investigational Drugs, 2020
Cystinosis is an ultra-rare autosomal recessive lysosomal storage disorder caused by mutations in the cystinosin gene (CTNS) which encodes the cystinosin lysosomal transporter [13,14]. When left untreated, cystinosis is characterized by the pediatric onset of progressive renal insufficiency requiring dialysis or kidney transplantation by 10–12 years of age [14]. Approximately 12% of cases of cystinosis are caused by nonsense mutations [15]. Cystinosin is ubiquitously expressed and functions as a cystine-proton co-transporter, an activity required to remove cystine released from protein degradation in the lysosome [13]. Defects in cystinosin may lead to cystine accumulation and the formation of intra-lysosomal crystals. The tissues impacted, severity and age of onset are dependent upon the patient’s CTNS genotype [16]. Mutations that result in a loss of cystine transport are associated with severe infantile presentation of the disease. Identification of mutations that inhibit transport activity can also be observed in individuals with later, juvenile onset disease suggesting that there may be additional cystinosin functions outside of cystine transport which contribute to some aspects of the disease [16]. Cystine accumulation within lysosomes can be reduced through cysteamine-mediated conversion of cystine to cysteine, which can then be removed from the lysosome [17]. The approval of cysteamine in the early 1990s and subsequent approval of extended release formulations has provided a therapeutic option for individuals with the disease. Early treatment with cysteamine bitartrate depletes intra-lysosomal cystine, helps manage the disease, and improves the outcome of cystinosis complications; however, it does not halt disease progression or kidney manifestations [18,19].