Effects Of Purine Analogues Research Articles

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.

Prevention of clinical relapse (resumption of symptoms of active disease) and endoscopic relapse (signs of mucosal inflammation upon examination with an endoscope) are key objectives in the management of Crohn’s disease. There is no treatment currently available that completely prevents relapse and is without significant side-effects. The purpose of this systematic review was to examine the effectiveness and side effects of purine analogue medications (azathioprine and 6-mercaptopurine) used to prevent relapse in Crohn's patients in surgically-induced remission This review identified seven studies that included a total of 584 participants. One study compared azathioprine to placebo (e.g. a sugar pill). Another study compared 6-mercaptopurine to 5-aminosalicylic acid (5-ASA) or placebo. Three studies compared azathioprine to 5-ASA drugs. One small study compared azathioprine to both 5-ASA and adalimumab (a biological drug that is a tumour necrosis factor-alpha antagonist). One small study compared azathioprine to infliximab (a biological drug that is a tumour necrosis factor-alpha antagonist). The study that compared azathioprine to infliximab (22 patients) found that the effects on the proportion of patients who had a clinical or endoscopic relapse were uncertain. A small study (33 patients) found reduced clinical and endoscopic relapse rates favouring adalimumab over azathioprine. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. A pooled analysis of two studies (168 patients) suggests that purine analogues may be superior to placebo for preventing clinical relapse in Crohn's patients in surgically-induced remission. One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. A pooled analysis of five studies (425 patients) found no difference in clinical relapse rates between purine analogues and 5-ASA agents. One study (35 patients) found no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA. Another study (91 patients) found reduced endoscopic relapse rates at 24 months favouring 6-mercaptopurine over 5-ASA patients. Patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to side effects. Commonly reported side effects across the studies included leucopenia (a decrease in the number of white blood cells), arthralgia (joint pain), abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis (inflammation of the pancreas), anaemia (a decrease in the number of red blood cells), exacerbation (worsening) of Crohn's disease, nasopharyngitis (common cold), and flatulence. The results of this review need to be interpreted with caution as they are based on small numbers of patients and the overall quality of the evidence from the studies was rated as low or very low due to lack of precision of the results, inconsistent results across studies and the low methodological quality of some studies. Further research investigating the effectiveness and side effects of azathioprine and 6-mercaptopurine in comparison to other medications in patients with surgically-induced remission of Crohn's disease is warranted.

Abstract 4595: Moxetumomab pasudotox spares CD4 and CD8 lymphocytes in multiply relapsed hairy cell leukemia patients, while prospective trials of first, second, and later lines of purine analogs show increasing toxicity

Abstract The purine nucleoside analogs cladribine and pentostatin damage DNA and cause long-term suppression of CD4 and CD8 lymphocytes in patients with hairy cell leukemia (HCL). There is increasing concern that these reductions, particularly in CD4+ T-cells, may be associated with opportunistic infections and secondary malignancies. The anti-CD22 recombinant immunotoxin moxetumomab pasudotox targets HCL without damaging DNA, and spares T-cells. In a phase 1 trial, 20 patients treated with 50 ug/Kg every other day for 3 doses for 2-8 (median 4) cycles were evaluated for T-cell subsets. CD4 cells increased -56% to 152% (median 46%) after end of treatment, decreasing in only 1 of the 20 patients. Because there is very little prospective data on the effect of purine analogs on T-cells, we analyzed data from 80 consecutively enrolled patients receiving cladribine in first line, 40 receiving cladribine in second line, and 52 receiving either pentostatin or bendamustine in third or later lines. The latter group was most appropriate to compare with moxetumomab pasudotox, which was also used in third or later-line treatment of HCL. CD4 counts after moxetumomab pasudotox were 85-600 (median 424), compared to 22-618 (median 73) after third or later line purine analog (p<0.0001). These CD4 counts after moxetumomab pasudotox were even higher than those after first line (86-954, median 259, p=0.0037) or second line (53-724, median 185, p<0.0001) cladribine. CD4 counts after first line cladribine were higher than those after second line cladribine (p=0004), which in turn were higher than those after third or later line purine analogs (p<0.0001). Even after 2 years, CD4 counts after third or later line purine analogs, 41-1004 (median 264), n=43, remained suppressed compared to 1st line cladribine, 191-1044 (median 392, n=68, p=0.0013). The percent decreases in CD4 counts after first line cladribine were significantly greater compared to those after moxetumomab pasudotox (median 63% decrease vs 46% increase, p<0.0001). CD8 counts were also preserved after moxetumomab pasudotox, increasing by -32% to 198% (median 46%). Similar differences between moxetumomab pasudotox and purine analog groups were observed with respect to CD8-cell suppression. Opportunistic infections, neutropenic fevers, and other infectious complications were much more common after purine analogs than after moxetumomab pasudotox, particularly in later lines of therapy. These data provide a rationale for avoiding repeated cycles of purine analog for relapsed HCL, and support the use of non-chemotherapy approaches like moxetumomab pasudotox before repeated courses of purine analog are tried. (Supported in part by MedImmune and NCI, Intramural Program). Citation Format: Robert J. Kreitman, Maryalice Stetler-Stevenson, Evgeny Arons, Ira Pastan. Moxetumomab pasudotox spares CD4 and CD8 lymphocytes in multiply relapsed hairy cell leukemia patients, while prospective trials of first, second, and later lines of purine analogs show increasing toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2017-4595

Glycobiology and the Paediatric Eye in Health and Disease

Inflammatory bowel disease, especially Crohn disease, had increased in the last five decades. We analyzed all the patients of our unit diagnosed with the disease between 2001-2012 but we just considered the patients who respected the Porto criteria to define IBD at presentation. We diagnosed 51 children and adolescents with the disease. Crohn disease was responsible for 62.7% of cases, ulcerative colitis for 31.4% and indeterminate colitis for 5.9%. Considering the 4 different periods of time (2001-2003/2004-2006/2007-2009 and 2010-2012), we observed and increase in the number of cases, but a decrease in the time from onset of symptoms to diagnosis. Our medical approach with tumor necrosis factor antagonists was reserved for severe disease cases and to spare patients from adverse effects of purine analogues and corticosteroids. Mucosal healing and remission of the disease was achieved in all of the patients under biologic therapy and no serious or life-threating event was reported with their use.

Decrease in factor V activity: A new adverse effect of purine analogs in inflammatory bowel diseases?

Decrease in factor V activity: A new adverse effect of purine analogs in inflammatory bowel diseases?

Purine metabolism and the microaerophily of Helicobacter pylori.

The requirements for purine nucleotide synthesis, the effects of purine analogues, and the metabolism of adenine in the bacterium Helicobacter pylori were investigated employing cell culture techniques and one-dimensional NMR spectroscopy. Bacterial cells grew and proliferated in media lacking preformed purines, indicating that H. pylori can synthesize purine nucleotides de novo to meet its requirements. Blocking of this pathway in the absence of sufficient preformed purines for salvage nucleotide synthesis led to cell death. Analogues of purine nucleobases and nucleosides taken up by the cells were cytotoxic, suggesting that salvage routes could be exploited for therapy. Adenine or hypoxanthine were able to substitute for catalase in supporting cell growth and proliferation, suggesting a role for these bases in maintaining the microaerophilic conditions essentially required by the bacterium.

Effects of purine analogues on spontaneous alternation in mice.

The Y-maze was used to examine the effects of purines acting at A1 and A2 adenosine receptors upon spontaneous alternation, a model of working memory, in mice. In support of previous work, scopolamine produced a loss of spontaneous alternation behaviour to the 0.5 chance level. The A1 receptor selective agonist N6- cyclopentyladenosine (CPA) did not change spontaneous alternation behaviour alone, but it prevented the decrease of spontaneous alternation scores produced by scopolamine. The A1 receptor selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (CPX) blocked the effect of CPA in combination with scopolamine but had no effect alone. The A2 receptor selective agonist (N6-[2-(3,5-dimethoxyphenyl)-2-(2- methylphenyl)ethyl] adenosine (DPMA), and the A2 receptor selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) had no effect of alternation behaviour alone and did not modify the effect of scopolamine. The results indicate the ability of A1 but not A2 receptor activation to modify working memory deficits induced by scopolamine, but suggest that endogenous adenosine does not normally participate in working memory processes.

P-137 - Effects of purine analogues on release of noradrenaline in rabbit pulmonary artery.

P-137 - Effects of purine analogues on release of noradrenaline in rabbit pulmonary artery.

The effect of purine analogues on neurotransmission in rabbit pulmonary artery

The effect of purine analogues on neurotransmission in rabbit pulmonary artery

Effect of Purine Analogs and Their Interactions with Benzyladenine on Bud Burst and Shoot Growth in Apple Bud Explants

AbstractThe purine analogs 8‐azaadenine, 8‐azaguanine, 4‐aminopyrazolo [3,4‐d] pyrimidine, 2‐fluoroadenine and 6‐methylpurine inhibited bud burst in non‐dormant vegetative axillary bud explants obtained from apple (Malus domestica Borkh.) seedlings. The reversal of inhibition was attempted by incorporating increasing concentrations of benzyladenine (BA) in the culture medium. The inhibition caused by 8‐azaadenine and 8‐azaguanine was reduced especially when BA was added to the media at equimolar ratios along with the inhibitors. The inhibition due to 4‐aminopyrazolo [3,4‐d] pyridine was reduced only with equimolar BA, BA was ineffective or only minimally effective in reducing inhibition due to 2‐fluoroadenine and 6‐methypurine. Short pretreatment with 8‐azaadenine and 8‐azaguinine failed to cause any inhibition when explants were subsequently transferred to BA ‐containing medium. The effectiveness of 2‐fluoroadenine and 6‐methylpurine was maintained or only slightly reduced, indicating their long‐term inhibitory action.

Pathways of nucleotide metabolism in Schistosoma mansoni—V Adenosine cleavage enzyme and effects of purine analogues on adenosine metabolism in vitro

Schistosoma mansoni extracts have been found to possess an active anabolic pathway for nucleotide biosynthesis in which adenosine is cleaved to adenine followed by conversion of adenine to AMP via adenine phosphoribosyltransferase. A significant fraction of labeled adenosine was found to enter the nucleotide pool by this pathway; howeverm, most of the nucleoside was converted to nucleotides by a pathway which employs adenosine deaminase, purine nucleoside phosphorylase and hypoxanthine phosphoribosyltransferase enzymes. Formycin A has been found to be a potent blocker of adenosine cleavage when tested in worm extracts. Arabinosyl-6-mercaptopurine and 6-thioguanosine are inhibitors of worm adenosine deaminase, and formycin B and 6-thioguanosine were found to inhibit the purine nucleoside phosphorylase of this parasite. Combinations of arabinosyl-6-mercaptopurine with either formycin A or formycin B result in substantial blockage of adenosine utilization for nucleotide synthesis. These studies thus suggest that adenosine analogues in combination might be useful in vivo for the chemotherapy of schistosomiasis.

Effect of purine analogues on IMP-pyrophosphorylase

IMP pyrophosphorylase was purified 35 times from an extract of beef liver by a modification of the method of Lukens and Herrington. It was found that increasing the temperature of the heating phases gives a better preparation. The kinetic constants of the enzyme was determined, K m (hypoxanthine) = 1.0·10 −5 M, K m (5-phosphoribosyl-1-pyrophosphate) = 5.5·10 −5 M. The effect of purine analogues was determined by measuring the conversion of [ 14C]hypoxanthine to [ 14C]IMP. 41 substances were examined and 4 competitive inhibitors; 6-mercaptopurine, 2-amino-6-mercaptopurine, 4-hydroxy-6-aminopyrazolo (4,3d)pyrimidine and isoguanine, were found.

EFFECT OF PURINE ANALOGS ON ENCEPHALOMYOCARDITIS AND VACCINIA VIRUS GROWTH IN ANALOG SENSITIVE AND RESISTANT CELLS.

SummaryThe effect of 2 purine analogs, 2,6-diaminopurine (DP) and 8-azaguanine (AZA) on the multiplication of encephalomyocarditis (EMC) and vaccinia viruses in analog-sensitive and -resistant strain L cells has been investigated. It was shown that DP and AZA inhibit the multiplication of both viruses in analog-sensitive cells. DP does not inhibit the replication of EMC and vaccinia viruses in DP-resistant cells. The mechanism of cellular resistance to this analog might prevent the inhibitory action of DP on viral replication. On the other hand, AZA inhibits virus growth in AZA-resistant cells as well as in analog-sensitive cells. The mechanism of cell resistance is not effective in protecting viral replication from the inhibitory effect of the analog. It is suggested that the cell resistance to AZA may be at a step following ribophosphorylation and that virus-specific RNA synthesis might be affected by the antimetabolite, whereas cellular RNA synthesis is not significantly inhibited by the analog nucleotide.

EFFECT OF 8-AZAGUANINE ON THE SPECIFICITY OF ANTIGENS SYNTHESIZED BY E. COLI B/R2.

ROBLIN et al. synthesized azapurine analogues of naturally occurring purines and showed their ability to inhibit the growth of E. coli and S. aureus1. Since then many investigators have utilized analogues of purines and pyrimidines in studies of cell metabolism and protein biosynthesis2–7. The purpose for our initiating an investigation of the effects of purine analogues on growing cells was to explore the possibility of using such analogues to induce metabolic errors in the biosynthesis of protein antigens that would result in immunologically altered proteins. It was anticipated that this work would also contribute to our knowledge of protein biosynthesis because immunochemical methods are particularly well suited for differentiating even closely related substances on the basis of their immunological specificities.