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PubMed1988

Immunotherapy of genital warts with inosine pranobex and conventional treatment: double blind placebo controlled study.

In a multicentre, prospective, randomised, placebo controlled study of 55 patients with histories of genital warts for at least one year, a four week course of inosine pranobex 3 g a day improved the clinical response to conventional treatment (primarily podophyllin or trichloroacetic (now called trichlorethanoic) acid). Although more patients given inosine pranobex improved than those given placebo, the difference in general response between the two groups was not significant. When other variables (numbers of warts and extent of lesions) were considered, however, the patients given inosine pranobex fared significantly better. These results suggest that inosine pranobex may be worth considering as adjunct to treatment of patients with refractory genital warts.

Adult↗

PubMed1977

Salvage of adenosine, inosine, hypoxanthine, and adenisine by the isolated epithelium of guinea pig jejunum.

The metabolism of adenosine, inosine, hypoxanthine, and adenine (labelled with 14C in the carbon 8 position) at a concentration of 5 X 10(-6) M was studied in isolated epithelium of guinea pig jejunum. When adenosine or adenine was added to the antiluminal side of the epithelium, two-thirds or one-half, respectively, of cellular radioactivity was incorporated into the nucleotide fraction, mainly in the form of adenine nucleotides. Nucleotides synthesis from inosine or hypoxanthine was significantly smaller than that from adenosine. By contrast, another metabolic patern was found after luminal administration of adenosine, inosine, or hypoxanthine: the incorporation rate into the nucleotide fraction was equally high and the label was recovered in IMP and adenine nucleotides to about the same extent with all three substrates. Purine riboside (10(-4) M) significantly depressed nucleotide formation from adenosine, with respect to IMP formation in particular, while no change was observed in inosine or hypoxanthine salvage. The results suggest compartmentation of the enzymes of purine metabolism within the intestinal mucosa. The significance of this conclusion with regard to the salvage pathway is discussed.

Adenine↗

PubMed1986

Inosine pranobex. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Inosine pranobex is a synthetic compound formed from the p-acetamido benzoate salt of N-N dimethylamino-2-propanol and inosine in a 3:1 molar ratio. It has been reported to exert antiviral and antitumour activities in vivo which are secondary to an immunomodulating effect, and early results suggest beneficial clinical effects in several diseases and infections including mucocutaneous Herpes simplex infections, subacute sclerosing panencephalitis, genital warts, influenza, zoster, and type B viral hepatitis, as well as in homosexual men with persistent generalised lymphadenopathy. However, many of the studies have been preliminary in nature and deficient in design or in the reporting of their results. One must therefore conclude that while inosine pranobex may prove to be a valuable and innovative therapy for a number of diseases and infections for which no satisfactory therapy exist, further long term well controlled studies in larger numbers of patients are required before definitive conclusions about the efficacy of inosine pranobex in these disorders will be possible.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Comparative studies of inosine pranobex and acyclovir.

A total of 77 patients with first-attack genital herpes received acyclovir, 400 mg four times per day, inosine pranobex, 1 g four times per day, or both drugs for seven days. Patients treated with acyclovir healed in a shorter time and had a shorter duration of viral shedding and symptoms than those treated with inosine pranobex. Neither acyclovir nor inosine pranobex had any effect on the time to first occurrence or the frequency of subsequent recurrences. Preliminary results from two trials suggest that suppressive acyclovir is more efficacious than inosine pranobex in patients with frequently recurring genital herpes.

Acyclovir↗

PubMed1984

Purine nucleotide reutilization by human lymphoblast lines with aberrations of the inosinate cycle.

A purine nucleotide (inosinate) cycle is demonstrated with human lymphoblasts. The lymphoblast requires approximately 50 nmol of purine/10(6) cell increment. When the inosinate cycle is interrupted by the genetic, severe deficiency of either or both purine nucleoside phosphorylase (PNP) or hypoxanthine phosphoribosyltransferase (HPRT), purine accumulates in the culture medium as inosine, guanosine, deoxyinosine, and deoxyguanosine (PNP deficiency or PNP, HPRT deficiency) or hypoxanthine and guanine (HPRT deficiency). This accumulation represents an additional 25 to 32 nmol of purine which must be synthesized per 10(6) cell increment. PNP-deficient lymphoblasts have PPRibP contents characteristic of normal lymphoblasts, about 20 to 25 pmol/10(6) cells. HPRT-deficient lymphoblasts have four times higher PPRibP contents. The lymphoblast deficient for both PNP and HPRT has only a marginal elevation of PPRibP content, 1.5 times normal values. The elevated PPRibP content of HPRT-deficient cells reflects the efficient, unilateral reutilization of the ribose moiety of purine ribonucleotides and is not a cause of purine overproduction. Purine overproduction characterizing PNP-deficient lymphoblasts appears similar to overproduction from deficiency of HPRT, i.e. a break in the inosinate cycle rather than overactive de novo purine synthesis.

B-Lymphocytes↗

PubMed1981

The interaction of metal ions with nucleic acids. NMR study of the copper(II) interaction with inosine derivatives.

The interaction of copper(II) with inosine derivatives substituted at the purine ring, modified at the ribose residue, and with the syn conformation at the glycosidic bond was examined using 1H and 13C nuclear magnetic resonance techniques. The results imply that, in non-aqueous medium, the main site of copper(II) binding is N7 of inosine derivatives. No interaction with ribose hydroxyl groups was observed. CNDO/2 calculations performed for a copper(II) complex with 9-methyl-hypoxanthine support direct bonding of copper(II) ion to the ring. In aqueous medium, coordination of copper(II) with N1 and N7 of inosine is p2H-dependent: 98.7% of Cu(II) is bound with N7 at p2H 3.6, 49.4% at p2H 6.9, and only 35% at p2H 8.2 The relative dipolar and scalar contributions to the proton and carbon-13 transverse relaxation of the inosine derivatives nuclei have been assessed. The distances between the metal ion and the carbon and proton nuclei can not be estimated from T1 measurements because dipolar interaction contributing to relaxation is not only between the paramagnetic ion and the affected nucleus; there is also an important contribution from unpaired spin density on the ligand.

Chemical Phenomena↗

PubMed1978

Inosine nucleosidase from Azotobacter vinelandii. Purification and properties.

An enzyme catalyzing the hydrolysis of purine nucleosides was found to occur in the extract of Azotobacter vinelandii, strain O, and was highly purified by ammonium sulfate fractionation, DEAE-cellulose chromatography, hydroxylapatite chromatography and gel filtration on Sephadex G-150. A strict substrate specificity of the purified enzyme was shown with respect to the base components. The enzyme specifically attacked the nucleosides without amino groups in the purine moiety: inosine gave the maximum rate of hydrolysis and xanthosine was hydrolyzed to a lesser extent. The pH optimum of inosine hydrolysis was observed from pH 7 to 9, while xanthosine was hydrolyzed maximally at pH 7. The Km values of the enzyme for inosine were 0.65 and 0.85 mM at pH 7.1 and 9.0, respectively, and the value for xanthosine was 1.2 mM at pH 7.1. Several nucleotides inhibited the enzyme: the phosphate portions of the nucleotides were suggested to be responsible for the inhibition by nucleotides. Although the inhibition of the enzyme by nucleotides was apparently non-competitive type with respect to inosine, allosteric (cooperative) binding of the substrate was suggested in the presence of the inhibitor. The physiological significance of the enzyme was discussed in connection with the degradation and salvage pathways of purine nucleotides.

Azotobacter↗

PubMedDate not supplied

Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors.

Previously we have reported the presence of endogenous ligands that are involved in the regulation of the binding of muscimol to the GABA binding site of the GABAA receptors. Here, we report the presence of multiple forms of endogenous ligands in the brain which modulate the binding of flunitrazepam (FNZP) to the benzodiazepine (BZ) binding site of the GABAA receptor. Furthermore, one of the endogenous ligands for the BZ receptors, referred to as EBZ, has been identified as inosine based on the following observations: (1) standard inosine and the EBZ have identical NMR and UV spectra; (2) the elution profile of inosine and the EBZ from a HPLC column are indistinguishable, and (3) inosine and the EBZ show identical activity in inhibiting [3H]FNZP binding.

Animals↗

PubMed2003

The purine nucleoside cycle in cell-free extracts of rat brain: evidence for the occurrence of an inosine and a guanosine cycle with distinct metabolic roles.

The purine nucleoside cycle is a cyclic pathway composed of three cytosolic enzymes, hypoxanthine-guanine phosphoribosyltransferase, IMP-GMP specific 5'-nucleotidase, and purine-nucleoside phosphorylase. It may be considered a 'futile cycle', whose net reaction is the hydrolysis of 5-phosphoribosyl-1-pyrophosphate to inorganic pyrophosphate and ribose 1-phosphate. The availability of a highly purified preparation of cytosolic 5'-nucleotidase prompted us to reconstitute the purine nucleoside cycle. Its kinetics were strikingly similar to those observed when dialyzed extracts of rat brain were used. Thus, when the cycle is started by addition of inorganic phospate (Pi) and hypoxanthine or inosine (the 'inosine cycle'), steady-state levels of the intermediates are observed and the cycle 'turns over' as far as 5-phosphoribosyl-1-pyrophosphate is being consumed. In the presence of ATP, which acts both as an activator of IMP-GMP-specific 5'-nucleotidase and as substrate of nucleoside mono- and di-phosphokinases, no IDP and ITP are formed. The inosine cycle is further favored by the extremely low xanthine oxidase activity. Evidence is presented that ribose 1-phosphate needed to salvage pyrimidine bases in rat brain may arise, at least in part, from the 5-phosphoribosyl-1-pyrophosphate hydrolysis as catalyzed by the inosine cycle, showing that it may function as a link between purine and pyrimidine salvage. When the cycle is started by addition of Pi and guanine (the 'guanosine cycle'), xanthine and xanthosine are formed, in addition to GMP and guanosine, showing that the guanosine cycle 'turns over' in conjunction with the recycling of ribose 1-phosphate for nucleoside interconversion. In the presence of ATP, GDP and GTP are also formed, and the velocity of the cycle is drastically reduced, suggesting that it might metabolically modulate the salvage synthesis of guanyl nucleotides.

Animals↗

PubMed2006

Extracellular inosine participates in tumor necrosis factor-alpha induced nitric oxide production in cultured Sertoli cells.

Recent reports have described purinergic modulation of tumor necrosis factor-alpha (TNF-alpha) signaling in neutrophils and astrocytes. In Sertoli cells, both TNF-R1 and TNF-R2 TNF-alpha receptors are present and this cytokine modulates many functions of these cells related to the maintenance of spermatogenesis. Sertoli cells express distinct purinoreceptors and previous work has shown that these cells secrete extracellular nucleotides and their metabolites. In this work, we studied the possible role of extracellular purines in TNF-alpha signaling in cultured Sertoli cells. This cytokine increased inosine concentration from 30 min to 6 h, with no effect at 24 h. Both TNF-alpha and inosine increased nitrite accumulation and nitric oxide synthase activity. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, abolished the TNF-alpha induced inosine increase, nitrite accumulation and nitric oxide synthase activity. These results suggest that extracellular inosine acts as intermediary in TNF-alpha stimulated nitric oxide production in cultured Sertoli cells.

Adenine↗

PubMed1981

Distinct mechanisms of hypoxanthine and inosine transport in membrane vesicles isolated from Chinese hamster ovary and Balb 3T3 cells.

Both enzyme-mediated group translocation and facilitated diffusion have been proposed as mechanisms by which mammalian cells take up purine bases and nucleosides. We have investigated the mechanisms for hypoxanthine and inosine transport by using membrane vesicles from Chinese hamster ovary cells (CHO), Balb/c 3T3 and SV3T3 cells prepared by identical procedures. Uptake mechanisms were characterized by analyzing intravesicular contents, determining which substrates could exchange with the transport products, assaying for hypoxanthine phosphoribosyltransferase activity, and measuring the stimulation of uptake of hypoxanthine by phosphoribosyl pyrophosphate (PRib-PP). We found that the uptake of hypoxanthine in Balb 3T3 vesicles was stimulated 3--4-fold by PRib-PP. The intravesicular product was predominantly IMP. The hypoxanthine phosphoribosyltransferase activity copurified with the vesicle preparation. These results suggest the possible involvement of this enzyme in hypoxanthine uptake in 3T3 vesicles. In contrast to the 3T3 vesicles, CHO vesicles prepared under identical procedures did not retain hypoxanthine phosphoribosyltransferase activity and did not demonstrate PRib-PP-stimulated hypoxanthine uptake. The intravesicular product of hypoxanthine uptake in CHO vesicles was hypoxanthine. These results and data from our kinetic and exchange studies indicated that CHO vesicles transport hypoxanthine via facilitated diffusion. An analogous situation was observed for inosine uptake; CHO vesicles accumulated inosine via a facilitated diffusion mechanism, while in the same experiments SV3T3 vesicles exhibited a purine nucleoside phosphorylase-dependent translocation of the ribose moiety of inosine. Vesicles prepared from a CHO cell line temperature-sensitive for hypoxanthine uptake (Azarts) showed a temperature-sensitivity in Km for uptake parallel to that of the intact cells. This suggests that the defect in Azarts may be caused by a missense mutation in the gene coding for the hypoxanthine transport carrier.

Animals↗

PubMed1989

"Hormone-like" effect of adenosine and inosine on gluconeogenesis from lactate in isolated hepatocytes.

In isolated rat hepatocytes adenosine and inosine showed a dose-dependent increase in the rate of glucose synthesis from lactate with a Ka of 7.5 x 10(-8) and 9 x 10(-8) M, respectively. Absence of this action was recorded with: IMP, xanthosine, adenine, hypoxanthine, and uric acid. A reciprocal inhibition of individual gluconeogenic stimulation was found in cells incubated with glucagon or epinephrine and adenosine, but not with inosine. 5'-(N-ethyl) carboxamido adenosine was more potent than adenosine, whereas N6-(L-2-phenylisopropyl)-adenosine antagonized the stimulation of gluconeogenesis by adenosine. Neither of the analogs used modified the stimulatory role of inosine on the studied pathway. Adenosine and inosine may be involved in the short term regulation of gluconeogenesis.

Adenosine↗

PubMed1983

Pentylenetetrazol seizures in mice: effect on brain inosine and hypoxanthine.

Brain inosine and hypoxanthine were measured in mice at intervals following the intraperitoneal injection of pentylenetetrazol (PTZ), 100 mg/kg. These purines increased only after myoclonic jerks appeared and were maximal at the time of tonic hindlimb extension. Phenytoin and phenobarbital, which prevent tonic hindlimb extension, delayed the elevations of inosine and hypoxanthine. Although inosine has been found to have both epileptogenic and antiepileptic actions, the late increase in inosine found following PTZ probably has no physiological role.

Animals↗

PubMedDate not supplied

Responses of neurons in the primate taste cortex to the glutamate ion and to inosine 5'-monophosphate.

To investigate the neural encoding of glutamate taste in the primate, recordings were made from taste responsive neurons in the cortical taste areas in macaques. Most of the neurons were in the orbitofrontal cortex taste area, with a small number in adjacent taste areas. First, it was shown that single neurons that had their best responses to sodium glutamate also had good responses to glutamic acid. The correlation between the responses to these two tastants was higher than between any other pair of tastants, which included glucose (sweet), sodium chloride (salty), HCl (sour), and quinine HCl (bitter). Accordingly, the responsiveness to glutamic acid clustered with the response to monosodium glutamate in a cluster analysis with this set of stimuli, and glutamic acid was close to sodium glutamate in a space created by multidimensional scaling. Second, it was shown that the responses of these neurons to the nucleotide umami tastant inosine 5'-monophosphate were more correlated with their responses to monosodium glutamate than to any prototypical tastant. Third, concentration response curves showed that concentrations of monosodium glutamate as low as 0.001 M were just above threshold for some of these neurons. Fourth, neurons have not yet been found in this cortical region that showed synergism of monosodium glutamate and the nucleotide inosine 5'-monophosphate: it was shown that mixtures of 0.0001 M inosine 5'-monophosphate with different concentrations (0.001, 0.01, and 0.1 M) of monosodium glutamate did not have a greater effect than the monosodium glutamate alone. Fifth, some neurons in the orbitofrontal region, which responded to monosodium glutamate and other food tastes, decreased their responses after feeding with monosodium glutamate to behavioural satiety. In some cases this reduction was sensory-specific. These findings show that the taste neurons activated by monosodium glutamate can also be activated by other umami tastants, including glutamic acid and the nucleotide inosine 5'-monophosphate. The responses to these umami tastants were more similar to each other than to any of the other prototypical tastants, providing evidence that in this system umami is encoded differently from the other tastants. Moreover, the findings with these tastants provide additional evidence that the responses to monosodium glutamate are not due just to activation of a sodium taste channel.

Animals↗

PubMed1985

Nucleoside transport and metabolism in erythrocytes from the Yucatan miniature pig. Evidence that inosine functions as an in vivo energy substrate.

Erythrocytes from the Yucatan miniature pig, like those from the normal domestic pig, lack functional glucose transporters and were unable to utilize plasma glucose as an energy source. In contrast, inosine and adenosine entered the cells rapidly. The nucleoside transporter responsible for this uptake was identified as a band 4.5 polypeptide (5000 copies per cell; apparent Mr 45 000-66 000). Inosine concentrations in the physiological plasma range (1.6-2.5 microM) were found to maintain normal erythrocyte ATP levels and ATP/ADP ratios during prolonged in vitro incubation of cells at 37 degrees C, an effect that was blocked by the specific nucleoside transport inhibitor, nitrobenzylthioguanosine. In the absence of extracellular nucleoside, cells 'protected' themselves against some of the consequences of deprivation of energy substrate by glycolyzing the ribose moiety of inosine produced during ATP catabolism. Although erythrocytes from the miniature pig were capable of utilizing extracellular adenosine as an energy substrate, plasma samples from these animals contained less than 0.4 microM adenosine. It is concluded that inosine is a major physiological energy source of pig erythrocytes.

Adenosine↗

PubMed1975

Individual variation in inosine triphosphate accumulation in human erythrocytes.

Erythrocytes from 5% of a normal population accumulated relatively high amounts of radioactive inosine triphosphate (i.e., greater than 70 nmoles/10(10) cells in 2 hr) when they were incubated with [14C]hypoxanthine. The incidence of this characteristic in a mentally retarded population was 16%. Inosine triphosphate was synthesized from [14C]hypoxanthine, but not from [14C]adenine or [14C]guanine. The metabolism of [14C]adenine and [14C]guanine was the same in erythrocytes that accumulated "normal" and "high" amounts of inosine triphosphate. Inosine triphosphate did not accumulate in leukocytes.

Adenine↗

PubMed1992

Purine nucleoside phosphorylase. Inosine hydrolysis, tight binding of the hypoxanthine intermediate, and third-the-sites reactivity.

Purine nucleoside phosphorylase from calf spleen is a trimer which catalyzes the hydrolysis of inosine to hypoxanthine and ribose in the absence of inorganic phosphate. The reaction occurs with a turnover number of 1.3 x 10(-4) s-1 per catalytic site. Hydrolysis of enzyme-bound inosine occurs at a rate of 2.0 x 10(-3) s-1 to form a stable enzyme-hypoxanthine complex and free ribose. The enzyme hydrolyzes guanosine; however, a tightly-bound guanine complex could not be isolated. The complex with hypoxanthine is stable to gel filtration but can be dissociated by acid, base, or mild denaturing agents. Following gel filtration, the E.hypoxanthine complex dissociates at a rate of 1.9 x 10(-6) s-1 at 4 degrees C and 1.3 x 10(-4) s-1 at 30 degrees C. The dissociation constant for the tightly-bound complex of enzyme-hypoxanthine is estimated to be 1.3 x 10(-12) M at 30 degrees C on the basis of the dissociation rate. The stoichiometry of the reaction is 1 mol of hypoxanthine bound per trimer. The reaction is reversible since the same complex can be formed from enzyme and hypoxanthine. Addition of ribose 1-phosphate to the complex results in the formation of inosine without release of hypoxanthine. Thus, the complex is catalytically competent. Inorganic phosphate or arsenate prevents formation of the tightly-bound E.hypoxanthine complex from inosine or hypoxanthine. Direct binding studies with hypoxanthine in the presence of phosphate result in 3 mol of hypoxanthine bound per trimer with a dissociation constant of 1.6 microM. In the absence of phosphate, three hypoxanthines are bound, but higher hypoxanthine concentrations cause the release of two of the hypoxanthines with an apparent inhibition constant of 130 microM. The results establish that enzymatic contacts with the nucleoside alone are sufficient to destabilize the N-glycosidic bond. In the absence of phosphate, water attacks slowly, causing net hydrolysis. The hydrolytic reaction leaves hypoxanthine stranded at the catalytic site, tightly bound to the enzyme with a conformation related to the transition state. In the phosphorolysis reaction, ribose 1-phosphate causes relaxation of this conformation and rapid release of hypoxanthine.

Animals↗

PubMed1998

Significance of the 5-phosphoribosyl-1-pyrophosphate pool for cardiac purine and pyrimidine nucleotide synthesis: studies with ribose, adenine, inosine, and orotic acid in rats.

Several experimental approaches have been applied to examine the significance of the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) for purine and pyrimidine nucleotide metabolism in the rat heart. In a series of studies including some pentoses and pentitols, in particular ribose, it was shown that these sugars were all capable of elevating the cardiac PRPP pool and stimulating the rate of adenine nucleotide biosynthesis. In several pathophysiological situations that were characterized by a decrease in ATP content, the increase in adenine nucleotide biosynthesis elicited by ribose was of such magnitude that the ATP level was replenished partially or completely in a considerably shorter period of time than that without any intervention. In two experimental models, in cardiac hypertrophy induced by aortic constriction with additional isoproterenol administration and in the noninfarcted rat heart after permanent coronary artery ligation, there was also an improvement in global heart function under the influence of ribose. The myocardial cell damage induced by isoproterenol was prevented by ribose. Combination of ribose with adenine or inosine led to an even quicker ATP normalization in the isoproterenol-stimulated rat heart than with either intervention alone. Ribose had no functional effects on the cardiovascular system, whereas adenine, inosine, and orotic acid were demonstrated to have different hemodynamic influences. Adenine and inosine had negative chronotropic and inotropic effects in the intact rat, whereas orotic acid had a positive influence both on the left and right rat heart. On the basis of these experimental studies, a new therapeutic strategy is suggested in which elevation of the available PRPP plays a key role. Once this has been elevated by ribose, additional substrates, such as adenine, inosine, and orotic acids, should be included. This would exploit the full potential of a therapeutic approach that corrects a natural metabolic deficiency of the heart that is the low capacity of the oxidative pentose phosphate pathway in which PRPP is generated.

Adenine↗