Gender-Related Difference in the Toxicity of Ultraviolet Absorber 2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet absorber. Previously, we showed that male rats had more than a 100 times higher susceptibility to the toxic effects of DBHCB than females. In order to investigate the role of sex steroids in the mediation of this gender-related difference, DBHCB (0 or 250?mg/kg/day) was given to male and female young intact and castrated rats by gavage for 28 days in the current study. In intact rats, relative liver weight increased to more than two times that of the control in males, while the rate of change was less than 10% in females. On histopathology, hypertrophy of hepatocytes was observed in males but not in females. In castrated rats, an approximately 40% increase in the relative liver weight was found only in males, and no histopathological changes in the liver were detected in either sex. The gender-related difference was also determined in preweaning rats administered DBHCB at 0, 250, or 500?mg/kg/day by gavage from postnatal days 4 to 21. Blood biochemical changes, including increases in the levels of AST, ALT, and ALP, 80–95% increase in the relative liver weight and histopathological changes in the liver, such as hypertrophy and single cell necrosis of hepatocytes, were observed at both doses in both sexes. In conclusion, the gender-related difference in the toxicity of DBHCB, which was observed in young rats, was markedly reduced by castration and abolished in preweaning rats.     

Evaluation of Developmental Toxicity of Ultraviolet Absorber 2-(3′,5′-Di-tert-Butyl-2′-hydroxyphenyl)-5-Chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as a UV absorber. In this study, the developmental toxicity of DBHCB was evaluated in rats. Pregnant rats were given DBHCB at 0, 62.5, 250, or 1000 mg kg^?1 day^?1 by gavage on days 5–19 of pregnancy. No deaths were observed in the pregnant rats of any group. No effect of DBHCB on the general conditions, body weight gain, or feed consumption was observed in the pregnant rats. There were no changes in the ovarian weight, gravid uterine weight, or necropsy findings in the maternal rats of the DBHCB-treated groups. No significant effects of DBHCB were found in the number of corpora lutea, implantations, live fetuses, resorptions or dead fetuses, incidence of pre- or postimplantation embryonic loss, viability of fetuses, fetal weight, or sex ratio of live fetuses. No significant difference in the incidence of fetuses with malformations or variations or degree of ossification was detected between the DBHCB-treated and control groups.     

A 28-Day Repeated Dose Toxicity Study of Ultraviolet Absorber 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl) benzotriazole in Rats

To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg^?1 day^?1 for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg^?1 day^?1 in male rats and 2.5 mg kg^?1 day^?1 in female rats.     

A 52-Week Repeated Dose Toxicity Study of Ultraviolet Absorber 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole in Rats

A 52-week repeated dose toxicity study of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′ -di-tert-butylphenyl)benzotriazole (HDBB), was conducted according to OECD TG 452 under GLP. CD(SD)IGS rats were given HDBB by gavage at 0, 0.1, 0.5, or 2.5 mg/kg/day in males and 0, 0.5, 2.5, or 12.5 mg/kg/day in females. No substance-related deaths or clinical signs of toxicity were observed in any group; however, a lowered body weight was found from day 36 to the end of the 52-week administration period at 2.5 mg/kg in males. At the completion of the dosing period, a decrease in red blood cells at 0.5 mg/kg and higher, and in hematocrit at 2.5 mg/kg, was detected in males. Blood biochemical changes, including increases in the levels of alkaline phosphatase and glucose and the A/G ratio, were also found at 0.5 mg/kg and higher in males and at 12.5 mg/kg in females. At necropsy, absolute and relative liver weight was increased at 0.5 mg/kg and higher in males and at 12.5 mg/kg in females. Histopathological changes were observed in the liver; centrilobular hypertrophy of hepatocytes at 0.5 mg/kg and higher in males, and at 12.5 mg/kg in females, and altered hepatocellular foci at 0.5 mg/kg and higher, and cystic degeneration and lipofuscin deposition in hepatocytes at 2.5 mg/kg in males. Based on these findings, the no observed adverse effect level was concluded to be 0.1 mg/kg/day in male rats and 2.5 mg/kg/day in female rats.     

Gonadal Influence on the Toxicity of 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl) benzotriazole in Rats

Previously, we showed that susceptibility of male rats to the toxicity of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), was nearly 25 times higher than that of females. In the current study, we investigated the role of sex steroids in the mediation of the gender-related difference using castrated rats. Male and female castrated CD(SD) rats were given HDBB by gavage at 0, 0.5, 2.5, or 12.5 mg/kg/day for 28 days. No deaths, clinical signs of toxicity, or changes in body weight or food consumption were found at any doses. Blood biochemical changes suggestive of hepatic damage, such as increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase, were detected at 12.5 mg/kg/day in males. Absolute and relative liver weight increased at 0.5 mg/kg/day and above in males and at 12.5 mg/kg/day in females. In the liver, histopathological changes, such as nucleolar enlargement, increased mitosis, hypertrophy in hepatocytes, and/or focal necrosis were observed at 0.5 mg/kg/day and above in males, and at 2.5 mg/kg/day and above in females. These findings indicate that castration markedly reduced the gender-related differences in toxicity of HDBB in rats.     

Lack of Gender-Related Difference in the Toxicity of 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole in Preweaning Rats

In our previous toxicity studies using young rats, we showed that an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), principally affected the liver, and male rats had nearly 25 times higher susceptibility to the toxic effects than females. In the present study, the toxicity of HDBB was investigated in preweaning rats. HDBB was administered by gavage to male and female CD(SD) rats from postnatal days 4 to 21 at a dose of 0, 0.1, 0.5, 2.5, or 12.5 mg/kg/day. No substance-related deaths, clinical signs of toxicity, or body-weight changes were observed. Increased levels of albumin, AST and ALP in both sexes, BUN in males, and LDH in females were found at 12.5 mg/kg. Liver weights increased at 2.5 mg/kg and above in both sexes. Histopathologically, hepatocellular findings, such as nucleolar enlargement, anisokaryosis, increased mitosis, and/or hypertrophy, were observed at 2.5 mg/kg and above in both sexes. These results indicate no gender-related differences in the susceptibility to the toxic effects of HDBB in preweaning rats.     

Pharmacokinetics of Oral 2′,3′-Dideoxyinosine in Rats

Pharmaceutical Research -     

Percutaneous Absorption of 2′,3′-Dideoxyinosine in Rats

This study explored the topical route for administering of 2,3-dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (180 mg/kg) dispersed in ~1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [³H]ddI. At 24 hr, the experiment was terminated and skin sections at the application site were removed. After topical application, average plateau plasma levels of about 0.6 µg/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route for ddI. The effect of a mixture of penetration enhancers, Azone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. However pre-treatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr. In summary, the transdermal bioavailability of ddI exceeded the 15% oral bioavailability found in previous studies by more than 3 folds and was further increased by the pretreatment with absorption enhancers. These data indicate the topical route as an attractive administration route.     

Nonlinear Disposition of Intravenous 2′,3′-Dideoxyinosine in Rats

The pharmacokinetics of 2,3-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses, ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phos-phorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.     

Disposition of 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine in mice

Summary Mice were dosed with [³H]2,3-dideoxyadenosine ([³H]ddA) in three procedures: intravenously, intraperitoneally, and interperitoneally following a dose of 2 -deoxycoformycin (dCF). For mice dosed intravenously, the content of radioactivity in plasma and tissue samples were essentially constant after 30 min. Of the radioactivity in plasma and brain samples collected between 30 min and 24 hr, more than 94% was present as ³H₂O, indicating that most of the tritium from [³H]ddA had exchanged with water. No intact ddA was detected, and the deamination product, 2,3 -dideoxyinosine (ddI), was present only transiently. In the urine, the major radioactive material was [³H]ddI. Also detected were ³H₂O and small amounts of [³H]hypoxanthine and [³H]ddA. Following intraperitoneal doses to mice, levels of radioactivity in plasma, liver, and kidney increased to a maximum by 15–30 min after dosing but dropped to essentially constant levels thereafter, again indicating that the tritium had exchanged with water. At 5, 15, and 30 min after dosing, ddI was the major radioactive component in plasma. Only small amounts of ddA were present. When dCF was administered 24 hr prior to intraperitoneal [³H]ddA, levels of radioactivity in plasma, liver, and kidney reached a maximum at 30 to 60 min after dosing and decreased to essentially constant levels thereafter. The dCF transiently inhibited the deamination of ddA to ddI, since, in plasma, [³H]ddA was the main radioactive component at 5 and 15 min after dosing. Comparison of HPLC assays based on radioactivity detection and UV absorbance showed that they were equivalent for measuring ddA and ddI in samples derived from dosed mice. Therefore, exchange of tritium must have occurred at a metabolic step beyond ddI.For mice dosed intravenously and orally with unlabeled ddI, there was evidence of a saturated process. Nevertheless, for the high and low intravenous doses of ddI, the percent of dose excreted in the urine as unchanged drug was the same.     

Distribution and excretion of 2,3,6,2′,3′,6′- and 2,4,5,2′,4′,5′-hexachlorobiphenyl in senescent rats

The disposition of two symmetrical [¹⁴C]hexachlorobiphenyls (HCBs), 2,3,6,2′,3′,6′-HCB (236) and 2,4,5,2′,4′,5′-HCB (245), was studied in 24-month-old male Sprague-Dawley rats after iv treatment. Because body composition changes with age, complete dissections were performed on all rats to determine the size of the skin and adipose tissue depots. More than 50% of 236 was metabolized and excreted via the bile into the feces within 2 days. In contrast, 245 redistributed from the liver, muscle, and skin to adipose tissue where it accumulated without being metabolized. Only 2% of the total dose of 245 was excreted primarily in the feces within 21 days. The data obtained in this study were compared to results previously obtained from 2- to 3-month-old rats in this laboratory (Matthews and Tuey, 1980, Toxicol. Appl. Pharmacol.53, 377–388). Although the general pattern of HCB disposition did not change with age, i.e., metabolism and excretion of 236 versus persistence of 245, there were differences in the rates of elimination and in the tissue levels. There was enhanced metabolite retention in the muscle, skin, and adipose tissue of older animals which suggested an age-related decrease in tissue clearance. The large volume of adipose tissue in these older Sprague-Dawley rats could in part explain this observation. In general, there were few changes in decay rates from tissues or in biliary excretion. Age had a greater effect on the disposition of the persistent 245 than on the metabolizable 236. Thus, changes in body composition seemed to play a major role in age-related changes in the distribution and excretion of polychlorinated biphenyls.     

Pharmacokinetic Interaction Between Intravenous 2′,3′-Dideoxyinosine and Pentamidine in Rats

Purpose. This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddl) and pentamidine. Background, ddl and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs. Methods. ddl (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay. Results. Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddl from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddl from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddl distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddl coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003). Conclusions. These data indicate that pentamidine increased the distribution of ddl into pancreas and muscle, whereas ddl increased the renal elimination of pentamidine.     

Extensive Absorption of 2′,3′-Dideoxyinosine by Intratracheal Administration in Rats

Purpose. To evaluate the intratracheal route of administration as an alternative to oral administration for 2,3-dideoxyinosine (ddI). Methods. A ddI dose (40 mg/kg/300 µl or 6.5 mg/kg/50 µl) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 µg/kg) of ³H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. Results. ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 µL dose spilled over to the gastrointestinal tract, where the entire 50 µL dose was retained in the lungs. The different distribution of the two doses/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes. Conclusions. These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.     

Biotransformation of 3-(2′,4′,5′-Triethoxybenzoyl)propionic Acid,a New Biliary Smooth Muscle Relaxant with Choleretic Activity,in Rats

1. By the combined use of deuterium labelling and gas chromatographic-mass spectrometric analysis, the metabolite pattern of 3-(2′,4′,5′-triethoxybenzoy!)propionic, acid (triethoxybenzoylpropionic acid), a new biliary smooth muscle relaxant with choleretic activity, has been determined in the rat.

2. The metabolites excreted in urine and/or bile were isolated and characterized as follows: the parent drug, 3-(2′,5′-diethoxy-4′-hydroxybenzoyl)propionic acid (metabolite II), 3-(2′-ethoxy-4′-hydroxy-5′-methoxybenzoyl)propionic acid or 3-(2′-ethoxy-5′-hydroxy-4′-methoxybenzoyl)propionic acid (III), 3-(2′,4′-diethoxy-5′-hydroxybenzoyl)propionic acid (V) and 3-[2′,4′-diethoxy-5′-(2-hydroxyethoxy)benzoyl]propionic acid (VI).

3. The primary route of biotransformation of triethoxybenzoylpropionic acid in the rat was either O-de-ethylation at the C-4′ and C-5′ positions or β-hydroxylation of the ethoxy group at the C-5′ position in the parent molecule.

4. All these excreted products except metabolite VI were eliminated both unconjugated and in conjugates (probably glucuronides and/or sulphates).

5. The rat excreted mainly metabolites V and VI in the urine and parent drug, metabolites V and VI in the bile.     

Hydrolysis of the Prodrug, 2′, 3′, 5′ -Triacetyl-6-azauridine

Purpose. The purposes were to study the kinetics of hydrolysis of 2,3,5-triacetyl-6-azauridine ( 1 ) in aqueous solution (µ = 0.5) and to identify the main intermediates and products of the reaction. Methods. A stability indicating isocratic LC assay was used to study the rate of degradation of 1 A gradient LC assay was used to study the time courses of the degradants. The products of hydrolysis were isolated by preparative liquid chromatography and identified by ¹H-NMR and CI-MS. The pK_a value was obtained by potentiometric titration. Results. At 36.8°C, the pH-rate profile of 1 in water was adequately described by a four-term rate equation. The intermediates were identified as the primary and secondary di-acetates, and the primary and secondary mono-acetates. The final product was 6-azauridine. Conclusions. A simplified kinetic scheme could be used to describe the concentration-time profiles of 1, the intermediates and the final product.     

Role of Brain Tissue Localized Purine Metabolizing Enzymes in the Central Nervous System Delivery of Anti-HIV Agents 2′-β-Fluoro-2,3′-Dideoxyinosine and 2′-β-Fluoro-2′,3′-Dideoxyadenosine in Rats

Purpose. This study examines the central nervous system (CNS) delivery of 2--fluoro-2,3-dideoxyadenosine (F-ddA) and 2--fluoro-2,3-dideoxyinosine (F-ddl), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. Methods. Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddl, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. Results. The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain ( 8×) and CSF ( 11×) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5×) and CSF/plasma (3×) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5×) and CSF (6×). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.     

Synthesis and Pharmacological Properties of 1-Aryl-4-(3′4′,5′-trimethoxybenzoyl)piperazines

A series of 1-aryl-4-(3′,4′,5′-trimethoxybenzoyl)piperazines (IIa - IIg) having structures containing 3,4,5-trimethoxybenzoyl fragments were synthesized and characterized. Compounds IIa and IIc - IIg demonstrated weak anxiolytic properties and moderately decreased the spontaneous motor activity in rats. Compound IIb exhibited anxiolytic activity comparable with that of buspirone but, in contrast to this reference drug, increased the motor activity of test animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 12 – 14, May, 2005.     

Metabolism and presynaptic inhibitory activity of 2′,3′ and 5′-adenine nucleotides in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, [¹⁴C]labelled 5-AMP, 5-ADP and 5-ATP (10 M) inhibited twitch responses, were broken down to [¹⁴C]adenosine in the medium and incorporated into [¹⁴C]adenine ribonucleotides in the tissue. Pretreatment of tissues with 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBTGR), a potent inhibitor of adenosine transport, potentiated the presynaptic inhibitory action of these 5 nucleotides and reduced their incorporation in [¹⁴C]adenine nucleotides, but did not alter the appearance of [¹⁴C]adenosine in the medium.A series of 2, 3 and 5-substituted adenine nucleotides (10 M) inhibited the twitch responses of the vas deferens stimulated at 0.2 Hz. This effect was potentiated by NBTGR. Addition of exogenous adenosine deaminase very significantly reduced the inhibitory actions of adenosine, 5-AMP, 5-ADP and 5-ATP and also reduced those of 2, 5-ADP, NAD⁺ and dePCoA. The inhibitory actions of the other 2, 3 and 5 adenine nucleotides studied were not altered by exogenous adenosine deaminase.These results indicated that the presynaptic inhibitory actions of 5-AMP, 5-ADP and 5-ATP in rat vas deferens predominantly result from their prior hydrolysis to adenosine whereas the 2, 3 and 5-substituted adenine nucleotides appear to act mainly directly to inhibit transmitter release.Abbreviations. The following abbreviations are used 5-ADP 5-adenosine diphosphate - 2,5-ADP 2,5-adenosine diphosphate - 3,5-ADP 3,5-adenosine diphosphate - 2,3 or 5-AMP 2,3 or 5-adenosine monophosphate - 5-ATP 5-adenosine triphosphate - CoA coenzyme A - 2,3-cAMP 2,3-cyclic adenosine monophosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - dePCoA dephosphocoenzyme A - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - oxid CoA oxidized-coenzyme A