Effects of 2-chloroadenosine on cortical epileptic afterdischarges in immature rats.

Adenosine may represent an endogenous anticonvulsant in the brain. This study focused on the possible anticonvulsant action of an adenosine agonist, 2-chloroadenosine, against cortical epileptic afterdischarges (ADs) in immature rats. Three age groups of rat pups with implanted electrodes were studied: 12-, 18- and 25-days-old. The compound, 2-chloroadenosine, was injected after the first successful stimulation at doses of 1, 4 or 10 mg/kg intraperitoneally, and stimulation at the same intensity was repeated three more times. Movements directly elicited by stimulation, as well as clonic seizures accompanying electroencephalography (EEG) ADs, were markedly suppressed in only the 18-day-old animals. The effects in the 12- and especially the 25-day-old rats were moderate. The duration of the ADs decreased in all three age groups with 2-chloroadenosine treatment, and the shortest AD duration was seen in the treated, 12-day-old rats. The AD suppression also lasted longer in this age group than it did in the older animals. After a brief suppression of the second AD, the treated, 25-day-old group exhibited a significant AD rebound during the third and fourth stimulations. Taken together, our data show that 2-chloroadenosine exhibits an anticonvulsant effect that is dose- and age-dependent.

Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan.

The aim of this study was to assess the outcome of treatment with 2-chlorodeoxyadenosine (2-CdA) in pediatric patients with Langerhans cell histiocytosis (LCH) in Japan. We retrospectively identified 17 pediatric LCH patients treated with 2-CdA. All patients were refractory or reactivated cases who had been initially treated according to the JLSG-02 protocol of the Japan LCH study group. At initiation of 2-CdA therapy, 4 patients had primary refractory multisystem (MS) disease with risk organ (RO) involvement (MS+), 9 patients had reactivated MS disease [5 MS+ and 4 without RO involvement (MS-)], and the remaining 4 patients had refractory/reactivated multifocal bone disease (MFB). Treatment with 2-CdA (4-9 mg/m(2)/day) was administered on 2-5 consecutive days and repeated every 3-4 weeks for a period that ranged from 2 to 12 months. Four primary refractory patients were treated with 2-CdA combined with high dose of cytarabine. In MS+ patients, response to treatment was observed in 5 of the 9 patients. In MS-/MFB patients, 5 of the 8 patients showed response to treatment. In the patients who were primary refractory or had reactivation during initial chemotherapy, 4 of 10 patients showed good response. On the other hand, in the patients having reactivation while off therapy, 6 of 7 patients showed good response. These findings suggest that 2-CdA is effective for reactivated LCH while off therapy.

Significant efficacy of 2-CdA with or without rituximab in the treatment of splenic marginal zone lymphoma (SMZL).

BACKGROUND: Splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes is an indolent lymphoma that typically affects elderly patients. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best therapeutic strategy has not yet been identified. Among different possible chemotherapeutic approaches, purine analogues, alone or in association with rituximab, seem to be a valid therapeutic choice. PATIENTS AND METHODS: Fifty SMZL patients were treated with cladribine with or without anti-CD20 mAb. RESULTS: Forty-six of 50 patients were assessable for response. Overall response rate was 87%: 24 of 46 patients (52%) achieved a complete hematological response (CR), 16 of 46 (35%) a partial response and 6 (13%) were unresponsive. Interestingly, 15 of 24 cases (62%) in CR also achieved a molecular remission. CONCLUSIONS: The present results indicate that this schedule is a valid therapeutic approach in SMZL. Addition of rituximab significantly improved quality of response and consequently the outcome of the disease.

Stimulation of adenosine A2b receptors blocks apoptosis in the non-infarcted myocardium even when administered after the onset of infarction.

OBJECTIVE: Chronic adenosine A2b receptor stimulation has been shown to prevent ventricular remodelling after myocardial infarction (MI). We hypothesized that this effect is due to the inhibition of cardiac myocyte apoptosis in the myocardium remote from the infarction. METHODS: Rats were subjected to MI by LAD ligation in situ. Some animals were pre-treated with the stable adenosine analogue 2-chloro-adenosine (CADO). After 24 h, pro- and anti-apoptotic signals (protein kinase C isoforms, p38, g proteins, Bcl-2/Bax ratio, Akt, Bad), and marker of apoptosis execution (caspase-3, TUNEL) were quantified in the remote myocardium. RESULTS: CADO prevented the occurrence of apoptosis in the remote myocardium of an infarcted heart. This effect occured not only when CADO was started before the onset of ischemia but also when it started 3 h after the infarction. The anti-apoptotic effect of CADO was blocked by simultaneous administration of the selective adenosine A2b receptor antagonist MRS1754 (1 mg/kg). The anti-apoptotic effect of CADO seems to be mediated by g(alphaq) and by the activation of survival kinases (Bad) and by inhibition of the pro-apoptotic PKC-delta/p38-MAPK-pathway. CONCLUSION: Chronic adenosine A2b receptor stimulation blocks cardiac myocyte apoptosis in the remote myocardium even when started after the onset of infarction. This may explain the anti-remodelling-effect of the A2b receptor stimulation after infarction.

Intravenous 2-chloroadenosine protects BALB/c mice from Klebsiella pneumoniae B5055-induced sepsis by modulating the pro-inflammatory immune response.

Sepsis is a severe inflammatory immune response of the host against an infectious agent or its product i.e. lipopolysaccharide (LPS). Therefore, targeting the immune system during sepsis may lower the morbidity and mortality associated with sepsis. The present study shows the protective immunomodulatory action of 2-chloroadenosine (2-CADO) in K. pneumoniae B5055 induced sepsis in male BALB/c mice. Sepsis was induced by implanting the fibrin-thrombin clot containing known amount (10(2)cfu) of Klebsiella pneumoniae B5055 into the peritoneal cavity of mice. 100% mortality with in the 5 post infection days (PIDs) was observed in control group animals. Intravenous 2-CADO (10 microg/kg/day) treatment increased in survival of animals by 70% without significantly (p>0.05) decreasing the blood bacterial load. But a significant (p<0.05) decrease in the level of inflammatory markers (TNF-alpha, il-1alpha, MDA, NO) responsible for sepsis was observed. However, serum il-10 levels were found to be significantly (p<0.05) increased with 2-CADO treatment.

Complete remission of hairy cell leukemia variant (HCL-v) complicated by red cell aplasia post treatment with rituximab.

Hairy cell leukemia variant (HCL-v) is a rare form of a chronic B-cell lymphoproliferative disorder. Unlike typical hairy cell leukemia (HCL) where the complete response (CR) rate to 2-chlorodeoxyadenosine and 2'-deoxycoformycin can approach about 90%, in HCL-v CR is rare and partial response (PR) occurs in approximately 50% with these agents. Rituximab treatment in relapsed or refractory HCL results in a CR of 13% to 53%, but its use in HCL-v has not been reported in the literature to our knowledge. We describe a patient with HCL-v, whose course was previously complicated by pure red cell aplasia who achieved CR after treatment with rituximab. We also briefly review outcomes of treatments used in HCL-v reported in the current literature.

[Preparation of 8-chloro-adenosine long circulation liposomes and its pharmacokinetics in rats].

AIM: To prepare 8-chloro-adenosine (8-Cl-A) long circulation liposomes with high entrapped efficiency and prolonged action-time of 8-Cl-A in vivo. METHODS: To prepare 8-Cl-A long circulation liposomes of nanometer size by improved multiple emulsion. The entrapped efficiency, size and size distribution of 8-Cl-A long circulation liposomes were determined, and its pharmacokinetics in rats was evaluated. RESULTS: The entrapped efficiency of 8-Cl-A long circulation liposomes was 62.70% and mean diameter of the liposomes was 79.9 nm. The pharmacokinetics studies indicated that 8-Cl-A long circulation liposomes showed higher drug concentration and larger AUC values than that of 8-Cl-A after iv to rats. CONCLUSION: 8-Cl-A long circulation liposomes could prolong the action-time of 8-Cl-A in vivo.

Suppression of generalized seizures activity by intrathalamic 2-chloroadenosine application.

In the present study, we investigated the effects of micro-injecting 2-chloroadenosine (2-CADO; an adenosine receptor agonist) into the thalamus alone and with theophylline (a nonspecific adenosine receptor antagonist) pretreatment on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in male Wistar albino rats. Following intrathalamic 2-CADO injection alone or theophylline pretreatment, 50 mg kg(-1) PTZ was given ip after 1 and 24 hrs. The duration of epileptic seizure activity was recorded by cortical electroencephalogram (EEG), and seizure severity was behaviorally scored. Intrathalamic 2-CADO administration induced significant decreases in both seizure duration and seizure severity scores at 1 and 24 hrs, but the effects were more abundant on the seizures induced after 24 hrs. On the other hand, pretreatment with theophylline prevented the inhibitor effect of 2-CADO on seizure activity and increased both seizure duration and seizure scores. Present results suggest that the activation of adenosine receptors in the thalamus may represent another anticonvulsant/modulatory site of adenosine action during the course of the PTZ-induced generalized tonic-clonic seizures and provide additional data for the involvement of the adenosinergic system in the generalized seizures model.

Influence of depletion of alveolar macrophages on apoptosis in Candida-induced acute lung injury.

Apoptosis plays an important role in acute lung injury (ALI), and alveolar macrophages (AMs) are known to secrete proinflammatory cytokines and promote alveolar inflammation. The authors have previously reported that AMs can be depleted by inhalation of 1 mM 2-chloroadenosine (2-CA). In this study, the authors evaluated the effect of AM depletion by 2-CA inhalation on apoptosis in Candida-induced ALI. The results of in situ terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL) and immunohistochemical studies and measurement of cytokine levels and caspase 3 activities in lung homogenates indicated that the Fas-FasL system and apoptosis of alveolar epithelial cells are suppressed by depletion of AMs by 2-CA inhalation.

alpha,beta-Methylene ATP elicits a reflex pressor response arising from muscle in decerebrate cats.

In part, the exercise pressor reflex is believed to be evoked by chemical stimuli signaling that blood supply to exercising muscles is not adequate to meet its metabolic demands. There is evidence that either ATP or adenosine may function as one of these chemical stimuli. For example, muscle interstitial concentrations of both substances have been found to increase during exercise. This finding led us to test the hypothesis that popliteal arterial injection of alpha,beta-methylene ATP (5, 20, and 50 microg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 microg/kg), which stimulates P1 receptors, evokes reflex pressor responses in decerebrate, unanesthetized cats. We found that popliteal arterial injection of the two highest doses of alpha,beta-methylene ATP evoked pressor responses, whereas popliteal arterial injection of 2-chloroadenosine did not. In addition, the pressor responses evoked by alpha,beta-methylene ATP were blocked either by section of the sciatic nerve or by prior popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (10 mg/kg), a selective P2-receptor antagonist. We conclude that the stimulation of P2 receptors, which are accessible through the vascular supply of skeletal muscle, evokes reflex pressor responses. In addition, our findings are consistent with the hypothesis that the stimulation of P2 receptors comprises part of the metabolic error signal evoking the exercise pressor reflex.

8-Cl-adenosine mediated cytotoxicity and sensitization of T-lymphoblastic leukemia cells to TNFalpha-induced apoptosis is via inactivation of NF-kappaB.

These data show that 8-Cl-cAMP is cytotoxic to the lymphoblastic leukemia cell line CEM and its vinblastine selected multidrug resistant derivative, CEM/VLB100 although PKA was not involved in these effects. The cytotoxic effects of 8-Cl-cAMP was abrogated by cotreatment with either ADA or IBMX which indicated a degradation form of 8-Cl-cAMP was needed for this cytotoxicity. CEM and CEM/VLB100 cells displayed a notable sensitivity to 8-Cl-adenosine-induced growth inhibition and apoptosis. 8-Cl-adenosine increased the cytosolic levels of IkappaBalpha which prevented NF-kappaB nuclear translocation. 8-Cl-adenosine also prevented TNFalpha-induced IkB decay and NF-kappaB activation in CEM and CEM/VLB100 cells.

Anticonvulsant effect and neurotransmitter modulation of focal and systemic 2-chloroadenosine against the development of pilocarpine-induced seizures.

The present microdialysis study was aimed at evaluating the anticonvulsant effect of the adenosine A(1) receptor agonist 2-chloroadenosine (2-CADO) against pilocarpine-induced seizures in rats. The hippocampal neurotransmitter modulation on the action of 2-CADO and its possible activation of hippocampal adenosine A(2a) receptors was also assessed. Intrahippocampal perfusion of 2-CADO (100 microM) produced a sustained attenuation of baseline dopamine levels, while eliciting a delayed augmentation of both glutamate and GABA efflux. When co-perfused with pilocarpine (10 mM) or injected systemically (7.5 mg/kg), 2-CADO prevented the development of seizures as well as pilocarpine-evoked augmentation of the glutamate and dopamine levels. However, the delayed increase in glutamate overflow with intrahippocampal 2-CADO was still observed. Intraperitoneal injection of selective adenosine A(2a) receptor antagonist SCH 58261 reversed the 2-CADO-elicited attenuation of pilocarpine-induced increment in dopamine efflux and completely abolished the delayed augmentation of glutamate levels, irrespective of perfusion with pilocarpine. Intraperitoneal injection of 5 mg/kg 2-CADO mostly prevented the elevation of pilocarpine-induced glutamate efflux but could not confer adequate protection. We conclude that 2-CADO can prevent pilocarpine-induced seizures by both intrahippocampal perfusion and systemic administration. The attenuation of pilocarpine-induced dopamine efflux and the late elevations of glutamate are likely to be mediated by hippocampal A(2a) receptors. Inhibition of presynaptic glutamate release does not appear to be sufficient for the anticonvulsant action. Postsynaptic events could play a more important role.

Modulation of audiogenic seizures by histamine and adenosine receptors in the inferior colliculus.

Susceptibility to behaviorally similar audiogenic seizures (AGS) occurs genetically and is inducible during ethanol withdrawal (ETX). Comparisons between AGS mechanisms of genetically epilepsy-prone rats (GEPR-9s) and ethanol-withdrawn rats (ETX-Rs) are yielding information about general pathophysiological mechanisms of epileptogenesis. The inferior colliculus (IC) is the AGS initiation site. Excitatory amino acid (EAA) abnormalities in the IC are implicated in AGS, and histamine and adenosine receptor activation each reduce EAA release and inhibit several seizure types. Previous studies indicate that focal infusion of an adenosine receptor agonist into the IC blocked AGS in GEPR-9s, but the effects of adenosine receptor activation in the IC on AGS in ETX-Rs are unknown. The effects of histamine receptor activation on either form of AGS are also unexamined. The present study evaluated effects of histamine or a nonselective adenosine A(1) agonist, 2-chloroadenosine, on AGS by focal microinjection into the IC. Ethanol dependence and AGS susceptibility were induced in normal rats by intragastric ethanol. Histamine (40 or 60 nmol/side) significantly reduced AGS in GEPR-9s, but histamine in doses up to 120 nmol/side did not affect AGS in ETX-Rs. 2-Chloroadenosine (5 or 10 nmol/side) did not affect AGS in ETX-Rs, despite the effectiveness of lower doses of this agent in GEPR-9s reported previously. Thus, histamine and adenosine receptors in the IC modulate AGS of GEPR-9s, but do not modulate ETX-induced AGS. The reasons for this difference may involve the chronicity of AGS susceptibility in GEPR-9s, which may lead to more extensive neuromodulation as compensatory mechanisms to limit the seizures compared to the acute AGS of ETX-Rs.

Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia - updated results of the multicentre study of 378 patients.

Between January 1992 and January 1999, we treated 378 B-chronic lymphocytic leukaemia (CLL) patients with cladribine (2-CdA), and 255 of the patients were also treated with prednisone. A total of 194 patients were previously untreated, and 184 had relapsed or refractory disease after previous other therapy. Complete response (CR) was obtained in 111 (29.4%) and partial response (PR) in 138 (36.5%) patients, giving an overall response (OR) rate of 65.9%. CR and OR were achieved more frequently in patients in whom 2-CdA was a first-line treatment (45.4% and 82.5% respectively) than in the pretreated group (12.5% and 48.4% respectively) (P < 0.0001). The median duration of OR for previously untreated patients was 14.7 months and for pretreated patients 13.5 months (P = 0.09). The median survival evaluated from the beginning of 2-CdA treatment was shorter in the pretreated group (16.3 months) than in the untreated group (19.4 months) (P < 0.0001). A total of 117 (63.9%) patients died in the pretreated group and 63 (32.6%) in the untreated group. In pretreated patients, 2-CdA + prednisone (P) and 2-CdA alone resulted in similar OR (51.0% and 45.0% respectively; P = 0.4). In contrast, in untreated patients, 2-CdA + P produced a higher OR (85.4%) than 2-CdA alone (72.1%) (P = 0.04). Infections and fever of unknown origin, observed in 91 (49.4%) pretreated and 74 (38.1%) untreated patients (P = 0.03), were the most frequent toxic effects. Our results indicate that 2-CdA is an effective, relatively well-tolerated drug, especially in previously untreated CLL.

[2-CDA in treatment of hairy cell leukemia: a comparison between intravenous and subcutaneous administration. Swiss Study Group of Applied Cancer Research]. / 2-CDA bei der Behandlung der Haarzell-Leukämie: ein Vergleich zwischen intravenöser und subkutaner Verabreichung. Schweizerische Arbeitsgemeinschaft für angewandte Krebsforschung.

2-chlorodeoxyadenosine (2-CDA) is very effective in the treatment of patients with hairy-cell leukaemia, with an overall response rate of 80-95%. The standard treatment is a continuous intravenous infusion for 7 days. The bioavailability of 2-CDA after subcutaneous injection is 100%, but the concentration-time profile is completely different compared to continuous intravenous administration. In the present study we compared the intravenous standard treatment (group 1, n = 22; 0.1 mg/kg/d for 7 days, civ.) with subcutaneous administration of 2-CDA (group 2, n = 62; 0.14 mg/kg/d for 5 days, s.c.) in patients with hairy-cell leukaemia. In group 1, 96% (21/22) of patients responded to 2-CDA (complete remission 73%, partial remission 23%) and in the second group 97% were responsive (complete response 76%, 47/62; partial remission 21%, 13/62). The percentage for moderate and severe infections in the trial with intravenous and subcutaneous treatment was 14% and 26% respectively (p = 0.37). We conclude that subcutaneous administration of 2-CDA in patients with hairy-cell leukaemia is feasible and economical and results in comparable responses and toxicity compared to the intravenous standard treatment.

2-Chlorodeoxyadenosine (cladribine)-related eosinophilia in patients with lymphoproliferative diseases.

Eosinophilia and allergic skin reactions are uncommon events after 2-chlorodoxyadenosine (2-CdA, cladribine) administration. A multicentre retrospective analysis of eosinophilia in 360 patients treated with 2-CdA for lymphoid malignancies has been made. B-cell chronic lymphocytic leukaemia (B-CLL) was diagnosed in 153, hairy cell leukaemia (HCL) in 68, low-grade non-Hodgkin's lymphoma (LGNHL) in 119, high-grade NHL in 2 and Waldenstrom's macroglobulinaemia (WM) in 18 patients. 2-CdA was administered at a dose 0.12 mg/kg/d in 2-h intravenous infusion for 5 consecutive d. The courses were repeated monthly. Patients with HCL received 1 cycle of 2-CdA, with NHL 2-6 (mean 3.5) cycles and with B-CLL 3-6 (mean 5) cycles. Twenty patients (5.5%), including 5 with HCL, 6 with LGNHL, 7 with B-CLL and 2 with WM, developed peripheral blood eosinophilia. The mean values of absolute eosinophil count were 0.78x10(9)/l (0.58-1.06x10(9)/l), 0.71x10(9)/l (0.52-1.3x10(9)/l), 85 (0.56-1.82x10(9)/l) and 0.75 (0.74-0.76x10(9)/l), respectively. Eosinophilia occurred in 13 patients after 1 course, in 4 after 2 courses, and in 5 after > or =3 courses of the therapy. In 17 cases it resolved spontaneously. Allergic skin lesions with pruritus were noticed in 3 patients simultaneously with an increase in eosinophil count. All of them required antihistaminic drugs and/or corticosteroids. One patient with B-CLL experienced repeated episodes of eosinophilia. The highest incidence of 2-CdA-induced eosinophilia was noticed in patients with MW (11.1%) and HCL (7.4%) who received only 1 cycle of this drug and entered a complete remission. This side effect was less frequently observed in LGNHL and B-CLL, i.e. in 5.0% and 4.6% of cases, respectively. The mechanism of 2-CdA-induced eosinophilia is not clear. It has been postulated that massive tumour cell lysis may trigger a release of IL-5 and probably other cytokines. The allergic mechanism of 2-CdA-induced eosinophilia is also possible, especially in patients with simultaneous skin reactions.

The protective effect of 2-chloroadenosine against the development of amygdala kindling and on amygdala-kindled seizures.

The influence of 2-chloroadenosine, a non-metabolizable adenosine A1 receptor agonist, was tested on the development of electrically kindled amygdala and on the seizure responses of fully kindled rats. Focal intra-amygdaloid injection of 2-chloroadenosine (1-10 nmol/0.5 microl) 20 min before applying the daily kindling stimulus prevented the development of the kindling process. The behavioural seizure score and the afterdischarge duration were reduced below their initial values. The antiepileptogenic effects of 1 and 10 nmol of 2-chloroadenosine were reversible 8-10 days after withdrawal of the drug. When 2-chloroadenosine was tested on fully developed stage 5 amygdala-kindled seizures, it increased the generalised seizure threshold in a dose-dependent manner. A maximum efficiency of 125% (P < 0.001) was achieved with 5 nmol and the median effective dose was 0.55 nmol. Higher doses resulted in the reduced anticonvulsant effect (P < 0.05). With the same daily stimulation, 2-chloroadenosine 5 nmol in 0.5 microl vehicle, significantly reduced the maximum seizure score by 90%, the afterdischarge duration by 88% and completely blocked the generalised seizure duration. The antiseizure activity of the drug lasted for 3 days. In conclusion, 2-chloroadenosine not only acts as an anticonvulsant against electrically induced kindled seizures as described here, and against audiogenic seizures, electroshock and a variety of chemical convulsants as described by others, it prevents the development of the epileptic state by kindling-stimulation, i.e., it is antiepileptogenic. We theorise here that this is due to its blockade of presynaptic glutamate release.

Effect of intraperitoneal and intrahippocampal (CA1) 2-chloroadenosine in amygdaloid kindled rats.

Effects of intraperitoneal and intrahippocampal 2-chloroadenosine and caffeine were examined in fully kindled amygdaloid rats. Intraperitoneal administration of 2-chloroadenosine (5 and 10 mg/kg) decreased afterdischarge duration, stage 5 seizure duration and prolonged time taken to reach stage 4 seizure. Only the 10 mg/kg dose induced a significant reduction in seizure stage. Intraperitoneal administration of caffeine (50 mg/kg) increased both afterdischarge duration and stage 5 seizure duration but did not significantly alter other parameters. Intrahippocampal microinfusion of 2-chloroadenosine (1 mM) or caffeine (2 mM) did not alter any of the measured seizure parameters. Intraperitoneal but not intrahippocampal pretreatment of animals with caffeine (50 mg/kg and 2 mM, respectively) blocked the anticonvulsant effects induced by intraperitoneal administration of 2-chloroadenosine. It may therefore be concluded that the adenosine A1 receptors of the CA1 region of the hippocampus do not play a role in mediating the anticonvulsant effects of intraperitoneally administered 2-chloroadenosine in amygdaloid kindled rats.

Intra-amygdala infusion of 2-chloroadenosine suppresses amygdala-kindled seizures.

The seizure-modulating effects of 2-chloroadenosine (2-CLA) infused directly into the amygdala were investigated. Different groups of amygdala-kindled rats were infused (1 microliter) with 2-CLA (0.25, 1, 10 and 25 nM), caffeine (200 microM and 2 mM), a combination of the two or artificial cerebrospinal fluid (ACSF) applied directly through a cannula located in the amygdala. Infusion of 2-CLA dramatically suppressed seizure stage (SS), after discharge duration (ADD) and stage 5 seizure duration (S5D), while the latency to bilateral forelimb clonus (S4L) was significantly prolonged. These anticonvulsant effects were evident after 5 min, reached a maximum at the 60 min time point and were still detectable 360 min post-2-CLA infusion. Pretreatment with caffeine blocked the anticonvulsant effects of 2-CLA dose-dependently. These results may suggest that in amygdaloid-kindled rats, adenosine receptors located in the amygdala play a major role in the expression of the anticonvulsant activity of 2-CLA.

2-chlorodeoxyadenosine (2-CDA) therapy in previously untreated patients with follicular stage III-IV non-Hodgkin's lymphoma.

PURPOSE: This phase II multi-institutional trial was designed to assess response and toxicity of 2-chlorodeoxyadenosine (2-CDA) in patients with previously untreated follicular lymphoma. The clinical significance of detecting cells carrying the t(14;18) translocation (bcl-2/JH rearrangement) in peripheral blood and bone marrow by polymerase chain reaction (PCR) before, during and after treatment was also examined. PATIENTS AND METHODS: Between May 1993 and October 1995, 37 patients were accrued: male/female: 15/22, median age 51 years (range: 20-78), stage III/IV: 9/28. Patients received a total 2-CDA dose of 0.7 mg/kg as continuous s.c. or i.v. infusions over 7 days, every 28 days for a maximum of 5 cycles. A total of 165 cycles were administered. In 25 patients, blood and bone marrow before, during and after treatment were available for PCR analysis of the bcl-2/JH rearrangements. RESULTS: All 37 patients were evaluable for response and toxicity. The overall response rate was 84% (95% confidence interval, 68%-94%) with 14% CR (n = 5) and 70% PR (n = 26) and a median time to treatment failure of 15.7 months. bcl-2/JH rearrangement in peripheral blood and/or bone marrow was found in 10/25 of patients (40%) before treatment and 5 of these became repeatedly negative after 2-CDA therapy. There was no apparent association between bcl-2/ JH result and response. In 11 patients, 2-CDA was stopped because of progressive disease (n = 4), myelotoxicity (grade 2-3, n = 4), and other causes (n = 3, pulmonary embolism, metabolic disorder, and patient's decision). Four patients (11%) suffered from infections (grade 2-3). In 6 patients, persistent thrombocytopenia of 7.5 months (range: 3-21) occurred after completion of the 5 cycles. CONCLUSION: 2-CDA is active in untreated follicular lymphomas, but time to treatment failure suggests no advantage compared with standard treatment and toxicity on haematopoietic stem cells appears to be more pronounced. Molecular remission is induced in a considerable proportion of patients with disappearance of the bcl-2/JH rearrangement, and its possible significance as a predictive factor for quality of response and relapse warrants further study.