Antinociceptive effects of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis, and possible involvement of the adenosine system.

Incarvillea sinensis is a Bignoniaceae plant used to treat rheumatism and relieve pain in traditional Chinese medicine. As a major component of I. sinensis, incarvillateine has shown analgesic activity in mice formalin tests. Using a series of animal models, this study further evaluated the effects of incarvillateine against acute, inflammatory, and neuropathic pain. Incarvillateine (10 or 20 mg/kg, i.p.) dose-dependently attenuated acetic acid-induced writhing, but did not affect thermal threshold in the hot plate test. In a Complete Freund's Adjuvant model, incarvillateine inhibited both thermal hyperalgesia and paw edema, and increased interleukin-1ß levels. Additionally, incarvillateine attenuated mechanical allodynia induced by spared nerve injury or paclitaxel, whereas normal mechanical sensation was not affected. Incarvillateine did not affect locomotor activity and time on the rotarod at analgesic doses, and no tolerance was observed after 7 consecutive daily doses. Moreover, incarvillateine-induced antinociception was attenuated by theophylline, 1,3-dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl-1-propargylxanthine, but not naloxone, indicating that the effects of incarvillateine on chronic pain were related to the adenosine system, but not opioid system. These results indicate that incarvillateine is a novel analgesic compound that is effective against inflammatory and neuropathic pain, and that its effects are associated with activation of the adenosine system.

Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin neurons by activation of presynaptic adenosine A1 receptors, which may finely regulate the excitability of these neurons as well as eventually modulate the sleep-wakefulness.

The involvement of nitric oxide on the adenosine A(2) receptor-induced cardiovascular inhibitory responses in the posterior hypothalamus of rats.

This study was performed to investigate the putative relationship between nitric oxide (NO) and adenosine A(2) receptors on central cardiovascular regulation in the posterior hypothalamus of rats. Posterior hypothalamic injection of drugs was performed in anesthetized, artificially ventilated male Sprague-Dawley rats. Injection of adenosine A(2) receptor agonist 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 1, 2 and 5 nmol) produced a dose-dependent decrease of blood pressure and heart rate. Pretreatment with adenosine A(2) receptor antagonist 3,7-dimethyl-1-propargylxanthine (10 nmol) blocked the depressor and bradycardiac effects of CPCA (5 nmol). Pretreatment with soluble guanylate cyclase inhibitor LY-83,583 (5 nmol) attenuated the depressor and bradycardiac effects of CPCA (5 nmol). In addition, pretreatment with NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (40 nmol) attenuated the depressor and bradycardiac responses of CPCA (5 nmol). These results suggest that adenosine A(2) receptor in the posterior hypothalamus plays an inhibitory role in central cardiovascular regulation and that NO participates in the inhibitory response induced by adenosine A(2) receptor stimulation in the posterior hypothalamus.

The intrastratial injection of an adenosine A(2) receptor antagonist prevents frontal cortex EEG abnormalities in a rat model of Huntington's disease.

The influence of 3,7-dimethyl-1-propargylxanthine (DMPX) an adenosine A(2) receptor antagonist, was studied in the quinolinic acid (QA) model of Huntington's disease. Male Wistar rats received bilateral intrastriatal injections of QA (300 nmol) alone or plus DMPX (0.02, 0.2 and 2 microg). At the dose of 0.2 microg, DMPX completely prevented QA-induced EEG abnormalities at the level of frontal cortex. The results support the hypothesis of a neuroprotective role of adenosine A(2) receptor antagonists.

SPECT monitoring of improved cerebral blood flow during long-term treatment of elderly patients with nootropic drugs.

PURPOSE: In normal aging persons, oxygen and glucose consumption progressively decreases with reduced cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A data processing model with the use of Tc-99m SPECT of the human brain has been developed and found to be sensitive for monitoring the effects of drugs that increase CBF. In this study, the effect of two vasodilator drugs (the combination of pentifylline and nicotinic acid versus piracetam) was compared with the effect of placebo on CBF. MATERIALS AND METHODS: Thirty elderly volunteers had three different procedures using the Peelproc method to spatially standardize and compare CBF patterns by SPECT before and after drug intervention. The 30 patients were divided into five groups of six persons each who were randomly assigned in a 1:1 ratio to the treatment sequences consisting of three phases: the combination of pentifylline and nicotinic acid (C), piracetam (N), and placebo (P), or C-N-P; P-N-C; P-C-N; N-C-P; C-P-N; or N-P-C. Phases 1 to 3 each consisted of a baseline recording of parameters (day 0), treatment for 60 days (days 1 to 60), and recording of parameters after treatment (day 61). RESULTS: In elderly human volunteers (ages, 52 to 70 years), after 2 months of oral treatment with a combination of pentifylline and nicotinic acid (800 mg pentifylline, 200 mg nicotinic acid daily), SPECT results for the Peel-proc program indicated a statistically significant improvement in CBF of the total brain, with a more pronounced improvement in the cerebellum and frontal regions, where a definite shift from abnormal to normal blood flow was detected. Spontaneous communication from most of the volunteers suggested that they experienced an improvement in memory and general well-being from the combination treatment. After 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT results indicated a regional improvement in CBF, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. CONCLUSION: The in vivo method to quantitatively monitor the progress of long-term drug therapy on CBF described here could be useful to assess and even direct changes in therapy.

The influence of pentoxifylline and torbafylline on muscle blood flow in animals with peripheral arterial insufficiency.

The potential of pentoxifylline to enhance blood flow to relatively ischemic muscle during running was evaluated in rats with peripheral arterial insufficiency. Femoral artery stenosis, sufficient to limit exercise hyperemia but not affect resting blood flow, was surgically induced in adult male rats (approximately 350 g). Day three after stenosis, rats were assigned to either a control (N = 14) or treatment (N = 14) group and exercised 5 days a week for 3 weeks. Exercise tolerance of rats fed pentoxifylline (34 +/- 1.3 mg/kg/day) or an analog (torbafylline; 34 +/- 2.3 mg/kg/day) increased more (P less than .001) than control rats in the third week of treatment. This was evidenced by a higher treadmill speed and longer duration of running. Blood flows determined with 85Sr and 141Ce labeled 15 mu spheres at low (20 m/min) and high (30-35 m/min) treadmill speeds were similar for each group and approximately 50% of that found in normal nonstenosed rats. Blood flows to the entire hindlimb, to the proximal and distal hindlimb segments, and to individual muscle fiber sections were not different between control and pentoxifylline groups. Thus, the increase in exercise tolerance could not be attributed to an increase in muscle blood flow. Rather, an enhanced oxygen extraction by the working limb muscles should lead to the increased VO2, required by the faster running speed in the pentoxifylline rats. This suggests that pentoxifylline may act to improve microvascular flow heterogeneity in working muscle. Our findings support clinical evidence that pentoxifylline is effective in managing patients with peripheral arterial insufficiency.

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections.

Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10(8) Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PTX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug. PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).

Effects of pentoxifylline in experimental acute renal failure.

The beneficial effects of post-insult administration of pentoxifylline, a novel hemorheologic agent experimentally studied in various ischemic diseases, were evaluated in two models of acute renal failure (ARF): direct nephrotoxicity (mercuric chloride 4 mg/kg via femoral vein) and hemoglobinuria (glycerol 10 ml/kg i.m.). Glomerular filtration rate (GFR) was estimated at baseline and following drug administration by creatinine clearances; tubular function was assessed by renal fractional and absolute electrolyte excretions. The incidence of mortality was decreased with a single dose of pentoxifylline 45 mg/kg (21.4%) compared to control rats (71.4%) 48 hours following induction of ARF with mercuric chloride. Although GFR and renal electrolyte excretion were significantly greater in rats given pentoxifylline compared to saline, the magnitude of difference was minimal. A return to baseline GFR was observed in the glycerol group administered a single i.p. dose of pentoxifylline 45 mg/kg (100.8 +/- 54.8%) compared to saline controls (45.6 +/- 22.7%; P less than 0.05). No differences in renal electrolyte excretion or mortality were observed in this model. Taken together, these data suggest that pentoxifylline, administered shortly after the initiation of ARF, exerts an ameliorative effect on the course and mortality of experimental ARF. The mechanism of amelioration most likely involves the stimulation of renal vasodilator prostaglandins as well as prevention of vascular congestion.

Treatment of wound sepsis in irradiated mice.

Infections in the immunocompromised host are difficult to treat. The local and systemic effect of penicillin therapy, supplemented by immunoglobulins, and pentoxifylline on wounds infected by Staphylococcus aureus was evaluated in mice irradiated with 6.5 Gy 60Co gamma-rays. Three days after irradiation a suspension of S. aureus was inoculated subcutaneously over the gluteus muscle of anesthetized mice. The skin and the muscle were incised at the site of the inoculation. Treatment with 62.5 mg/kg penicillin-G was administered for 10 days. Numbers of bacteria per mg muscle and presence of organisms in spleens and livers were determined. Numbers of bacteria were significantly reduced from 7.3 (+/- 0.3) to 5.3 (+/- 0.4) log10 CFU/mg (+/- SEM) muscle in treated animals. Administration of immunoglobulin G i.v. or pentoxifylline i.p. alone, or in addition to penicillin-G, did not further reduce the number of bacteria. Increase in the dose of penicillin to 250 mg/kg decreased the number of bacteria more than 62.5 mg/kg. Bacteria were recovered from spleens and/or livers of all 13 untreated mice, and only in six of the 13 penicillin-treated mice (P less than 0.05). Penicillin therapy reduced the systemic spread of S. aureus. The model provides a means to evaluate regimens for treatment of bacterial wound infections in irradiated animals. The data illustrated the ability of antimicrobial agents to contain but not cure the infection in the immunocompromised host, and the lack of efficacy of immunoglobulins in neutropenic mice.

[Lipid metabolism and peripheral hemodynamics in arteriosclerosis obliterans treated with nifedipine--a comparison with pentoxifylline]. / Lipidstoffwechsel und periphere Hämodynamik bei Arteriosclerosis obliterans unter Nifedipin--ein Vergleich gegen Pentoxifyllin.

In the present study altogether 51 patients with obliterating arteriosclerosis stage II according to Fontaine were examined concerning the haemodynamic and lipid parameters under influence of nifedipine and pentoxifylline, respectively. An antiatherogenic effect under nifedipine takes place possibly by the diminution of the triglycerides in the serum and the blood pressure as well as by the increase of the linolenic acid in the serum (precursor of the vasoprotective prostacyclin I3). Pentoxifylline essentially behaves lipid-neutral. The increase of the intermittent claudication distance clearly speaks for pentoxifylline. - Nifedipine should only be used in concomitant indications.

Synergistic effects of pentoxifylline and hyperbaric oxygen on skin flaps.

This study investigated the effects of pentoxifylline and hyperbaric oxygen (HBO) on experimental skin flaps in rats under four conditions. Sixty animals were randomly divided into one of four groups: (1) a control group, (2) a pentoxifylline- or (3) an HBO-treated group, and (4) a pentoxifylline- plus HBO-treated group. Cranially based skin flaps were elevated on the dorsum. The surviving length was evaluated with fluorescein dye seven days after the operation. Rats that were treated with pentoxifylline received 20 mg/kg intraperitoneally at 24, 12, and 1 hour(s) before flap elevation and every 12 hours after the operation for seven days. Rats that were treated with HBO received a total of 14 two-hour treatments at 2.5 absolute atmospheres in divided doses. Results indicated that the surviving length of flaps in the pentoxifylline- or HBO-treated groups was significantly greater than those in the control group, but were not significantly different from each other. Animals treated with both pentoxifylline and HBO had significantly greater flap survival than animals in any of the other three groups. This reflected a 30% to 39% improvement over pentoxifylline alone- or HBO alone-treated animals, and an 86% improvement over control animals. Mechanisms of action for this apparent synergistic effect on flap survival are discussed.

[Use of trental for correcting the pharmacological effects caused by voltaren and indomethacin]. / Primenenie trentala dlia korrektsii farmakologicheskikh éffektov, vyzvannykh vol'tarenom i indometatsinom.

Treatment of the adjuvant disease in rats by intragastric administration of voltaren or indomethacin (3 mg/kg) was followed by approximately equal anti-inflammatory and analgesic effects on the affected joints. In this case the development of active dystrophic changes in the gastrointestinal tract and kidneys was observed. At combined administration of the antiphlogistics with trental there was noted an enhancement of their therapeutic action on the joints and also a weakening of the ulcerogenic effect and nephrotoxicity that was reflected in the clinical, pathological, morphological and laboratory studies.

Effect of pentoxifylline on the ischemic rat kidney monitored by 31P NMR spectroscopy in vivo.

The effect of pentoxifylline on the recovery of renal energy metabolism after ischemia and reperfusion was studied by 31P nuclear magnetic resonance spectroscopy in vivo. Rat kidneys were exposed to 15, 30 and 60 min, respectively, of ischemia by clamping the arteria renalis. Pre-ischemic application of pentoxifylline improves the recovery of renal energy metabolism. The concentration of ATP was found to be higher in pentoxifylline pretreated kidneys than in controls after ischemia. The 5'-nucleotidase inhibiting activity of pentoxifylline is suggested to be the mechanism responsible for the protective effect of the drug. 31P NMR spectroscopy proved to be a powerful tool for continuous follow-up of drug effects on metabolic processes.

Effects of pentoxifylline on experimental skin flap survival.

We studied the effects of pentoxifylline on experimental skin flap survival in the domestic pig. Random skin flaps were designed using a length-width ratio of 5:1. The pigs were then given pentoxifylline (25 mg/kg/d) or placebo for seven days. Fluorescein sodium was used to help determine surviving skin flap length seven days postoperatively. Results showed no significant difference in mean surviving skin flap length between the study and control groups. We question the value of pentoxifylline in increasing skin flap survival.

[Effect of fructose-1,6-diphosphate and trental on the erythrocyte aggregating capacity in ischemic heart disease]. / Vliianie fruktozo-1,6-difosfata i trentala na agregatsionnuiu sposobnost' éritrotsitov krovi pri ishemicheskoi bolezni serdtsa.

It was shown that fructose-1.6-diphosphate was capable of marked suppression of the aggregation power of the blood erythrocytes of patients with acute myocardial infarction and angina of effort. The antiaggregation effect of the drug was dose-related and enhanced with an increase in the time of its contact with erythrocytes. The antiaggregation effect of pentoxifylline was not of distinct dose-related nature. Its antiaggregation power did not considerably depend on the time of incubation with erythrocytes.

Study of antiosteoporotic agents in tissue culture.

Cultures of osteoblast-like cells were established from calvariae of Sprague-Dawley rats. Pentoxifylline increased cAMP levels and calcium uptake in these cultures. However, calcium uptake increased at lower levels than required to increase cAMP levels. Thus, it is likely that cAMP unrelated mechanisms are also involved in these phenomena.

Effect of pentoxifylline on alpha- and beta-adrenoceptor sites in cerebral cortex medial basal hypothalamus and pineal gland of the rat.

The intraperitoneal injection of the methylxanthine derivative pentoxifylline (3,7-dimethyl-1-(5-oxo-hexyl)-xanthine] brought about, 3 hr later, a significant depression of alpha- and beta-adrenoceptor sites in the cerebral cortex, and of beta-adrenoceptor sites in medial basal hypothalamus and pineal gland, (assessed from the specific binding of radioactive dihydroergocryptine and dihydroalprenolol respectively). The changes in the density of binding sites were not accompanied by significant modifications of the Kd's. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy (SCGx) abolished the changes of beta-adrenoceptor number in the pineal caused by pentoxifylline. The increase of alpha-adrenoceptor sites in the hypothalamus brought about by ganglionectomy was not affected by injection of pentoxifylline. Pentoxifylline did not compete in vitro for radioligand binding to brain membranes. These results suggest that methylxanthines depress brain adrenoceptor sites acutely, probably by down-regulation of receptors following the increase in catecholamine release caused by injection of the drug.