The anti-ischemic action of a perfluorocarbon emulsion (PFCE) on the canine myocardium

On the 60th minute after inducing the acute ischemia in the canine myocardium by the occlusion of the left anterior descending coronary artery, the animals were intravenously infused with perfluorochemical emulsion (PFCE), its salt composition (SC) or 4% surface-active substance (SAS), proxanol, at a dose of 10 ml/kg. Two hours after infusion, the occlusion was removed (reperfusion). The arterial pO2 was maintained at 120 mm Hg. Analysis of the blood flow, oxygen supply, acid-alkali balance, ECG, as well as creatine phosphokinase activity, measured in the ischemic area, has shown that PFC emulsion is capable of reducing ischemic damage and preventing reperfusion-induced myocardium injury. Thus, the presence of perfluorochemicals in the PFC emulsion is an essential factor in its ischemia-protective effect.     

Lymphoid tissue responses to perfluorocarbon emulsion in mice

The effects of either intraperitoneal or intravenous injection of low doses (5 or 10 ml/kg) of the proprietary emulsified perfluorocarbon-based blood substitute, Fluosol-DA 20%, on mouse lymphoid tissue and antibody production against sheep erythrocytes (SRBC) have been investigated. Mean liver weight was significantly increased and gut mesenteric lymph node (MLN) weights decreased in all animals injected with Fluosol-DA, irrespective of route of administration. In contrast, spleen weight decreased following intravenous injection of emulsion at 5 ml/kg. The mean plasma haemagglutination response to SRBC was significantly (P less than 0.01) increased in animals injected intraperitoneally with Fluosol at both doses but was similar to control in all other cases. These results show that lymphoid tissue responses to Fluosol-DA in mice are variable and that antibody production against intraperitoneally-injected SRBC is enhanced by prior injection of emulsion into the peritoneal cavity.     

Effect of a perfluorochemical emulsion on the radiation response of BA1112 rhabdomyosarcomas

The effect of treatment with a perfluorochemical emulsion (Fluosol DA, 20%), carbogen, or the combination of these two agents on the radiation response of BA1112 tumors in WAG/rij rats was examined. Fluosol and carbogen as single agents had only small effects on the tumor cell survival curve. The combination of Fluosol plus carbogen had a larger effect on tumor cell survival, reducing the hypoxic fraction of the tumor from 23 to 1.6%. The amount of sensitization was a function of the Fluosol dose, with maximal augmentation of the radiation response obtained at doses of 7.5-15 ml/kg. Carbogen pretreatments ranging from 5 to 60 min in duration all had similar effects on tumor radiosensitivity. The effect of the perfluorochemical emulsion plus carbogen on the survival of irradiated tumor cells appears to reflect changes in tumor oxygenation, rather than cytotoxic or immunological effects, since the perfluorochemical emulsion (with or without carbogen) had no effect on the viability of cells in unirradiated tumors. These experiments extend previous studies by ourselves and others using mouse tumors to show that the combination of a perfluorochemical emulsion and carbogen breathing can also increase the radiation response of a nonimmunogenic rat tumor.     

Investigation of remaxol efficacy in complex therapy of experimental generalized tuberculosis on mice

Efficacy of remaxol in complex chemotherapy of generalized drug resistant tuberculosis was studied on mice. Mycobacterium tuberculosis 5419 SPBNIIF isolated from a patient with freshey diagnosticated pulmonary tuberculosis resistant to isoniazid (10 mcg/ml), rifampicin (40 mcg/ml), streptomycin (10 mcg/ml) and ethionamide (30 mcg/ml) was used in the experiments. The main polychemotherapy included 4 antituberculosis drugs in the highest therapeutic doses: isoniazid, amikacin, ethambutol and tavanic, the treatment course was 8 weeks. Remaxol was administered in a dose of 25 ml/kg intraperitoneally 5 times a week (14 injections). Significant activating effect of remaxol on the tension of the lung tissue local immunity was revealed by changes in the granuloma cell composition (from mainly epitheliod to mainly lymphoid) and by more frequent large lymphohistiocytic infiltrates. The use of remaxol also greatly increased the absorptive and digestive activity of the peritoneal macrophages phagocytosis, inhibited in the process of the experimental tuberculosis development.     

Influence of acidic beverage (Coca-Cola) on pharmacokinetics of ibuprofen in healthy rabbits

The study was aimed at determining the effect of Coca-Cola on the pharmacokinetics of ibuprofen in rabbits. In a cross-over study, ibuprofen was given orally in a dose of 56 mg/kg, prepared as 0.5% suspension in carboxymethyl cellulose (CMC) and blood samples (1 ml) were drawn at different time intervals from 0-12 hr. After a washout period of 7 days, Coca-Cola in a dose of (5 ml/kg) was administered along with ibuprofen (56 mg/kg) and blood samples were drawn from 0-12 hr. To these rabbits, 5 ml/kg Coca-Cola was administered once daily for another 7 days. On 8th day, Coca-Cola (5 ml/kg) along with ibuprofen (56 mg/kg), prepared as a suspension was administered and blood samples (1 ml each) were drawn at similar time intervals. Plasma was separated and assayed for ibuprofen by HPLC technique and various pharmacokinetic parameters were calculated. The Cmax and AUC0-alpha of ibuprofen were significantly increased after single and multiple doses of Coca-Cola, thereby indicating increased extent of absorption of ibuprofen. The results warrant the reduction of ibuprofen daily dosage, frequency when administered with Coca-Cola.     

Effect of cicletanine on reperfusion-induced arrhythmias and its relation to 6-keto-PGF1 alpha and thromboxane B2 release

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine anti-hypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1 alpha and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1 alpha and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.     

Effect of sodium succinate on several carbohydrate metabolism indices of ischemic myocardium]

The influence of sodium succinate on the content of lactic, pyruvic acids and glucose in the venous blood flowing from the ischemic zone of the myocardium was studied in dogs with ligated coronary artery. The intracoronary injection of the preparation in doses of 2 and 10 mg/kg diminished the content of blood lactic acid flowing from the ischemic zone; a dose of 10 mg/kg decreased the consumption of glucose by the ischemic myocardium. Sodium succinate (100 mg/kg) intravenously reduced the content of the lactic acid significantly and inhibited the glucose consumption by the ischemic myocardium, with its increase in the arterial blood. A fall of lactacidemia can be connected with the activation of Krebs cycle and an increase of oxygen utilization by the ischemic myocardium.     

Abortifacient principle of Achyranthes aspera Linn

Achyranthes apsera is an abundant indigenous herb in India. Extracts of the whole plant had shown an abortifacient effect in mice. Maximal activity was in the benzene extract which was tested. The drug, in olive oil, was given orally to rabbits in doses of 50 mg/kg of body weight on the 8th day postcoitum. Laparotomy was done on the 11th day. No implantation sites were found. However, ovaries contained prominent corpus luteum, indicating that the drug had prevented pregnancy. In rats, the drug was given orally as a single dose of 50 mg/kg of body weight on the 6th or 7th day after mating. No effect was observed. In mice the drug was given at a single dose of either 10, 15, 25, or 50 mg/kg of body weight. For toxicity tests in mice, a single dose of 1000 mg/kg of body weight was given. After 1 month animals were autopsied and the organs examined. The drug was nontoxic. For a chronic toxicity test 75 mg/kg of body weight was given every 21 days. After 6 months of drug treatment, blood and tissue samples were examined. No toxic effects were observed. For a teratogenic study, 15 mated female mice were fed 10 or 25 mg/kg of body weight on Day 6 of gestation. 3 generations of offspring showed no malformations. In mice, abortifacient effects were noted with a maximum activity at 50 mg/kg of body weight. The drug showed no estrogenic, antiestrogenic, or androgenic effects in mice. Progesterone or pituitary extract given along with the drug did not prevent abortions in mice. The drug was species-specific in that no abortifacient effect was found in rats.     

Involvement of adenosinergic receptors in anxiety related behaviours

In the present study, the effect of adenosine (A1 and A2 receptor agonist), caffeine (A2A receptor antagonist), theophylline (A2A receptor antagonist) and their combination was studied in anxiety related behaviours using elevated zero maze and elevated plus maze paradigms and compared their various behavioural profiles. Adenosine (10, 25, 50,100 mg/kg) significantly showed anxiolytic effect at all the doses, whereas caffeine (8, 15, 30, 60 mg/kg) and theophylline (30, 60 mg/kg) showed psychostimulatory action at lower doses and anxiogenic effect at higher doses. Pretreatment with caffeine (8, 15, 30 mg/kg) and theophylline (30 mg/kg) reversed the anxiolytic effect of adenosine. The study suggested the involvement of adenosinergic receptor system in anxiety related behaviours.     

Biochemical and histologic presentations of female wistar rats administered with different doses of paracetamol/methionine

This study was carried out to compare the hepatoprotective effect of methionine on paracetamol treated rats at both the peaks of toxicity and absorption. Female Wistar rats were divided into 17 groups consisting of eight rats per group and treated with different doses of paracetamol/methionine (5:1). Each control rat received 5 ml of physiologic saline. The study was terminated at two different end points -the 4th and 16th hours. Results show that rats administered with toxic doses (1000 mg/kg, 3000 mg/kg, 5000 mg/kg BW) of paracetamol exhibited significant increases in the levels of ALT, AST, γ- GT compared with controls. These increases were much higher at the 16th than 4th hour but serum total protein, albumin and globulin were significantly decreased by the end of the 16th hour. Histology results of rats in the 3000 and 5000 mg/kg (by the end of the 16th hour) confirmed hepatic damage, light microscopic evaluation of liver showed remarkable centrilobular necrosis. Moreover, the presence of mononuclear cells in liver section of rats intoxicated with APAP (5000 mg/kg) suggests a possible involvement of inflammatory process which resulted in regurgitation of bilirubin leading to its elevated level as well as increase activity of ALP. The hepatoprotective effect of methionine, on the other hand, was demonstrated in these rats at the 4th and 16th hours, and both results were comparable and therefore not significantly different but elevation in GGT level still persisted. In conclusion, data obtained from this study suggest that these agents may be capable of inducing GGT, although further study is required to establish a possible relationship between methionine and this enzyme in some other animal species.     

Effects of a perfluorocarbon emulsion, Fluosol-DA, on rat lymphoid tissue and immunological competence

The effects of administration of low doses (5 or 10 ml/kg body wt) of the proprietary perfluorocarbon emulsion blood substitute, Fluosol-DA 20%, on rat lymphoid tissue and antibody production against sheep red blood cells (SRBC) have been studied. Spleen and mesenteric lymph nodes (MLN) were significantly heavier at eight days after injection of Fluosol, whereas liver and thymus weights were unchanged. The mean plasma antibody titre to sheep red blood cells was significantly (P less than 0.05) increased in animals injected intraperitoneally with both doses of Fluosol-DA before immunization. These results show that there are differences in the uptake of perfluorochemicals by certain rat lymphoid tissues and that immunological competence can be altered following administration of such materials.     

Inducibility of somatic colour and white spots in the mammalian spot test: Examination with,and experience in using,cyclophosphamideR, s.c.

F₁ embryos of the C57BL/6JHan × T-Stock were exposed in utero to 5, 10, 15 and 45 mg/kg b.w. of cyclophophamide (CP) s.c. on the 10th day of pregnancy. 3–5 weeks post-partum the offspring were examined for the appearance of recessive coat-colour mosaics and white midventral spots (WMVS). The frequencies of the coloured spots were 0.93 and 2.59% at 5- and 10-mg/kg doses of CP, res. These frequencies were dose-dependent, but the difference between the doses was not significant. No coloured spots were obtained with CP at 15 and 45 mg/kg. The frequencies of WMVS were much higher than those of coloured spots (1.40, 6.03 and 51.16%, resp.). The differences were highly significant. The reduction in the number of offspring compared with the ratio of the offspring/female of the control (control = 100%) were 16.16, 22.72, 72.48 and 100% at the different doses of CP (5, 10, 15 and 45 mg/kg b.w.).     

The effect of crocin and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats

In this study, the effect of crocin and safranal was studied against subacute toxicity of diazinon (DZN) on hematological and genotoxicity indices in rats. The rats were divided into 16 groups consisted of 6 rats in control, diazinon, vitamin E, vitamin E and DZN, crocin (3 doses), crocin (3 doses) and DZN, safranal (3 doses), safranal (3 doses) and DZN groups. Vitamin E (200 IU/kg), safranal at doses 0.025, 0.05 and 0.1 ml/kg and crocin at doses 50, 100 and 200 mg/kg were injected intraperitoneally to rats three times per week alone or with DZN (20 mg/kg/day, orally) for 4 weeks. Hematological parameters were evaluated at the end of 4 weeks. The evaluation of genotoxicity was done using the micronucleus assay. Vitamin E and, at lower doses, safranal (0.025 and 0.05 ml/kg) and crocin (50 mg/kg) restored the reduction of red blood cell, hemoglobin and hematocrit indices induced by DZN. These agents at some doses also prevented the reduction in platelets counts indices in diazinon treated group. A significant increase in reticulocyte was induced by diazinon. Vitamin E, safranal (0.025 or 0.05 ml/kg) and all doses of crocin decreased this effect of diazinon. In all doses vitamin E, crocin and safranal did not inhibit the effect of diazinon on RBC cholinesterase activity. A significant increase in micronucleus indices was seen with diazinon. Vitamin E, safranal and crocin could not prevent this genotoxicity. This study showed that vitamin E, safranal and crocin (without effects on cholinesterase) reduced diazinon hematological toxicity, but they did not prevent the genotoxicity induced by diazinon.     

Brain oxygenation and CNS oxygen toxicity after infusion of perfluorocarbon emulsion

Intravenous perfluorocarbon (PFC) emulsions, administered with supplemental inspired O(2), are being evaluated for their ability to eliminate N(2) from blood and tissue prior to submarine escape, but these agents can increase the incidence of central nervous system (CNS) O(2) toxicity, perhaps by enhancing O(2) delivery to the brain. To assess this, we infused a PFC emulsion (Oxycyte, 6 ml/kg iv) into anesthetized rats and measured cerebral Po(2) and regional cerebral blood flow (rCBF) in cortex, hippocampus, hypothalamus, and striatum with 100% O(2) at 1, 3, or 5 atmospheres absolute (ATA). At 1 ATA, brain Po(2) stabilized at >20 mmHg higher in animals infused with PFC emulsion than in control animals infused with saline, and rCBF fell by ~10%. At 3 ATA, PFC emulsion raised brain Po(2) >70 mmHg above control levels, and rCBF decreased by as much as 25%. At 5 ATA, brain Po(2) was ≥159 mmHg above levels in control animals for the first 40 min but then rose sharply; rCBF showed a similar profile, reflecting vasoconstriction followed by hyperemia. Conscious rats were also pretreated with PFC emulsion at 3 or 6 ml/kg iv and exposed to 100% O(2) at 5 ATA. At the lower dose, 80% of the animals experienced seizures by 33 min compared with 50% of the control animals. At the higher dose, seizures occurred in all rats within 25 min. At these doses, administration of PFC emulsion poses a clear risk of CNS O(2) toxicity in conscious rats exposed to hyperbaric O(2) at 5 ATA.     

Characteristics of the protective action of ethacizin on the ischemic myocardium

A study was made of the effect of ethacizine, a new antiarrhythmic phenothiazint derivative, on the size of experimental myocardial infarction in rabbits 7 days after ligation of the coronary artery. Ethmozine was used as reference. Ethacizine diminished the extent of necrosis by 22.8% (P less than 0.05) when injected intravenously in divided doses beginning from the 30th minute of 2-hour ligation, the total dose being 1.5 mg/kg. The six-day cycle of ethacizine treatment instituted 24 h after coronary artery ligation (daily dose 1.2 mg/kg) provoked a more considerable reduction of the myocardial infarction size (by 44.9%). The effect of ethmozine was less pronounced though statistically significant. Ethacizine increased ATP content in both the ischemic and "intact" myocardium and minimized the impairment of membrane permeability in the occlusion zone 3 h after ligation when injected according to the first above-described scheme. It is assumed that these effects may contribute to the drug protective action on the ischemic myocardium.     

The interrelationship of doses and the pharmacological effects of cardiac peptides]

Low-molecular weight peptides prepared according to an original procedure from a cattle heart possess a protecting effect on the myocardium during ischemia. Peptides in doses of 10(-7) g/ml and less improve the indexes of contractility function of the isolated heart after total ischemia and correct respiration warranting cardiomyocytes survival during hypoxia. However, in different models high doses of heart peptides (5 x 10(-6) g/ml and more) are shown to inhibit contractility, to stop respiration, the action of the peptides increasing with myocardial ischemia degree.     

Behavioral effects and benzodiazepine antagonist activity of Ro 15-1788 (flumazepil) in pigeons

The selective benzodiazepine receptor antagonist, Ro 15-1788, produced behavioral effects in pigeons at doses at least 100 times lower than those previously reported to possess intrinsic pharmacological activity in mammals. In contrast to its effects in mammalian species, in pigeons, Ro 15-1788 does not exhibit partial agonist activity. Key-peck responses of pigeons were studied under a multiple fixed-interval 3-min, fixed-interval 3-min schedule in which the first response after 3-min produced food in the presence of red or white keylights. In addition, every 30th response during the red keylight produced a brief electric shock (punishment). Under control conditions, punished responding was suppressed to 30% of unpunished response levels. Ro 15-1788 (0.01 mg/kg, i.m.) increased unpunished response rates by 33% without affecting rates of punished responding. Doses of 0.1 to 1.0 mg/kg Ro 15-1788 produced dose-related decreases in both punished and unpunished responding. As is characteristic of other benzodiazepines, midazolam (0.1 and 0.3 mg/kg, i.m.) markedly increased punished responding but had little effect on rates of unpunished responding. Ro 15-1788 antagonized the increases in punished responding and also reversed the rate-decreasing effects of higher doses of midazolam. However, the effectiveness of Ro 15-1788 as a benzodiazepine antagonist was limited by its intrinsic activity: rate-decreasing doses of Ro 15-1788 were unable to completely reverse behavioral effects of midazolam. Midazolam was an effective antagonist of the behavioral effects of Ro 15-1788 (up to 0.1 mg/kg) but midazolam did not influence the rate-decreasing effects of 1.0 mg/kg Ro 15-1788 across a 100-fold dose range. In the pigeon, the behavioral effects of relatively low doses of Ro 15-1788 (0.01-0.1 mg/kg) appear to be related to benzodiazepine receptor mechanisms, whereas other systems appear to be involved in the effects of higher doses.     

General pharmacological propertiesof Sho-seiryu-to (TJ-19) extracts

The general pharmacological properties of TJ-19 extracts were orally investigated in various experimental animals. TJ-19 extracts showed no effect on general behavior and on central nervous system such as spontaneous locomotor activity, proconvulsant and anti-convulsant responses, analgesic activity, body temperature and hexobarbital sleeping time at all doses of 0.5, 1 and 2 g/kg in mice. Further, TJ-19 extracts showed no effect on contractile responses of isolated guinea pig ileum induced by acetylcholine, histamine and BaCl2 at concentrations of 10(-6), 10(-5), and 10(-4) g/ml. TJ-19 extracts, however, increased the respiratory rate, heart rate, blood pressure, systolic pressure, diastolic pressure, and decreased the blood flow in dogs at all doses of 0.5, 1 and 2 g/kg via duodenal administration. Further, TJ-19 extracts decreased the interval of PR and QT of EKG parameters in dogs at doses of 1 and 2 g/kg. TJ-19 extracts increased the intestinal transport of charcoal meal in rats at doses of 1 and 2 g/kg. TJ-19 increased the urinary Na+ excretion at all doses of 0.5, 1, and 2 g/kg, and increased the urinary K+ and Cl- excretion at 1 and 2 g/kg, although it showed no effect on urine volume output in rats. These data suggest that TJ-19 stimulates the sympathetic nervous system function at a pharmacological dose of under 0.5 g/kg, and has possibility to increase the intestinal peristalsis and urinary electrolyte excretion at higher doses.     

Corticosteroid potentiation of surfactant dose response in preterm rabbits

Fetal rabbits were treated with corticosteroids by maternal administration for 48 h before delivery at 27 days gestational age. Both corticosteroid-treated and control animals then received exogenous natural rabbit surfactant at birth at doses of 0-75 mg lipid/kg. After 10 min of ventilation at tidal volumes of 12-15 ml/kg, static pressure-volume measurements were made. At all surfactant doses there was a significantly higher maximal lung volume, higher dynamic compliance, and lower pressure requirement in the corticosteroid-treated than in the control rabbits (P less than 0.01). Control animals showed incremental improvements in dynamic compliances and maximal lung volumes up to a dose of 50 mg/kg, whereas corticosteroid treated animals improved to a maximum at the low dose of 15 mg/kg (P less than 0.01). However, surface tension as assessed by lung stability index improved with increasing surfactant dose but was not significantly different between corticosteroid-treated and control animals at a given dose. The results imply that maternal corticosteroid treatment potentiates surfactant replacement by a change in lung structure that is independent of surface tension effects.     

Evidence for suppression of serum LH without elevation in serum estradiol or prolactin with a brain-enhanced redox delivery system for estradiol

We developed a redox system for brain-enhanced delivery of estradiol based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Estradiol (E2), when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces the rate of exit of the estradiol-carrier complex from the brain. Subsequent hydrolysis of the carrier provides sustained production of estradiol in the brain. The aim of the study was to evaluate the effects of single vs. multiple injections of the estradiol-chemical delivery system (E2-CDS) on both central and peripheral estrogen-responsive tissues. Ovariectomized Sprague-Dawley rats received an intravenous injection of E2-CDS at 10, 33, 100 or 333 micrograms/kg BW or the drug vehicle, dimethyl sulfoxide (DMSO; 0.5 ml/kg) every 2 days for 7 injections (2 weeks) or a single injection only at 2 days before sacrifice. With a single injection, E2-CDS did not affect serum luteinizing hormone (LH) levels at the 10 micrograms/kg dose but caused a dose-dependent reduction in serum LH of 39-52% at the dose range of 33 to 333 micrograms/kg. By contrast, multiple injections of E2-CDS caused a 32 to 76% reduction in serum LH levels at doses ranging from 10 micrograms/kg to 333 micrograms/kg. Additionally, multiple doses of E2-CDs caused a dose-dependent reduction in body weight at the 10 and 33 micrograms/kg doses with the higher doses causing no further weight reduction. For both single and multiple dosage groups, serum E2 levels remained unchanged after doses of E2-CDS of 10 and 33 micrograms/kg, then increased to 21 pg/ml for the single dosage group and to 23 pg/ml for the multiple dosage group at the 100 micrograms/kg dose, and to 59 pg/ml for singly-injected rats and 60 pg/ml for multiply-injected rats at the 333 micrograms/kg dose. Serum prolactin concentrations were closely correlated with serum E2 levels for both the single and multiple dose groups. These data reveal that a single or multiple doses of E2-CDS can reduce serum LH levels without elevating serum E2 or prolactin concentrations, supporting the concept of brain-enhanced delivery of estradiol with an estradiol chemical delivery system.