Mechanisms underlying the supra-maximal thermogenesis elicited by aminophylline in rats

Previous studies showed that acute treatment with aminophylline (AMPY) significantly elevated maximum thermogenesis and improved cold tolerance in rats and man in severe cold. However, the exact mechanism by which AMPY enhances thermogenesis was unknown. Rats receiving enprofylline (ENPRO) (1.5 and 15 mg/kg, i.p.), a selective phosphodiesterase inhibitor, failed to show enhanced thermogenesis. In contrast, treatment with a selective adenosine receptor antagonist, 8-phenyltheophylline(8-PT; 2.5 to 10 mg/kg, i.p.), significantly increased (p less than 0.05) thermogenesis and cold tolerance. However, the maximal thermogenic effect by optimal dose of 8-PT (5 mg/kg) was significantly lower than that with optimal dose of AMPY (18.7 mg/kg, i.p.); the deficit could be eradicated by combining optimal 8-PT dose with a low dose of AMPY (1.25 mg/kg), but not with ENPRO. These results indicate that the thermogenic effect of AMPY is not by inhibition of phosphodiesterase but at least partially by antagonism of adenosine receptors. It is also apparent that older mechanisms in addition to adenosine antagonism are also involved in AMPY's thermogenic action.     

Role of adenosine in the hypoxia-induced hypothermia of toads

The concept that hypoxia elicits a drop in body temperature (T(b)) in a wide variety of animals is not new, but the mechanisms remain unclear. We tested the hypothesis that adenosine mediates hypoxia-induced hypothermia in toads. Measurements of selected T(b) were performed using a thermal gradient. Animals were injected (into the lymph sac or intracerebroventricularly) with aminophylline (an adenosine receptor antagonist) followed by an 11-h period of hypoxia (7% O(2)) or normoxia exposure. Control animals received saline injections. Hypoxia elicited a drop in T(b) from 24.8 +/- 0.3 to 19. 5 +/- 1.1 degrees C (P < 0.05). Systemically applied aminophylline (25 mg/kg) did not change T(b) during normoxia, indicating that adenosine does not alter normal thermoregulatory function. However, aminophylline (25 mg/kg) significantly blunted hypoxia-induced hypothermia (P < 0.05). To assess the role of central thermoregulatory mechanisms, a smaller dose of aminophylline (0.25 mg/kg), which did not alter hypoxia-induced hypothermia systemically, was injected into the fourth cerebral ventricle. Intracerebroventricular injection of aminophylline (0.25 mg/kg) caused no significant change in T(b) under normoxia, but it abolished hypoxia-induced hypothermia. The present data indicate that adenosine is a central and possibly peripheral mediator of hypoxia-induced hypothermia.     

Nifedipine and atenolol singly and combined for treatment of essential hypertension: comparative multicentre study in general practice in the United Kingdom

A randomised double blind parallel group study was performed to compare the efficacy and acceptability of slow release nifedipine (maximum dose 40 mg twice a day) with those of atenolol (maximum dose 100 mg once a day) as single agents for the treatment of essential hypertension. Of 410 patients recruited almost exclusively from general practices in 22 centres in the United Kingdom 210 received nifedipine and 200 atenolol. Both drugs significantly reduced blood pressure, and control—a reduction of the diastolic pressure to less than 95 mm Hg—was obtained in about 65% of patients. Those who received nifedipine had more pronounced reductions in systolic pressure than those who received atenolol. One hundred and forty nine patients who failed to respond adequately to either atenolol or nifedipine in low doses were given both drugs once daily for eight weeks in a fixed combination capsule that contained atenolol 50 mg and nifedipine 20 mg. All patients showed further reductions in blood pressure, although those who were taking β atenolol before the combination capsule had more pronounced reductions in systolic pressures. Twenty six patients (12%) were withdrawn because of adverse effects while taking nifedipine compared with 19 (10%) taking atenolol. Flushing and oedema were more common after the calcium antagonist, whereas diarrhoea and dyspepsia were more common after atenolol. The frequencies of headaches, dizziness, fatigue, and dyspnoea were equally distributed between the two groups. When the fixed combination capsule was taken side effects such as flushing and oedema continued.Nifedipine was more effective than atenolol in lowering systolic blood pressure, although neither drug used alone controlled the pressure of more than two thirds of the patients studied. When used in a fixed combination slightly better control of blood pressure was achieved with a lower dose of each drug.     

Inhalation of adenosine 5'-monophosphate increases methacholine airway responsiveness

Airway hyperresponsiveness is a characteristic feature in asthmatic subjects, but the mechanism of the hyperresponsiveness is not known. The purpose of this study was to investigate whether methacholine airway responsiveness was increased 24 h after inhalation of adenosine 5'-monophosphate (AMP). Ten atopic asthmatic subjects and six atopic normal subjects were studied on 4 study days. On the 1st day, a methacholine inhalation test was performed, followed within 48 h by an AMP inhalation test. Seven days later the second AMP test was performed, and 24 h later the methacholine inhalation test was repeated. Response was measured using partial flow-volume curves, and the concentration required to cause a 40% fall in the partial flow-volume curve (PC40) was calculated. The geometric mean methacholine PC40 fell from 1.36 mg/ml on day 1 (before AMP inhalation) to 0.71 mg/ml on day 4 (24 h after AMP inhalation, P less than 0.01). There was no change in the mean PC40 for adenosine on the 2 study days (5.82 and 7.06 mg/ml, P greater than 0.1). These findings suggest that adenosine release may contribute to the increase in airway responsiveness after allergen challenge.     

A phase I study of intrapleural Corynebacterium parvum after complete resection of bronchogenic carcinoma

Summary Corynebacterium parvum (C. parvum) was instilled into the pleural space via the chest tube in 11 patients after curative resection for lung cancer. Doses were escalated from 20–70 mg in approximately every third patient in an attempt to determine the maximum tolerated dose. Fever and chest pain were the only toxicities encountered; severity and duration were not dose-related. Six of seven surgical stage I patients were alive and free of recurrence with a median follow-up of 2 1/2 years. A single patient developed light-chain-producing multiple myeloma 1 year after C. parvum injection.American Cancer Society Clinical Fellow     

Pharmacological studies on mechanisms of aminophylline-induced seizures in rats

In the present study, the possible role of free radicals in aminophylline-induced seizures was evaluated in albino rats. Aminophylline (theophylline in ethylene diamine; 50 - 300 mg/kg) induced convulsions in rats in a dose-dependent manner, and both incidence of seizure and mortality were maximum at 300 mg/kg. Conventional anti-epileptics, diphenylhydantoin and dizocilpine, as well as adenosine agonists were ineffective in antagonizing these seizures. On the other hand, phosphodiesterase inhibitors, pentoxyphylline and rolipram, showed insignificant seizurogenic effects. Pretreatment with antioxidants (ascorbic acid, alpha-tocopherol, and melatonin) showed differential attenuating effects on aminophylline seizures and lethality. Further, prior administration of 1-buthionine sulfoxamine (BSO, glutathione depletor) and triethyltetramine (TETA, superoxide dismutase inhibitor), precipitated seizures and enhanced lethality in response to subthreshold doses of aminophylline. The present results suggested of the possible involvement of oxidative stress during aminophylline-induced seizures.     

Respiratory effects of analgesia after cholecystectomy: comparison of continuous and intermittent papaveretum.

Two methods of administering papaveretum for relieving postoperative pain were compared in two groups of patients who had undergone cholecystectomy. In one group a loading dose of papaveretum was administered by continuous intravenous infusion (1 mg/min) until the patient could breathe deeply without undue pain. Eight times this loading dose was given as a continuous intravenous infusion over the subsequent 48 hours. This regimen was compared with a conventional intermittent intramuscular dose (0.25 mg/kg at four hourly intervals as necessary) in a second group of patients. The intravenous regimen relieved pain better than the intramuscular regimen, which may have reflected the larger dose of papaveretum given to the intravenous group, but it was accompanied by a greater degree of respiratory depression and potentially life-threatening changes in respiratory pattern. These findings suggest that the fear which often accounts for inadequate postoperative pain relief-that larger dose of analgesics will cause respiratory complications-is well founded.     

Incorporation of intravenously administered urea-15N into sheep plasma proteins and their amide groups.

Two sheep with a low and high nitrogen intake (7.6 and 24 g N/day respectively) were given a single intravenous dose of 15N-labelled urea (15.3 mg 15N/kg b.w.) The findings were as follows. The greater part of non-retained 15N from the administered dose was excreted during the first day after the intravenous administration of 15N-urea. Daily excretion in the faeces amounted to 1.35-2.37% of the 15N in the given dose. With a low N intake, more 15N from the given dose (59.4%) was retained in the N pool than with a high N intake (50.5%). The net passage of 15N into the rumen and 15N incorporation into the amide-N of the plasma proteins was likewise greater. 15N incorporation into the amide-N of the plasma proteins rose steadily for 3 days. The porportion of amidic 15N in the plasma proteins rose steadily for 3 days. The proportion of amidic 15N in the plasma protein total 15N changed on the second and third day after administering 15N-urea from 8% to 16%, with the maximum at the beginning of the second day. The amount of 15N incorporated into the proteins in 1 litre plasma attained up to 3% of the given dose. It is concluded from the results that the synthesis of amino acids and their amide groups is both a quantitatively and a qualitatively important metabolic route for the reutilization of blood urea nitrogen for protein synthesis in ruminants.     

Enhancement of maximal thermogenesis by reducing endogenous adenosine activity in the rat

Adenosine has been shown in vitro to be a potent antilipolytic agent and an inhibitor of insulin-stimulated glucose utilization in skeletal muscle. To test whether endogenously produced adenosine (e.g., from ATP hydrolysis) shares these deleterious effects on substrate mobilization and utilization and thus limits maximum thermogenesis in vivo, adenosine deaminase (converts adenosine to inosine) was given to rats 15 min before cold exposure. Significant (P less than 0.05) increases in thermogenesis were observed under both well-fed (100 units/kg ip) and food-rationed (200 units/kg ip) states. Significant (P less than 0.05) increases in thermogenesis and cold resistance were also observed after pretreatment with selective adenosine receptor antagonists [8-cyclopentyltheophylline (1 microgram/kg ip) greater than 1,3-dipropyl-8-p-sulfophenylxanthine (1.25 mg/kg ip) greater than aminophylline (18.7 mg/kg ip)], indicating an A1-receptor-mediated effect. These results indicate that endogenously released adenosine can indeed attenuate the thermogenic capacity in severe cold and that adenosine antagonists, especially those selective for A1-receptor, are useful in improving cold resistance under varying nutritional states.     

Central adenosine receptor signaling is necessary for daily torpor in mice

When calorically restricted at cool ambient temperatures, mice conserve energy by entering torpor, during which metabolic rate (MR), body temperature (T(b)), heart rate (HR), and locomotor activity (LMA) decrease. Treatment with exogenous adenosine produces a similar hypometabolic state. In this study, we conducted a series of experiments using the nonspecific adenosine receptor antagonists aminophylline and 8-sulfophenyltheophylline (8-SPT) to test the hypothesis that adenosine signaling is necessary for torpor in fasted mice. In the first experiment, mice were subcutaneously infused with aminophylline while T(b), HR, and LMA were continuously monitored using implanted radiotelemeters. During a 23-h fast, saline-treated mice were torpid for 518 ± 43 min, whereas aminophylline-treated mice were torpid for significantly less time (54 ± 20 min). In a second experiment, aminophylline was infused subcutaneously into torpid mice to test the role of adenosine in the maintenance of torpor. Aminophylline reversed the hypometabolism, hypothermia, bradycardia, and hypoactivity of torpor, whereas saline did not. In the third and fourth experiments, the polar adenosine antagonist 8-SPT, which does not cross the blood-brain barrier, was infused either subcutaneously or intracerebroventricularly to test the hypothesis that both peripheral and central adenosine receptor signaling are necessary for the maintenance of torpor. Intracerebroventricular, but not subcutaneous, infusion of 8-SPT causes a return to euthermia. These findings support the hypothesis that adenosine is necessary for torpor in mice and further suggest that whereas peripheral adenosine signaling is not necessary for the maintenance of torpor, antagonism of central adenosine is sufficient to disrupt torpor.     

Theophylline-induced protection in myoglobinuric acute renal failure: further characterization

We have reported previously that aminophylline has an ameliorating effect on the course and severity of glycerol-induced myoglobinuric acute renal failure in rats. Since aminophylline dissociates into theophylline in biological fluids and since theophylline is an adenosine receptor antagonist, we attributed the ameliorating effects to antagonism of the hemodynamic effects of endogenous adenosine. However, theophylline blocks tubuloglomerular feedback and produces natriuresis, and either of these effects might have accounted for the beneficial effects in acute renal failure. Therefore, this study was designed to further characterize the effects of theophylline in glycerol-induced acute renal failure in rats. Aminophylline had dose-dependent beneficial effects, as judged by the peak serum creatinine during the 3 days following induction of acute renal failure, by the number of animals with peak serum creatinine greater than 1 mg/dL, and by the mortality rate. Both furosemide and theophylline block tubuloglomerular feedback and produce natriuresis, but aminophylline had protective effects, whereas furosemide actually increased mortality, compared with aminophylline, following induction of myoglobinuric acute renal failure. Therefore, aminophylline's protective effects are independent of tubuloglomerular feedback and natriuresis. These results offer further support for the hypothesis that adenosine-induced hemodynamic changes play a pathogenic role in glycerol-induced acute renal failure in rats.     

Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised,double blind,multicentre study. European Multicentre Study Group for Cabergoline in Lactation Inhibition.

OBJECTIVE--To compare the efficacy and safety of a single dose of 1 mg of cabergoline with that of bromocriptine 2.5 mg twice daily for 14 days in the inhibition of puerperal lactation. DESIGN--Prospective, randomised, double blind, parallel group, multicentre study. SETTING--University of hospital departments of obstetrics and gynaecology in different European countries. SUBJECTS--272 puerperal women not wishing to lactate (136 randomised to each drug). INTERVENTIONS--Women randomised to cabergoline received two 0.5 mg tablets of cabergoline and one placebo tablet within 27 hours after delivery and then placebo twice daily for 14 days. Those randomised to bromocriptine received 2.5 mg of bromocriptine and two placebo tablets within 27 hours and then 2.5 mg of bromocriptine twice daily for 14 days. MAIN OUTCOME MEASURES--Success of treatment (complete or partial) according to milk secretion, breast engorgement, and breast pain; rebound symptomatology; serum prolactin concentrations; and number of adverse events. RESULTS--Complete success was achieved in 106 of 136 women randomised to cabergoline and in 94 of 136 randomised to bromocriptine and partial success in 21 and 33 women respectively. Rebound breast symptomatology occurred respectively in five and 23 women with complete success up to day 15 (p less than 0.0001). Serum prolactin concentrations dropped considerably with both drugs from day 2 to day 15; a prolactin secretion rebound effect was observed in women treated with bromocriptine. cabergoline and 36 receiving bromocriptine (p = 0.054), occurring most during the first treatment day. CONCLUSION--A single 1 mg dose of cabergoline is at least as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. Because of the considerably lower rate of rebound breast activity and adverse events and the simpler administration schedule cabergoline should be the drug of choice for lactation inhibition.     

The Effect of O,O-DIMETHYL-O-(2,4,5-Trichlorophenyl) Phosphorothioate (Fe Nc H Lor Phos) On Cholinesterases in the Blue Fox (Alopex Lagopus)

Four blue fox bitches were used in the experiments. Two foxes were given fenchlorphos in the feed, one 100 mg/kg body weight and the other 200 mg/kg daily for 30 days. The maximum inhibition of plasma Cholinesterase was 65 and 69 %, respectively. The corresponding values of the erythrocyte acetylcholinesterase were 43 and 63 %. For the third bitch given 0.4 mg/kg as a single dose i.v. the effect was only measurable as a small transient decrease of the plasma Cholinesterase level. Eighty % of the plasma Cholinesterase of the fourth fox, given 500 mg/kg as a single oral dose, was inhibited on the third day. The erythrocyte acetylcholinesterase activity level only showed a slight decline. This fox vomited during feeding the day after administration. Symptoms as salivation, tremors, diarrhea, pinpoint pupils and respiratory distress were never seen in any of the foxes. It was concluded that fenchlorphos administration in the feed in doses recommended to dogs is well tolerated by healthy foxes as far as Cholinesterase inhibition is concerned.     

Ventilatory response to sustained hypoxia after pretreatment with aminophylline

During sustained hypoxia the decline in ventilation that occurs in normal adult humans may be related to central accumulation of a neurochemical with net inhibitory effect. Recent investigations have shown that the putative neurotransmitter adenosine can effect a prolonged respiratory inhibition. Therefore we evaluated the possible role of adenosine in the hypoxia ventilatory decline by employing aminophylline as an adenosine blocker. We evaluated the ventilatory response to 25 min of sustained hypoxia (80% arterial O2 saturation), in eight young adults after pretreatment with either intravenous saline or aminophylline. With a mean serum aminophylline level of 15.7 mg/l, over 25 min of sustained hypoxia, peak hypoxic ventilation decreased by only 12.8% compared with 24.8% with saline, a significant difference. However, the ventilatory decline during sustained hypoxia was not abolished by the aminophylline pretreatment. Unlike the usual tidal volume-dependent attenuation of hypoxic ventilation exhibited after saline, after aminophylline the ventilatory decline was achieved predominantly through alterations in respiratory timing. Thus aminophylline pretreatment did alleviate the hypoxic ventilatory decline, although the associated alterations in breathing pattern were uncharacteristic. We conclude that adenosine may play a contributing role in the hypoxic ventilatory decline.     

Unequal Day-Night Terbutaline I.V. Dosing in Acute Severe Asthma: Effect on Nocturnal Bronchial Patency, Heart Rate, and Arterial Pressure

Our study investigated the differential effects of continuous or unequal day-night terbutaline dosing on circadian bronchial patency, heart rate, and arterial pressure in severe acute asthma. Forty-five hospitalized asthmatic patients (19 women and 26 men, mean age 45.4 years, mean weight 63.5 kg) were included in this multicenter study. Three groups of patients (corresponding to three dosing schedules) were randomized; the three groups were comparable, since no statistically significant difference was detected in the age, weight, or peak expiratory flow values at the beginning of the study. In order to reach immediately the concentrations of terbutaline corresponding to the desired unequal day-night concentrations, a theoretical pharmacokinetic simulation was done to predict the outcome in terms of the plasma concentrations after the three dosing regimens; the results of this simulation allowed us to calculate the initial bolus dose to be given over 5 min to groups A, B, and C, i.e., 1.47, 2.94, and 4.41 Mg/kg, respectively. This bolus was given to all patients at 0700 h, the beginning of the study. The patients were randomly divided into three groups (A, B, C) receiving one of these treatments: 0.0111 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate delivered by an electrical pump and 0.0222 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (A) (one third the total daily dose during the day and the remaining two thirds at night), 0.0166 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate and 0.0166 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (B) (one half the total daily dose during the day and the remaining one half at night), or 0.0222 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate and 0.0111 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (C) (two thirds the total daily dose during the day and the remaining one third at night). Since acute severe asthma could not be treated without steroids, a 40 mg dose of SoluMedrol was injected into all patients at 0700. Peak expiratory flow rate, heart rate, systolic arterial pressure, and possible side effects were recorded at different times during the 24-h scale: 0700, 1000, 1300, 1600, 1900, 2300, 0300, and 0700 h. Our results have shown a significant therapeutic effect of terbutaline i.v. dosing in severe acute asthma whatever the unequal daynight dosing, but did not demonstrate the efficacy of one of the three dosing schedules over the others.     

Adenosine cardioprotection study in clinical setting of paroxysmal supraventricular tachycardia

PSVT attack of >20min and frequency >160 is well-recognized model of myocardial dysfunction. We measured 6-keto-PGF1alpha and TXB(2) before and after adenosine administration to assess its cardioprotective potential. A total of 64 patients were randomly assigned as having acute episode of PSVT to adenosine or verapamil group. A bolus of 6mg of adenosine up to the maximum dose of 12 or 5mg of verapamil up to the maximum dose of 10mg were given, until the sinus rhythm was restored. The levels of PGI(2), TXA(2) and TAS were measured in three different time intervals. In adenosine group all parameters were normalized after 20min of conversion to sinus rhythm. The ratio of PGI(2)/TXA(2) increased after 5min of conversion to SR (P<0.01). Also, the ratio of TXA(2)/TAS was decreased for ADO (P<0.01). This is the first study to demonstrate that adenosine exerts cardioprotective effect.     

Unequal Day-Night Terbutaline I.V. Dosing in Acute Severe Asthma: Effect on Nocturnal Bronchial Patency,Heart Rate,and Arterial Pressure

Our study investigated the differential effects of continuous or unequal day-night terbutaline dosing on circadian bronchial patency, heart rate, and arterial pressure in severe acute asthma. Forty-five hospitalized asthmatic patients (19 women and 26 men, mean age 45.4 years, mean weight 63.5 kg) were included in this multicenter study. Three groups of patients (corresponding to three dosing schedules) were randomized; the three groups were comparable, since no statistically significant difference was detected in the age, weight, or peak expiratory flow values at the beginning of the study. In order to reach immediately the concentrations of terbutaline corresponding to the desired unequal day-night concentrations, a theoretical pharmacokinetic simulation was done to predict the outcome in terms of the plasma concentrations after the three dosing regimens; the results of this simulation allowed us to calculate the initial bolus dose to be given over 5 min to groups A, B, and C, i.e., 1.47, 2.94, and 4.41 Mg/kg, respectively. This bolus was given to all patients at 0700 h, the beginning of the study. The patients were randomly divided into three groups (A, B, C) receiving one of these treatments: 0.0111 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate delivered by an electrical pump and 0.0222 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (A) (one third the total daily dose during the day and the remaining two thirds at night), 0.0166 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate and 0.0166 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (B) (one half the total daily dose during the day and the remaining one half at night), or 0.0222 mg/kg of terbutaline i.v. from 0700 to 1900 h at a constant rate and 0.0111 mg/kg of terbutaline i.v. from 1900 to 0700 h at a constant rate (C) (two thirds the total daily dose during the day and the remaining one third at night). Since acute severe asthma could not be treated without steroids, a 40 mg dose of SoluMedrol was injected into all patients at 0700. Peak expiratory flow rate, heart rate, systolic arterial pressure, and possible side effects were recorded at different times during the 24-h scale: 0700, 1000, 1300, 1600, 1900, 2300, 0300, and 0700 h. Our results have shown a significant therapeutic effect of terbutaline i.v. dosing in severe acute asthma whatever the unequal daynight dosing, but did not demonstrate the efficacy of one of the three dosing schedules over the others.     

The effects of low-dose caffeine on perceived pain during a grip to exhaustion task

This double-blind, placebo-controlled, within-subject experiment examined the effects of low-dose caffeine on pain reported during an exhaustive grip task. The grip task consisted of holding a metal block attached to standard Olympic weight plates with the arm at the side until the participants could no longer maintain their grip. Apparently healthy recreationally trained college-aged adults (men, n = 5; women, n = 5) were given either a piece of Stay Alert? gum that delivered 85% of the effective dose of 100 mg of caffeine in 5 minutes or an identical placebo gum that contained no caffeine. Subsequently, pain perception and ratings of perceived exertion were recorded during an exhaustive grip task every 15 seconds and the overall time to exhaustion. No significant difference was found in time to exhaustion between treatments. A significant main effect of treatment for reported pain (p < 0.001, Φ = 0.377) was observed. Thus, in a population of recreationally trained college-aged adults, low-dose caffeine may attenuate the individual's perception of pain during a grip to exhaustion task.     

Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.     

Effect of misoprostol, a synthetic equivalent of prostaglandin E1, on bronchodilation in bronchial spasm]

A effect of a single dose 400 micrograms misoprostol (Cytotec-Searle) on a degree of the bronchospasm relief has been investigated in 8 patients, and the results have been compared with those produced by aminophylline i.v. infusion in the rate of 500 mg/hour. Prior to and 10, 20, 30, 60, 90, 120, 150 and 180 minutes after administration of both drugs, the following parameters of pulmonary ventilation have been determined: VC, VC%, FEV1, FEV1%, MVV, and MEFR. The results have shown that misoprostol given in a single oral dose of 400 micrograms to patients with bronchospasm has the bronchodilating activity which is statistically significant. However, this activity is rather weak and significantly lower than that of intravenous aminophylline infusion.