[ effect of aminophylline on hemodynamic parameters and recovery time after propofol infusion]

This study is aimed to assess the effect of aminophylline [1mg/kg] on reversal of the sedative effects of propofol and the recovery time in patients under propofol anesthesia. Due to the known effects of aminophylline on myocardial contractility and the increase in cardiac output, its effects on hemodynamic changes of propofol are also assessed. In a double blinded randomized clinical trial on 154 patients, intubation was done after induction of anesthesia with sufentanil [0.2 mcg/kg], propofol [2.5 mg/kg] and atracurium [0.5 mg/kg]. Anesthesia was maintained with 200 mcg/kg/min of propofol infusion. After discontinuing propofol at the end of the surgery patients were randomly allocated to receive either aminophylline 1 mg/kg or normal. Heart rate, blood pressure and oxygen saturation were recorded before and after injection, and every 2 minutes until extubation was performed, and thereafter every 5 minutes till the patients' discharge from recovery. The time interval between injection and extubation plus the duration of recovery stay were also recorded. The mean arterial pressure 2,6, and 8 minutes post-extubation ; the heart rate 2,4,6, and 8 minutes just after extubation; and oxygen saturation 2,4,5, and 10 minutes post-extubation; were higher in the aminophylline group. The discharge time was on the contrary, shorter in this group. Aminophylline [1mg/kg] will result in a shorter recovery time following propofol anesthesia and can control propofol-induced blood pressure decrease and bradycardia

Effects of hydrocortisone and aminophylline on the aggregation of equine platelets in vitro

The purpose of this study was to evaluate in vitro the effects of hydrocortisone and aminophylline on adenosine diphosphate (ADP)-induced platelet aggregation in horses. Blood samples from 30 healthy Thoroughbred horses were collected by via jugular venipuncture to assess platelet aggregation. Platelet-rich and platelet-poor plasma were prepared from all samples by centrifugation and divided into three different aliquots. In the first aliquot, platelet aggregation was measured after platelet activation with 1 microM and 0.5 microM ADP (Group A). In the other two aliquots, the effect of a 10 min preincubation with hydrocortisone (Group B) or aminophylline (Group C) on ADP-induced aggregation at final ADP concentrations of 1 microM and 0.5 microM was observed. Platelet aggregation, recorded by an aggregometer, was evaluated by measuring the maximum degree of platelet aggregation and the initial velocities of platelet aggregation were obtained. Our results demonstrated the inhibitory effect of hydrocortisone and the induction effect of aminophylline on equine platelet responses in vitro.

Estabilidade dos fármacos ceftazidima e aminofilina em soluções parenterais de grande volume (SPGV) carreados pelo copolímero Pluronic® F68. Emprego da proteína verde fluorescente (GFP) como biossensor da estabilidade de fármacos em SPGV / Stability of ceftazidime and aminophyline carried by Pluronic®F68 in parenteral solutions. Green Fluorescent Protein (GFP) as a biossensor for drug stability in parenteral solutions

Diante da extensa utilização de fármacos associados às soluções parenterais de grande volume (SPGV) e muitas vezes da impossibilidade da administração dos mesmos em diferentes veículos de infusão, sejam pela perda da estabilidade ou por insolubilidade destes, a utilização de copolímeros como carreadores de fármacos vêm a favorecer a associação destes às SPGV. Este trabalho visa avaliar a estabilidade dos fármacos ceftazidima e aminofilina nas SPGV carreados pelo copolímero Pluronic® F68 e o estudo da GFP como potencial biossensor da estabilidade de fármacos nas SPGV. A estabilidade dos fármacos ceftazidima (320ug/mL) e aminofilina (160ug/mL) em SPGV foi avaliada, na presença e na ausência de Pluronic® F68, através da utilização de HPLC logo após preparo e após período de 24hs, usando sistema Schimadzu LC10, LC-solution software, Schimadzu C18, fluxo 0,5mL/min, detecção em λ=255nm (ceftazidima) e λ=275nm (aminofilina), volume de injeção 20uL, 25ºC. A determinação da concentração mínima inibitória (CMI) foi realizada em amostras de ceftazidima (240ug/mL) na presença e na ausência de Pluronic® em SPGV de 5% glicose usando E. coli ATCC 25922 e P.eruginosa ATCC 9721 na concentração de 106UFC/mL . Pluronic® F68 foi utilizado nas amostras para avaliação da estabilidade dos fármacos ceftazidima e aminofilina na concentração 10% m/m. Resultados mostraram uma incompatibilidade entre a associação dos fármacos em SPGV de 5% glicose, com perda de concentração de 25% do fármaco ceftazidima na ausência de Pluronic®. Nos ensaios de CMI realizados com fármaco ceftazidima em SPGV de 5% glicose observou-se uma melhora dos valores de CMI quando o fármaco foi associado ao copolímero Pluronic® para ambos os microrganismos estudados. O estudo da GFP mostrou que fatores como (i) as propriedades físico-químicas dos fármacos, (ii) valores de pH das soluções e (iii) interações entre a proteína e as SPGV, podem favorecer mudanças de intensidade de fluorescência da GFP...

Drug association administered through parenteral solutions is a common hospital practice. Copolymers as carriers in parenteral solutions may allow originally unstable or insoluble drug combinations, or even improve their action. The aim of this work was to evaluate the stability of ceftazidime and aminophylline in parenteral solutions carried by Pluronic® F68, besides the application of the green fluorescent protein as a biossensor of drug stability. To evaluate the stability of ceftazidime (320 µg/mL) and aminophylline (160 µg/mL) carried by Pluronic® F68 (10%) in parenteral solutions, HPLC measurements were made immediately after the drug mixture preparation and after 24 hours, detected at λ=255nm (ceftazidime) and λ=275nm (aminophylline). In addition, minimal inhibitory concentration test (MIC) was used to determine the biological activity of ceftazidime (240 µg/mL) in 5% glucose parenteral solution, with or without Pluronic® F68 (10%). The strains tested by MIC were E. coli ATCC 25922 and P.aeruginosa ATCC 9721 (106UFC/mL). The HPLC experiments showed incompatibility of ceftazidime and aminophylline associated in 5% glucose parenteral solution, with 25% loss for ceftazidime without Pluronic® F68. MIC analysis for ceftazidime, with or without aminophylline, showed that lower antibiotic concentration values were required to inhibit E. coli and P.aeruginosa growth, when the copolymer Pluronic® F68 was present in the samples. It was also showed that physical chemical drugs alterations, pH values and protein-parenteral solution interactions can change GFP fluorescence intensity (detected by espectrofluorimeter λex=394nm, λem=509nm). These data endorse the potential of this protein as a biosensor of drug stability in parenteral solutions.

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.

Influence of adenosine, dipyridamole, adenosine antagonists and antiepileptic drugs on EEG after discharge following cortical stimulation.

The effects of adenosine (100 nM, icv), dipyridamole (DPM, 5 mg/kg, i.p.), adenosine A1 receptor antagonist 8-cyclopentyl-theophylline (8-CPT, 10 mg/kg, i.p.), and aminophylline (AMP) and caffeine (CAF) (at equivalent doses of 35 mg/kg, i.p.), were examined in rats. Anti-epileptic drugs (AEDs) were also administered i.p., viz, carbamazepine (CBZ, 10 mg/kg); phenobarbitone (PB, 10 mg/kg); phenytoin (PHT, 20 mg/kg); valproic acid (VPA, 300 mg/kg); and diazepam (DZP, 10 mg/kg), to study their effects on EEG after discharge (AD) and postictal depression (PID) induced by cortical stimulation. The AD parameters: (1) duration of EEG-AD (sec) and (2) number of spikes was noted both during pre and post drug treatment sessions. Adenosine and DPM had no special effects on AD parameters but showed significant prolongation of PID. All the adenosine antagonists, 8-CPT, AMP and CAF produced significant prolongation of AD duration, increase in number of spikes and reduced the duration of PID to a significant extent. Interestingly, some of the AEDs, viz. CBZ, VPA and DZP showed abolition of all the EEG-AD parameters whereas PB and PHT failed to show any significant effect. The results confirm previous findings on involvement of adenosine in postictal events.

Effect of aminophylline on muscle fatigue.

The effects of two different concentrations of aminophylline, 50 microM/L and 500 microM/L on muscle fatiguability were tested using frog gastrocnemius-sciatic preparations. Two stimulation protocols, one high energy demand, and the other low energy demand were used to induce muscle fatigue. The indices of fatigue employed were (a) the decrease in peak tetanic contraction, (b) the increase in half-contraction time and (c) the increase in the contraction period in response to a high-energy-demand stimulation protocol of fatigue-induction. At the same time, it prolongs the increase in relaxation50-80 time in response to the same protocol.

Acute hemodynamic response to vasodilators in primary pulmonary hypertension.

Acute hemodynamic effects of high flow oxygen (O2) inhalation, sublingual isosorbide dinitrate (ISDN), intravenous aminophylline (AMN) and sublingual nifedipine (NIF) were studied in 32 patients with primary pulmonary hypertension (PPH). In 30 out of 32 patients the basal ratio of pulmonary to systemic vascular resistance (Rp/Rs) was > 0.5 (mean = 0.77 +/- 0.20). Oxygen caused significant decrease in the mean resistance ratio to 0.68 +/- 0.20 (p = 0.005). ISDN, AMN and NIF caused increase in the resistance ratio to 0.79 +/- 0.26; 0.78 +/- 0.26; and 0.80 +/- 0.23 respectively. O2, ISDN, AMN and NIF caused a fall of Rp/Rs in 21 (65.6%), 10 (31.2%), 10(31.2%) and 9(28.1%) patients respectively. Thus, of the four drugs tested high flow O2 inhalation resulted in fall of Rp/Rs in two thirds of patients whereas ISDN, AMN and NIF caused a mean rise in Rp/Rs. One third of patients did respond acutely to the latter three drugs. Acute hemodynamic studies are useful before prescribing vasodilators in patients with PPH since more of the commonly used drugs like ISDN, AMN, NIF could have detrimental hemodynamic responses in some patients. However, great caution should be exercised before performing hemodynamic study as the procedure has definite mortality and morbidity.

Lo antiguo de la aminofilina y lo actual de la teofílina / The antique of aminophylline and the current of teophylline

La aminofilina fue descubierta en forma independiente por David I. Macht en 1921 y por Samson Hircht en 1922. Los primeros en usarla para el tratamiento del asma bronquial fueron Herman y Greene en los Estados Unidos. En México, Salazar mallén fue el primero en emplearla (1938). Los primeros en cuantificar la dosificación de este medicamento en la sangre fueron Wasler y Sack. El empleo de la teofilina de acción prolongada, así como su dosificación en la sangre de los pacientes, fueron establecidos en México por Montes y Amezcua. actualmente hay beta-2-agonistas de acción prolongada que posibilitan el control asmático día y noche. La teofilina también tiene esta acción. Su farmacológia consiste en la inhibición de la enzima fosfodiesterasa y en el bloqueo de los receptores A1; también potencia la contracción del músculo diafragmático y aumenta el flujo de sangre a los músculos intercostales; disminuye además la formación de los leucotrienos B4 y C4 y tiene efecto antiinflamatorio por aumento del cAMP intracelular. Las dosis mayores aumentan su toxicidad; cuando las concentraciones sanguíneas son mayores a 20 µg/mL, el paciente puede presentar convulsiones letales. La teofilina se puede usar con otros broncodilatadores y corticosteroides. Su dosis se ha ajustado a la baja con el fin de tener un efecto terapéutico sin toxicidad (5-7 mg/kg en 24 horas). Se recomienda que sus concentraciones en el suero sean de 5-10 µg/mL para conseguir tambíen el efecto antiinflamatorio. En el Servicio de Alergia e Inmunología Clínica del Hospital General de México se continúa usando como medicamento de primera elección para romper el broncoespasmo de los pacientes asmáticos

Aminofilina y fenoterol en niños con crisis asmática / Aminophylin and fenoterol in children with asthmatic crisis

El presente estudio compara los efectos clínicos y colaterales de dos esquemas de medicación, fenoterol en MDI (micro dosificador inhalatorio) de 100 urg versus fenoterol en MDI de 100 ugr más aminofilina endovenosa, para el tratamiento de crisis de asma leve-moderadas en población pediátrica. Los parámetros evaluados fueron: puntuación de crisis de asma de Bierman-Pierson, frecuencia cardíaca, presencia de tremor, pico espiratorio forzado (PEF). Además se consignó la aparición de otros efectos colaterales, durante un período de 2 horas. Fueron incluídos cincuenta pacientes: veinticinco para cada esquema en forma randomizada. Se encontró que no hubo diferencia significativa entre los grupos de pacientes en cuanto a sus características al ingreso y el efecto clínico del tratamiento, siendo la mejoría en ambos casos similar. Por otro lado el esquema de fenoterol en MDI más aminofilina endovenosa se asoció a un número mayor de efectos adversos, principalmente gastrointestinales. Se observó además que los puntajes clínicos al ingreso constituyen un factor pronóstico para ambos esquemas

Influence of cyclic AMP on the biosynthesis of phosphatidylcholine in Microsporum gypseum.

The influence of intracellular cAMP on phosphatidylcholine biosynthesis in Microsporum gypseum has been examined using radiolabelled precursors. The incorporation of labelled choline, methionine and ethanolamine into total lipids, phospholipids and choline containing phospholipids increased in aminophylline and decreased in atropine grown cells as a result of rise and fall in cAMP levels in these cells. The enhanced uptake of labelled methionine and ethanolamine in comparison to labelled choline in choline containing phospholipids in aminophylline grown cells suggests that methylation pathway is more influenced by cAMP than CDP-choline pathway.

Infraadditive diuretic efficacy of concurrent aminophylline and frusemide.

Male albino rats weighing between 150-225 gm fasted over night but freed having water ad libitum were used to assess the diuretic efficacy of intramuscular aminophylline and frusemide separately and concurrently after intraperitoneal 10 ml of distilled water loading. The normal rate of diuretic weight loss was less augmented by aminophylline and more augmented by frusemide. The diuretic response was more by the concurrent intramuscular administration of aminophylline and frusemide in comparison with that due to either drug alone. However, the observed diuretic response of the two drugs administered concurrently was lesser (infraadditive) than the sum of the individual diuretic response (additive).

Further studies on the influence of aminophylline on lipids of Microsporum gypseum.

Aminophylline added to the growth medium of Microsporum gypseum for varying periods exhibited varied effects on lipid synthesis. A decreased incorporation of [14C]acetate into both lipids and phospholipids was initially observed which showed increase after 24 hr of incubation. Short-time exposure of aminophylline also resulted in decreased activity of glycerol-3-phosphate acyltransferase, the key enzyme of lipid synthesis, which, however, got stimulated on longer incubation, supporting the decreased/increased synthesis of lipids during short/long time exposure. Changes in the intracellular levels of cAMP at different time points account for the induced alterations in lipid synthesis, possibly due to formation of metabolites of aminophylline during growth of the organism.

Effect of aminophylline preperfusion on digoxin-induced cardiac arrest in isolated frog heart.

Digoxin (DGN) and aminophylline (theophylline ethylenediamine, APH) being frequently prescribed cardioactive drugs, the present study investigated the effect of APH (10(-4) M) preperfusion on DGN-cardiotoxicity employing the isolated frog heart preparation. The mean DGN perfusion time (sec) and mean DGN exposure (microgram/10 mg heart wt.) for cardiac arrest were the parameters studied. APH preperfusion caused a significant elevation in both the parameters, signifying that it afforded protection against DGN-cardiotoxicity. This protective effect was not observed with the preperfusion of ethylenediamine (EDA) instead of APH, which led to the inference that the protective effect of APH was solely due to its theophylline component. The present finding that APH-pretreatment might modulate DGN-cardiotoxicity, of considerable pharmaco-toxicological interest.

Influence of adenosine receptor antagonists, aminophylline and caffeine, on seizure protective ability of antiepileptic drugs in rats.

Interaction of methylxanthines, aminophylline (AMP) and caffeine (CAF) on seizure protective ability of various antiepileptic drugs (AEDs), diphenylhydantoin (DPH), phenobarbitone (PB), diazepam (DZP), sodium valproate (SV) and ethosuximide (ESM) was investigated in rats. In the maximal electroshock seizure (MES) test, ED100 doses (mg/kg, ip), against hind limb tonic extension (HLTE) were DPH, 20; PB, 10; DZP, 10 and SV, 300. The interaction of AEDs with AMP (100 mg/kg, ip) reduced the seizure protection afforded by DPH, PB and DZP to 20%, while the efficacy of SV remained unimpaired. Interaction with CAF (200 mg/kg, ip) abolished the seizure protection by DPH and DZP, reduced that by PB to 20%, while the protective effect of SV was unchanged. In pentylenetetrazole (PTZ, 70 mg/kg, sc) induced seizure test, ED100 doses (mg/kg, ip) against clonic convulsions were PB, 10; DZP, 1; SV, 300 and ESM, 200. Complete seizure protection against clonic convulsions following SV or ESM was not significantly influenced by either AMP or CAF, whereas the protective effect of PB and DZP was reversed. SV and ESM showed a qualitative departure in their anti-seizure activity profiles following interaction with either AMP or CAF when compared with the other AEDs.

Inhibition of anticonvulsant action of carbamazepine by aminophylline and caffeine in rats.

Interaction of two well known methyl xanthines, aminophylline--an antiasthmatic agent--and caffeine--commonly present in beverages, on the seizure protective ability of carbamazepine (CBZ) against electrically and chemically induced seizures in rats was investigated. Aminophylline (75 mg/kg, ip) did not alter the activity of CBZ (10 mg/kg, ip; ED100) on maximal electroshock seizures while dose dependent antagonism of CBZ efficacy was seen at 100 and 150 mg/kg, ip. Similar effects were observed with caffeine (200 and 250 mg/kg, ip). At the highest tolerated doses, aminophylline (150 mg/kg, ip) and caffeine (250 mg/kg, ip) produced antagonism of CBZ protection against pentylenetetrazole seizures. These observations support the possibility that the antagonism due to the interaction of these drugs could be related to their action at adenosine receptor sites in the brain.

Effect of bronchodilators on surfactant system of lung.

Pulmonary surfactant activity of healthy male albino rats was estimated in terms of the maximum and minimum surface tension values of alveolar washings and the phospholipid content of the extract. The results obtained in these (control) animals were compared with those in three groups of animals treated with therapeutic doses of terbutaline, adrenaline and aminophylline. A significant decrease in the surface tension values without a significant increase in the phospholipid content was observed with aminophylline, whereas a significant increase in phospholipid concentration without a significant decrease in surface tension values was observed in case of terbutaline and adrenaline. These findings suggest that aminophylline, in addition to a bronchodilator action, lowers the elastic resistance of lung. The study also indicates caution in interpreting phospholipid concentration as surfactant activity.

Aminofilina en perfusión intravenosa a 0,5 mg/kg/hora en niños asmáticos: farmacocinética y evolución clínica / Aminophylline in intravenous perfusion at 0,5 mg/kg/hour in asthmatic children: pharmacokinetics and clinical evolution

La aminofilina (principio activo: teofilina) es un medicamento de primera línea en el tratamiento de ataques agudos de asma bronquial en niños y adultos. Su uso con eficacia y seguridad para el paciente precisa que se alcancen niveles terapéuticos en la sangre y evita niveles que desencadenan toxicidad, lo cual requiere adecuada dosificación, control y observación de la evoluición del enfermo. Se realiza un estudio farmacocinético y de evolución clínica de 20 niños con ataque agudo de asma tratados con perfusión continua de aminofilina a 0,5 mg/kg/hora y otros medicamentos de apoyo. Se concluye que en la muestra estudiada no se alcanzaron niveles terapéuticos óptimos de concentración sérica de teofilina aún al cabo de 24 horas de tratamiento. Se recomienda optimizar los esquemas de dosificación y trabajar en la introducción de métodos rápidos y confiables de análisis de teofilina sérica con vistas a mejorar e individualizar la terapéutica para evitar efectos tóxicos