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PubMed1998

Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients.

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Adult↗
PubMed1997

Combined effects of caffeine and nicotine on cardiovascular hemodynamics in canine model.

The independent effects of caffeine and nicotine on cardiodynamics are well documented, but combined effects of both are not reported. Initially, in phase I, 18 experiments were performed to study the dose-response curve of both the drugs. In phases II and III, 13 mongrel dogs were subjected to 30 experiments. In phase II, caffeine, 5 mg/kg, was given i.v. followed by nicotine, 50 micrograms/kg, and in phase III, the sequence of drug administration was reversed to study the effects on hemodynamics. In phase II, caffeine did not show significant changes in all the cardiovascular parameters, but nicotine administration after caffeine produced marked significant synergistic excitatory effects: the rate of increase of the first derivative of left ventricular pressure (dP/dt) increased from 1,101 +/- 111 to 3,194 +/- 872 (p < 0.003). In phase III, nicotine significantly increased heart rate, mean arterial pressures; left ventricular end-diastolic pressure (LVEDP); and pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Nicotine increased dP/dt (964 +/- 182 to 1,639 +/- 60 mm Hg/s; p < 0.004). The excitatory effects of nicotine were attenuated by administration of caffeine (dP/dt, 918 +/- 140 reduced to 715 +/- 144 mm Hg/s; p < 0.04). Caffeine and nicotine, alone, caused nonsignificant and significant increases in hemodynamics, respectively. In combination, caffeine + nicotine administration produced significant synergistic excitatory effects in dogs. On the other hand, the nicotine + caffeine combination caused attenuation by caffeine of the excitatory effects produced by nicotine.

Animals↗
PubMed2000

Enhancement of 2000-m rowing performance after caffeine ingestion.

PURPOSE: To investigate the effect of caffeine ingestion on short-term endurance performance in competitive rowers. METHODS: In this randomized double-blind crossover study, eight competitive oarsmen (peak oxygen uptake [VO2peak] 4.7+/-0.4 L x min(-1), mean +/- SD) performed three familiarization trials of a 2000-m rowing test on an air-braked ergometer, followed by three experimental trials at 3- to 7-d intervals, each 1 h after ingesting caffeine (6 or 9 mg x kg(-1) body mass) or placebo. Trials were preceded by a standardized warm-up (6 min at 225+/-39 W; 75+/-7.7% VO2peak). RESULTS: Urinary caffeine concentration was similar before ingestion (approximately 1 mg x L(-1)) but rose to 6.2+/-3.6 and 14.5+/-7.0 mg x L(-1) for the low and high caffeine doses, respectively. Plasma free fatty acid concentration before exercise was higher after caffeine ingestion (0.29+/-0.17 and 0.39+/-0.20 mM for 6 and 9 mg x kg(-1), respectively) than after placebo (0.13+/-0.05 mM). Respiratory exchange ratio during the warm-up was also substantially lower with caffeine (0.94+/-0.09 and 0.93+/-0.06 for the low and high dose) than with placebo (0.98+/-0.12). Subjects could not distinguish between treatments before or after the exercise test. Both doses of caffeine had a similar ergogenic effect relative to placebo: performance time decreased by a mean of 1.2% (95% likely range 0.4-1.9%); the corresponding increase in mean power was 2.7% (0.4-5.0%). Performance time showed some evidence of individual differences in the effect of caffeine (SD 0.9%; 95% likely range 1.5 to -0.9%). CONCLUSIONS: Ingestion of 6 or 9 mg x kg(-1) of caffeine produces a worthwhile enhancement of short-term endurance performance in a controlled laboratory setting.

Caffeine↗
PubMed2002

Caffeine is ergogenic after supplementation of oral creatine monohydrate.

PURPOSE: The purpose of this investigation was to assess the acute effects of caffeine ingestion on short-term, high-intensity exercise (ST) after a period of oral creatine supplementation and caffeine abstinence. METHODS: Fourteen trained male subjects performed treadmill running to volitional exhaustion (T(lim)) at an exercise intensity equivalent to 125% VO(2max). Three trials were performed, one before 6 d of creatine loading (0.3 g x kg x d(-1) baseline), and two further trials after the loading period. One hour before the postloading trials, caffeine (5 mg x kg(-1)) or placebo was orally ingested in a cross-over, double-blind fashion. Four measurements of rating of perceived exertion were taken, one every 30 s, during the first 120 s of the exercise. Blood samples were assayed for lactate, glucose, potassium, and catecholamines, immediately before and after exercise. RESULTS: Body mass increased (P < 0.05) over the creatine supplementation period, and this increase was maintained for both caffeine and placebo trials. There was no increase in the maximal accumulated oxygen deficit between trials; however, total VO(2) was significantly increased in the caffeine trial in comparison with the placebo trial (13.35 +/- 3.89 L vs 11.67 +/- 3.61 L). In addition, caffeine T(lim) (222.1 +/- 48.9 s) was significantly greater (P < 0.05) than both baseline (200.8 +/- 33.4 s) and placebo (198.3 +/- 45.4 s) T(lim). RPE was also lower at 90 s in the caffeine treatment (13.8 +/- 1.8 RPE points) in comparison with baseline (14.6 +/- 1.9 RPE points). CONCLUSION: As indicated by a greater T(lim), acute caffeine ingestion was found to be ergogenic after 6-d of creatine supplementation and caffeine abstinence.

Adult↗
PubMedDate not supplied

Persistent cardiovascular effects with repeated caffeine administration.

Although habitual caffeine users ingest the drug repeatedly throughout each day, the persistence of caffeine's known cardiovascular effects with such repeated use has not been investigated. Blood pressure and heart rate were measured under resting conditions in 10 healthy, male coffee or tea drinkers for 2 hours following a pretreatment dose of caffeine (125 mg) on two separate days after overnight abstinence. Either a second caffeine dose or placebo was administered and measurements continued for 1.5 hours. Compared to placebo, the second dose of caffeine produced significant increases in heart rate and diastolic and mean arterial, but not systolic, blood pressures. The results suggest that the cardiovascular effects of caffeine may persist throughout the day with repeated administration of moderate amounts of caffeine. Habitual caffeine use does not necessarily lead to complete tolerance, which suggests that caffeine's cardiovascular effects could contribute to an increased risk of cardiovascular disease.

Adult↗
PubMed1995

Interaction between two probes used for phenotyping cytochromes P4501A2 (caffeine) and P4502E1 (chlorzoxazone) in humans.

The first steps in the metabolism of caffeine and chlorzoxazone are primarily catalysed by CYP1A2 and CYP2E1, respectively. Accordingly, these compounds have been developed as metabolic probes for non-invasive phenotyping of these two P450s. Their specificities, however, have been shown to overlap. In this study, 140 mg of caffeine and 500 mg of chlorzoxazone were administered alone or together in 16 healthy subjects under standardized conditions. The metabolites of these two probes were measured in the blood and also in the urine for caffeine. CYP1A2 activity was determined either by the paraxanthine/caffeine ratio in the blood or by the usual caffeine metabolic ratio in the urine. The CYP2E1 activity was determined by the 6-OH-chlorzoxazone/chlorzoxazone ratio in blood. CYP1A2 activities measured in blood and urine were highly significantly correlated. CYP2E1 activity was not modified when chlorzoxazone was given together with caffeine. In contrast, an inhibition of CYP1A2 by chlorzoxazone was demonstrated by a 16% decrease in the caffeine metabolic ratio in urine when both caffeine and chlorzoxazone were given together. Under the same conditions, the paraxanthine/caffeine ratio in plasma also decreased by about 20%. These results were confirmed in vitro by the incubation of 1 mM caffeine with human hepatic liver microsomes in the presence of 0.4 mM chlorzoxazone. The overall metabolism of caffeine decreased by 38% compared to controls incubated without chlorzoxazone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.

Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethylation and phenacetin 0-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/caffeine ratio, and several metabolite ratios from spot urine sampled 6 h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r= 0.584-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazine-N-acetylation in vitro. In contrast to CYP1A2 parameters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.

Aged↗
PubMed2002

The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the progressive enlargement of cysts derived from tubules. Tubule cell proliferation and chloride-dependent fluid accumulation, mechanisms underlying cyst expansion, are accelerated by adenosine 3':5'-cyclic monophosphate (cAMP). This study examined the extent to which caffeine may stimulate the production of cAMP by cyst epithelial cells, thereby adversely increasing proliferation and fluid secretion. Mural epithelial cells from ADPKD cysts and normal human kidney cortex cells (HKC) were cultured, and cAMP levels were determined in response to caffeine and receptor-mediated agonists linked to adenylyl cyclase. Caffeine, a methylxanthine, slightly increased basal levels of cAMP, as did other nonselective phosphodiesterase (PDE) inhibitors, 1-methyl-3- isobutyl xanthine and theophylline and rolipram, a specific PDE IV inhibitor. More importantly, clinically relevant concentrations of caffeine (10 to 50 micro M) potentiated the effects of desmopressin (DDAVP), prostaglandin E(2) (PGE(2)), and isoproterenol to increase cAMP levels in both ADPKD and HKC cells. By contrast, at concentrations that augmented the DDAVP response, caffeine attenuated cAMP accumulation by adenosine, implicating an action apart from the inhibition of PDE. Caffeine enhanced the effect of DDAVP to stimulate transepithelial short-circuit current of polarized ADPKD monolayers, reflecting an increase in chloride secretion. Caffeine potentiated the effect of DDAVP and PGE(2) to increase the levels of phosphorylated extracellular signal-regulated kinase (P-ERK). By contrast, P-ERK levels in HKC cells were not raised by increased intracellular concentrations of cAMP. It is concluded that PDE inhibition by caffeine increases the accumulation of cAMP, and through this mechanism activates the ERK pathway to cellular proliferation and increases transepithelial fluid secretion in ADPKD cystic epithelium. Caffeine is, therefore, a risk factor for the promotion of cyst enlargement in patients with ADPKD.

Caffeine↗
PubMedDate not supplied

Caffeine affects cardiovascular and neuroendocrine activation at work and home.

OBJECTIVE: This study investigated the effects of moderate doses of caffeine on ambulatory blood pressure and heart rate, urinary excretion of epinephrine, norepinephrine, and cortisol, and subjective measures of stress during normal activities at work and at home in the evening. METHODS: Healthy, nonsmoking, habitual coffee drinkers (N = 47) participated in 3 days of ambulatory study. After a day of ad lib caffeine consumption, caffeine (500 mg) and placebo were administered double-blind in counter-balanced order on separate workdays. Ambulatory blood pressure and heart rate were monitored from the start of the workday until bedtime. Urinary excretion of catecholamines and cortisol was assessed during the workday and evening. RESULTS: Caffeine administration significantly raised average ambulatory blood pressure during the workday and evening by 4/3 mm Hg and reduced average heart rate by 2 bpm. Caffeine also increased by 32% the levels of free epinephrine excreted during the workday and the evening. In addition, caffeine amplified the increases in blood pressure and heart rate associated with higher levels of self-reported stress during the activities of the day. Effects were undiminished through the evening until bedtime. CONCLUSIONS: Caffeine has significant hemodynamic and humoral effects in habitual coffee drinkers that persist for many hours during the activities of everyday life. Furthermore, caffeine may exaggerate sympathetic adrenal-medullary responses to the stressful events of normal daily life. Repeated daily blood pressure elevations and increases in stress reactivity caused by caffeine consumption could contribute to an increased risk of coronary heart disease in the adult population.

Adult↗
PubMed1985

Caffeine disposition in obesity.

Caffeine pharmacokinetics were studied in 16 obese (mean +/- s.e. mean body weight; 110 +/- 8 kg; % ideal body weight (IBW); 186 +/- 14%) and 23 normal body weight (64 +/- 3 kg; 103 +/- 3% IBW) subjects. Eight obese and four control subjects were cigarette smokers. After abstaining from caffeine for 48 h and an overnight fast, each subject ingested 162 mg caffeine orally. Concentrations of caffeine were measured in plasma samples obtained during the 24 h following the dose and pharmacokinetic variables were determined. The apparent volume of distribution was increased markedly in obese subjects (69.9 +/- 5.9 vs 43.6 +/- 2.8 l; P less than 0.001) in the absence of any change in oral clearance (135 +/- 14-obese vs 112 +/- 12 ml/min; NS), resulting in a trend toward increased elimination half-life (7.05 +/- 1.08-obese vs 5.40 +/- 0.40 h; NS). Apparent volume of distribution correlated well with percent IBW (r = 0.65; P less than 0.001). Caffeine clearance, suggested as a measure of in vivo cytochrome P-448 activity in humans, was not altered in obesity. In contrast, the extent of caffeine distribution increased in direct relation to body weight. If caffeine is used therapeutically, the loading dose should be calculated as a function of total body weight. Since clearance of caffeine is not related to body weight, these data indicate that a chronic dosing regimen to maintain a given plasma caffeine concentration should not be altered due to obesity.

Adult↗
PubMed2006

Metabolic effects of caffeine ingestion and physical work in 75-year old citizens. A randomized, double-blind, placebo-controlled, cross-over study.

OBJECTIVE: Whereas caffeine has been demonstrated to impact substantially on the metabolic response to exercise in healthy young subjects, this issue remains to be addressed in healthy elderly subjects. DESIGN AND PATIENTS: The metabolic response to caffeine ingestion (6 mg/kg) and exercise in healthy elderly citizens at 70 years was examined in a randomized, double-blind, placebo-controlled, cross-over study. We included 30 subjects attending for driver license renewal at their general practitioner. Participants abstained from caffeinated drinks and food for 48 h and were randomized to receive placebo-caffeine or caffeine-placebo with 1 week between sessions. MEASUREMENTS: A cycling endurance test at 65% of the expected maximal heart rate was performed 1 h after intervention. Blood samples were taken before intervention, before cycling, after 5 min of cycling, and at exhaustion. Analysis was by intention-to-treat and P < 0.05 was regarded as significant. RESULTS: Caffeine significantly increased the concentration of plasma epinephrine (by 42%, 39%, and 49%), serum-free fatty acids (by 53%, 44%, and 50%), and plasma lactate (by 46%, 36%, and 48%), and insulin resistance (homeostasis model assessment-IR) (by 21%, 26%, and 23%) during rest, after 5 min of cycling, and at exhaustion. At exhaustion, the concentration plasma norepinephrine was elevated by 29%. A decrease was seen with caffeine treatment in blood potassium after 5 min of cycling and at exhaustion (by 3% and 2%, respectively). CONCLUSIONS: Caffeine treatment increased epinephrine, fatty acids, lactate and norepinephrine at different times during test session and led to insulin-resistance. Hence, caffeine ingestion elicits a similar metabolic response in elderly participants at 70 years old to that seen in younger subjects.

Administration, Oral↗
PubMed1975

Caffeine- and kallikrein-induced stimulation of human sperm motility: a comparative study.

Stimulation of human sperm motility by caffeine and kallikrein was compared in the same semen material. Caffeine, a cyclic nucleotide phosphodiesterase inhibitor, induced an immediate stimulation of sperm motility the intensity being relatively constant during the first two hours of incubation. Kallikrein, a kinin-releasing proteinase, induced a similar enhancement of total sperm motility, but showed a delayed type of reaction with maximum stimulation at 2 hours of incubation. In contrast to the effect of caffeine lasting some hours, enhancement of sperm motility induced by kallikrein was observed 24 hours. Simultaneous addition of serum (kininogen source) and kallikrein to semen samples led to a sitmulation of total sperm motility with higher mean values than those obtained by caffeine of kallikrein alone. However, the ratio of spermatozoa with very good forward progression was highest during caffeine stimulation. Simultaneous addition of caffeine and kallikrein led to a further improvement of sperm motility which was significantly above that produced by caffeine or kallikrein alone. This observation and the finding of a different response of the spermatozoa of two ejaculates towards caffeine of kallikrein indicate that caffeine (cyclic AMP) interferes quite differently in comparison to kallikrein (kinins) in stimulating sperm motility.

Caffeine↗
PubMed2005

The appetite-suppressant effect of nicotine is enhanced by caffeine.

AIM: To test whether the anorectic effect of nicotine may be amplified by caffeine. METHODS: Chewing gums with nicotine and caffeine were administered to 12 healthy young men of normal weight. Different combinations of 0, 1 or 2 mg of nicotine and 0, 50 or 100 mg of caffeine were applied during a 2-h period in a randomized, double blind, cross over design. Appetite sensations were measured using visual analogue scales. RESULTS: Hunger and prospective food consumption were negatively associated with the increasing doses of nicotine, whereas satiety and fullness were positively associated with the increasing doses of nicotine (p < 0.05). Caffeine appeared to amplify the effects of nicotine on hunger and fullness as a caffeine x nicotine x time interaction was observed in these scores (p < 0.05). The 2-mg dose of nicotine in combination with the 100-mg dose of caffeine caused nausea in four of the non-smokers. However, the effects of nicotine and the caffeine x nicotine x time interaction persisted after the exclusion of these subjects. CONCLUSION: Caffeine added to nicotine chewing gum appears to amplify its attenuating effects on appetite and the combinations of 1-mg of nicotine with caffeine seem to be well tolerated.

Adolescent↗
PubMed1994

An endothelium-dependent contraction in canine mesenteric artery caused by caffeine.

1. We examined whether or not caffeine caused an endothelium-dependent contraction (EDC) in canine mesenteric artery and whether the endothelium-dependent contracting factors (EDCF) were arachidonic acid metabolites. 2. Caffeine (1, 3 and 10 mM) caused a transient contraction in endothelium-intact arterial strips. Removal of the endothelium significantly attenuated the caffeine (1 and 3 mM)-induced contraction. 3. Caffeine (1 mM)-induced EDC was not affected by quinacrine and manoalide (phospholipase A2 inhibitors), indomethacin and aspirin (cyclo-oxygenase inhibitors), ONO-3078 and S-1452 (thromboxane A2 antagonists) or AA-861 and TMK-777 (lipoxygenase inhibitors). 4. Caffeine (1 mM)-induced EDC was also unaffected by 50-235 (an endothelin A receptor antagonist). In addition, catalase combined treatment with superoxide dismutase, or allopurinol (antioxidant) did not affect the EDC. 5. Gro-PIP and NCDC (phospholipase C inhibitors) did not affect the caffeine-induced EDC. However, wortmannin (a phospholipase D inhibitor) and staurosporine (a protein kinase C inhibitor) attenuated the caffeine-induced EDC. 6. The present experiments demonstrate that caffeine causes an EDC in canine mesenteric artery and suggest that the EDCF mediating this response is probably not arachidonic acid metabolites, endothelin or superoxide. Instead, caffeine-induced EDC may be due to activation of the phospholipase D pathway.

Animals↗
PubMed1995

Regenerative caffeine-induced responses in native rabbit aortic endothelial cells.

1. Single native aortic endothelial cells obtained by enzymatic dispersion of the rabbit aortic endothelium were held under voltage clamp using patch pipette and whole-cell membrane currents were measured. In parallel experiments performed on cells from the same batches, the free internal calcium concentration, [Ca2+]i, in the cell was estimated by use of the Ca(2+)-sensitive fluorescent dye, fura-2. 2. Caffeine (20 mM) applied to the cell evoked an outward current and an initial peak in [Ca2+]i followed by a lower sustained rise (plateau). Ca(2+)-free, EGTA-containing solution applied outside the cells did not reduce these responses. 3. Following caffeine stimulation there was a biphasic rising phase of outward current both in the presence and absence of extracellular Ca2+. 4. Application of graded doses of caffeine revealed all-or-none type responses of both the outward current and the rise in [Ca2+]i. 5. Preincubation with lower doses of caffeine reduced the magnitude of both the outward current and the [Ca2+]i transient evoked by 20 mM caffeine. 6. Tetraethylammonium (3 mM) applied to the bathing solution blocked unitary and spontaneous transient outward currents (STOCs) stimulated by Ca(2+)-free solution, but only reduced the outward current evoked by caffeine (20 mM). 7. In conclusion, our results reveal the all-or-none nature of Ca2+ release from the endoplasmic reticulum (ER) in native aortic endothelial cells. Lower concentrations of caffeine (0.4-0.5 mM) may deplete intracellular Ca2+ stores. Extracellular Ca2+ is not necessary for maintaining the activity of spontaneous and caffeine-induced outward currents in native aortic endothelial cells. Spontaneous outward currents are believed to represent the sporadic release of calcium from store sites independent of both extracellular Ca2+ and the caffeine-sensitive Ca2+ stores which stimulate the outward current.

Animals↗
PubMed1991

Interactive effects of ethanol and caffeine on rat fetal hepatocyte replication and EGF receptor expression.

This study reports on the interactive effects of ethanol and caffeine on growth of rat fetal hepatocytes. Exposure of cultured rat fetal hepatocytes (RFH) to ethanol in concentrations above 1 mg/ml, causes a blockade of EGF-dependent cell replication along with an overexpression of surface EGF receptors (EGF-R). However, RFHs exposed for 24 hours to ethanol at a concentration of 1 mg/ml alone had little effect on cell replication. Caffeine, when combined with this concentration of alcohol, progressively impaired RFH growth by up to 100%. Caffeine alone up to 10 micrograms/ml, on the other hand, caused a progressive increase in RFH replication associated with a 69% enhancement of DNA synthesis. Caffeine concentrations in excess of 50 micrograms/ml had no effect on replicative capacity. Concomitant caffeine exposure had no effect on the ethanol-related increase in cell DNA content, yet it caused a further enhancement of the cell protein accural induced by ethanol alone. Caffeine (10 micrograms/ml) alone had no effect on EGF-R expression, while ethanol (2 mg/ml) increased it by almost 200%. Addition of caffeine to ethanol reduced this enhanced EGF binding by 45%. Scatchard analysis indicated that no treatment altered ligand affinity for the receptor, but that the alterations in binding caused by ethanol and the caffeine/ethanol combination reflected changes in binding capacity, in both low and high affinity components. It is concluded that (1) ethanol blocks EGF-mediated replication accompanied by a reduction in DNA synthesis, (2) caffeine alone at low concentrations has the opposite effect and can actually potentiate the EGF-mediated mitogenic response, (3) caffeine in combination with ethanol acts synergistically to reduce RFH replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Lung function in immature baboons with respiratory distress syndrome receiving early caffeine therapy: a pilot study.

AIM: The cardiopulmonary effects of early caffeine therapy in surfactant-treated immature baboons were measured. METHODS: Nine 125-d (term = 185 d) baboons receiving caffeine citrate at 1 and 12 h age as part of a pilot study on the use of nasal CPAP at 24 h were compared to six untreated animals destined for prolonged ventilator support. All received surfactant prior to their first breath and again at 6 h age. Serial physiologic and ventilatory parameters were recorded. Lung mechanics were measured by body plethysmography. Data were compared from 1 through 24 h age. RESULTS: There were no between-group differences in any study variables prior to caffeine therapy at 1 h age. Airway resistance (RA) was significantly lower in caffeine-treated compared to non-caffeine-treated animals at 12 and 24 h age [median (range)12 h: 47 (35-107) cm H2O/l/s to 135 (120-259) cm H2O/l/s; and 24 h: 93(60-137) cm H2O/l/s to 211 (86-235) cm H2O/l/s; p < 0.05]. Respiratory system compliance (CRS) was higher in caffeine-treated compared to non-caffeine-treated animals at 18 and 24 h age [median (range) 18 h: 0.60 (0.29-1.58) ml/cm H2O/kg to 0.39 (0.33-0.46) ml/cm H2O/kg; and 24 h: 0.68 (0.36-1.20) ml/cm H2O/kg to 0.36 (0.33-0.55) ml/cm H2O/kg; p < 0.05]. Ventilatory efficiency index and arterial/alveolar ratio significantly improved in caffeine-treated animals over the 24-h study period (p < 0.05, repeated measures ANOVA). CONCLUSIONS: In this pilot study, early caffeine treatment, combined with prophylactic surfactant therapy, was associated with better lung function during the initial 24 h of life. This combined approach may facilitate earlier extubation or prophylactic efforts to support infants on nasal CPAP. Randomized, controlled investigation is warranted.

Animals↗
PubMed1974

The effects of caffeine on the contraction of the frog heart.

1. The force of contraction and the membrane potentials have been measured from preparations of frog heart, with methods that also allow the rapid exchange of the extracellular fluid.2. In regularly beating preparations, caffeine induces only weak contractures at temperatures above 15 degrees C, but it does cause a marked potentiation of the twitch responses; longer exposure results in a depression of contraction. The build up and decline of the twitch strength, on addition and on removal of caffeine approximates to a single exponential, time constant 26-45 sec, and this time constant is not altered by variation of the [Ca](o), the stimulus rate or the caffeine concentration. This time course of the change of twitch strength is less complex than the changes seen when either [Ca](o) or the stimulus rate is altered, suggesting a more direct action of caffeine on excitation-contraction coupling.3. Caffeine increases the strength of the contractures initiated by potassium-rich or sodium-depleted solutions in isolated atrial trabeculae.4. After the spontaneous relaxation of the contracture, evoked by either sodium-free or potassium-rich fluids, the application of caffeine initiates a redevelopment of tension. This caffeine contracture is transient and its strength is dependent on the caffeine concentration. The response in sodium-free solution can be elicited in the virtual absence of extracellular calcium.5. Local anaesthetics antagonize the caffeine contracture.6. The results suggest that the sarcoplasmic reticulum of frog heart muscle plays an important role in the initiation and control of contraction and relaxation.

Action Potentials↗