High-dose Caffeine Research Articles

High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial

Objective: To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects....

Effects of Repeated Caffeine Administration on Voluntary Wheel Running in Mice

0144 Caffeine administration can have ergogenic effects on endurance exercise performance during a single bout of maximal forced exercise in both humans and animals. However, little is known about the effects of specific dosing regimens of caffeine on 24-hour voluntary physical activity patterns over multiple days. Purpose: To examine voluntary running patterns over 3 days in male mice in response to 3 consecutive doses of caffeine given at hourly intervals at the beginning of their inactive/sleep period (lights on). Methods: 7–9 week old male CD1 mice (n = 16) took part in 3 treatment conditions involving consumption of highly palatable food pellets (0.5g) containing no caffeine (CON), low dose caffeine (LO; 6mg/kg), or high dose caffeine (HI; 12mg/kg) at 7, 8, and 9 am for 3 days in a repeated measures design. Daily voluntary running patterns were recorded by computer with Vital View data collection/analysis software (Mini-Miter). Results: Repeated measures ANOVA showed no main effect of treatment (caffeine at two doses) on overall 24 hr wheel running (distance, time on wheel, and peak speed). However, there was a significant treatment × time interaction that showed differences between treatments at the beginning of the light period (when caffeine was given) and the subsequent dark period (when mice are most active). Between 7–11am when caffeine was administered, both HI and LO caffeine increased distance, time and peak speed above that of CON. There were no significant differences between HI and LO during this period. Conversely, during the subsequent 4-hr period at the beginning of the dark period there was a greater rebound decrease in distance, time, peak speed for HI compared to LO and CON. Conclusion: Both high and low doses of caffeine showed similar increases in voluntary running behavior when given at hourly intervals during the 1st 3 hours of the inactive/sleep period in mice. However, the lower dose of st caffeine would be recommended because it was without the possible disadvantage of reducing activity during the subsequent peak activity period. Information such as this could be useful when designing nutritional strategies to maximize worker performance in military or industrial settings when frequent changes in work schedule is necessary.

Caffeine protects against Parkinson's disease?

A large prospective study, based on the Health Professionals’ Follow-Up and Nurses’ Health Study cohorts, reports an inverse association between coffee consumption and risk for Parkinson's disease in men and women. Similar results were obtained when the caffeine consumption from other sources was investigated. Because earlier studies have shown that addition of high-dose caffeine to other drugs used in the treatment of Parkinson's disease does not provide additional benefits, the effect of caffeine seems to be preventive rather than curative. It is known that caffeine, an antagonist at the adenosine A2 receptor, protects against chemically induced neurotoxicity in an animal model of Parkinson's disease, and that it might have a role in the modulation of dopamine-mediated transmission. [Ascherio, A. et al. (2001) Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann. Neurol. 50, 56-63]. AB

Effects of caffeine with repeated dosing

We have recently demonstrated dose-dependency of caffeine metabolism under multiple dosing conditions. Whether there are persistent pharmacodynamic actions of caffeine under such circumstances is the focus of this report. Nine healthy subjects were given, in randomized 5 day blocks, placebo, 4.2 (low) and 12 (high) mg.kg-1.day-1 of caffeine in 6 divided doses. After 5 days, complete tolerance developed to the effects of caffeine on blood pressure, heart rate and plasma glucose concentrations. The 24-h area under the curve (AUC) for plasma norepinephrine and the AUC for the total sum of free fatty acids (FFA) both demonstrated a trend to increase with the high dose caffeine treatment. When the AUC for norepinephrine was split into 12 h time periods, a significant difference between the placebo and the high dose treatment block was seen. We conclude that regular consumption of 12 mg.kg-1 of caffeine per day (equivalent to approximately 6 to 11 cups of coffee per day) may produce pharmacodynamic effects not completely compensated for by the development of tolerance. Mechanisms of tolerance may be overwhelmed by the nonlinear accumulation of caffeine and other methylxanthines in the body when caffeine metabolism becomes saturable.

Caffeine‐induced behavioural stimulation is dose‐ and concentration‐dependent

1. The relationship between plasma and brain caffeine and metabolite concentrations and behavioural stimulation was investigated over a 4 h time course. 2. CD-1 mice receiving single intraperitoneal doses of caffeine-sodium benzoate solution (caffeine doses: 0, 20, and 40 mg kg-1) were evaluated in an activity monitor, and their plasma and brain caffeine and metabolite concentrations were determined by high performance liquid chromatography (h.p.l.c.). 3. Kinetic variables for caffeine at low and high caffeine doses were: volume of distribution (Vd), 1.16 and 0.88 l kg-1; plasma elimination half-life (t1/2), 1.25 and 1.62 h; brain t1/2, 0.93 and 1.30 h; clearance, 0.64 and 0.38 l h-1 kg-1, respectively, with Vd and brain t1/2 differing significantly between the two caffeine doses. 4. Low-dose caffeine stimulated vertical behaviours significantly more than high-dose, during the first 150 min post-dosage; both doses stimulated vertical behaviours significantly more than vehicle treatment. 5. Low-dose and high-dose caffeine stimulated horizontal and stereotypic behaviours equivalently, during the first 150 min post-dosage; both doses stimulated these behaviours significantly more than vehicle. 6. Only later, 150 min post-dosage, did high-dose caffeine stimulate all behaviours significantly more than both low-dose and vehicle treatment; this occurred when caffeine concentrations had fallen to approximately 10 micrograms g-1 in the high-dose group. 7. The maximal stimulant effects of caffeine occurred in an intermediate concentration range, between 10-20 micrograms g-1, while lower and higher concentrations produced either no additional stimulation or decrements in activity.

High-dose Caffeine Suppresses Postoperative Apnea in Former Preterm Infants

Thirty-two former preterm infants (less than or equal to 44 weeks postconceptual age) undergoing inguinal hernia repair were prospectively studied. General inhalational anesthesia with neuromuscular blockade was used. No barbiturates or opioids were given. Infants were randomly divided into two groups. Group 1 received iv caffeine 10 mg/kg immediately after induction of anesthesia. Group 2 received iv saline. Respiratory pattern, heart rate, and SpO2 were monitored using an impedance pneumograph and a pulse oximeter, respectively, for at least 12 h postoperatively. Tracings were analyzed for evidence of apnea, periodic breathing, and/or bradycardia by a pulmonologist unaware of the drug given. None of the patients who received caffeine developed postoperative bradycardia, prolonged apnea, or periodic breathing, and none had postoperative SpO2 less than 90%. In the control group 13 (81%) developed prolonged apnea 4-6 h postoperatively. Fifty percent of the patients had SpO2 less than 90% at the time. This study shows that iv caffeine 10 mg/kg is effective in the control of apnea in otherwise healthy expremature infants between 37 and 44 weeks of postconceptual age. It is still recommended, however, that all infants at risk be monitored for at least 12 h for apnea and bradycardia following general anesthesia.

High-Dose Caffeine and Cardiac Rate and Rhythm in Normal Subjects

In a previous 24-hour study of the electrophysiologic effects of moderate dose caffeine (1 mg/kg body weight/half-life), we found a significant (p less than 0.01) increase in ventricular ectopic beat (VEB) frequency among 18 patients with preexisting primary ventricular dysrhythm (mean 207 +/- 350 VEBs/hour, no caffeine, versus 307 +/- 414 VEBs/hour, caffeine). We also found a statistically insignificant (NS) increase in the incidence of infrequent VEBs in 18 normal control subjects (four of 18, no caffeine vs nine of 18 caffeine). Because of the high risk of beta-error among the previously-studied normal control subjects, we tested another group of 34 normal subjects, 15 males and 19 females with a mean age of 31 years (range 21 to 49 years), using a higher dose of caffeine. All subjects abstained from caffeine for 72 hours and had a control 24-hour Holter ECG recorded between hours 48 and 72. Caffeine half-life was calculated for each subject and caffeine was then ingested at 1 mg/kg every 0.5 half-life during all waking hours. A 24-hour Holter test was recorded, beginning just prior to the second caffeine dose. It was concluded that in normal adults, even high-dose caffeine does not affect prevailing cardiac rhythm and rate, and moreover, does not cause clinically significant ventricular or supraventricular dysrhythm.

Renal effects of theophylline and caffeine in newborn rabbits.

Renal hemodynamics and functions were assessed in four groups of anaesthetized newborn rabbits receiving a single intravenous dose of methylxanthines, i.e.: aminophylline: 3 mg/kg (A1) or 6 mg/kg (A2); sodium benzoate caffeine: 5 mg/kg (C1) or 10 mg/kg (C2). Each animal acted as its own control. The mean PAH extraction ratio was not modified by the methylxanthines. Renal blood flow and glomerular filtration rate were determined by clearances of para-aminohippuric acid and inulin, respectively. No changes in renal hemodynamics or renal functions were observed in group C1. In group C2, renal blood flow and filtration fraction did not vary significantly but renal vascular resistance showed a delayed increase. Systemic infusion of the two aminophylline regimens induced a delayed increase in renal vascular resistance with a concomitant fall in renal blood flow and an increase of filtration fraction in group A2. Glomerular filtration rate was either reduced (3 mg/kg aminophylline) or increased (6 mg/kg aminophylline and 10 mg/kg caffeine). Moreover, diuresis increased and tubular water reabsorption declined in groups A1, A2, and C2. High dose caffeine enhanced sodium fractional excretion. The acute renal effects of methylxanthines appeared dose- and time-related in immature animals and caffeine proved safer than aminophylline at doses used in human neonates.

Effects of postnatal caffeine exposure through dam's milk upon weanling rats.

The effects of postnatal caffeine exposure received through mother's milk were examined in rat pups by administering 0.0125 or 0.05% caffeine solution to the dams throughout lactation. Offspring of caffeine-treated dams showed significantly earlier onset of auditory startle and air righting reflexes. No direct effects of treatment were observed on eight measures of open field activity. At weaning, high-dose caffeine pups exhibited a transient increase in caffeine acceptance in two-bottle taste preference tests and showed cyclic exaggerations in caffeine preference-aversion functions which persisted throughout the 22-day postweaning test period. The caffeine levels in the dams' milk had a 30-fold daily fluctuation reflecting the fluid ingestion pattern related to the light-dark cycle and caffeine elimination rate. Caffeine concentrations in the brains of the pups varied between 0.01 and 9.0 micrograms/g.

Food intake: Opioid/purine interactions

The exogenous opioids butorphanol tartrate (BT) and ethylketocyclazocine (EKC) have been reported to stimulate feeding in rats. In this study we evaluated the effects of purines (known to suppress feeding) and the adenosine antagonist, caffeine, on opioid induced feeding. Adenosine and inosine significantly suppressed BT and EKC induced feeding at various doses and time points. Caffeine enhanced food consumption was suppressed by various doses of naloxone, but was not suppressed by adenosine or inosine. Although caffeine itself induced further feeding, it did not enhance BT induced food consumption. Adenosine and inosine failed to suppress BT induced feeding when 12.5 mg/kg of caffeine was administered to the rats suggesting blockade of the adenosine receptor by caffeine. In contrast to 12.5 mg/kg caffeine, high dose caffeine (50 mg/kg) suppressed BT induced feeding over a 4 hour time period. Adenosine (50 mg/kg) and inosine (50 mg/kg) injected one hour after injection of BT and caffeine (50 mg/kg) reversed the suppressive effect of high dose caffeine in BT induced feeding. These studies indicate that opioid induced feeding can be suppressed by adenosine and inosine. Also, caffeine can reverse the suppressive effect of adenosine and inosine on feeding and vice versa. Naloxone's suppression of caffeine enhanced food consumption indicate that at least part of caffeine's effect on food intake may be mediated through an opioid mechanism.

Effect of caffeine on thyroid and pituitary function in newborn rats.

The possibility that caffeine, a central nervous system stimulant used in neonatal apnea, may produce acute or chronic changes in growth hormone (GH), thyroxine (T4) and thyrotropin (TSH) was studied in the newborn rat. Five-day-old rats were separated into three groups: control (0) group receiving saline, Group I (low dose caffeine) receiving 5 mg/kg and Group II (high dose caffeine) receiving 50 mg/kg. Acute effects were studied at 2, 4, and 24 h after injection. Chronic effects were studied 24 h after the last of 10 daily injections. GH, T4, and TSH were measured by radioimmunoassay and caffeine by high pressure liquid chromatograph. GH was increased at all times and all doses after a single injection of caffeine. After chronic therapy, the increase in GH was small, suggesting depletion of pituitary reserve. A high dose of caffeine had a biphasic effect on T4 with an increase at 4 h and a decrease at 24 h. Thyrotropin-releasing hormone (TRH)-induced TSH release at 24 h was not influenced by caffeine administration. Chronic caffeine therapy stimulated both T4 and TSH; however, TRH-stimulated TSH release was decreased, suggesting that chronic therapy may blunt pituitary TSH response.