Plasma Caffeine Concentrations Research Articles

Pharmacokinetics and Brain Regional Distribution of Caffeine in Rats

A liquid chromatographic method with a rapid clean-up procedure was used for the determination of caffeine in rat plasma and brain tissue after administration of a single dose of caffeine (2mg/kg, iv). Plasma and brain tissue homogenates were deproteinated by acetonitrile and then centrifuged. Separation was achieved on a Cosmosile C18 column with a mobile phase of 0.1 M borate buffer (pH 6.4)-methanol (72:28, v/v). The limit of detection of caffeine was 0.01μg/mL. The results suggest that the plasma concentration versus time profile of caffeine fits a two-compartment open model, and that the elimination half-life of caffeine is 77.2±4.4min in rat blood. Fifteen mm after caffeine administration, there were no significant differences in caffeine concentration among various regions of the rat brain (cerebral cortex, cerebellum, hippocampus, brain stem, striatum and midbrain).

Regulation of G proteins and adenylyl cyclase in brain regions of caffeine-tolerant and -dependent mice

Regulation of post-receptor signaling provides a mechanism of adaptation to chronic psychotropic drug treatment. In this study, the regulation of guanine nucleotide binding proteins (G proteins) and G protein-stimulated adenylyl cyclase activity was examined in brain regions of caffeine-tolerant and -dependent mice. Chronic caffeine doses were administered via mini-osmotic pumps over 7 days at 0, 42, 85 and 125 mg kg −1 day −1. These chronic caffeine doses were linearly correlated with plasma caffeine concentrations. In behavioral studies, the stimulant effects of acute caffeine on motor activity were significantly diminished in a dose-dependent manner after chronic caffeine, suggesting the development of tolerance. Abrupt discontinuation of chronic caffeine treatment (at 85 and 125 mg kg −1 day −1) produced a dose-dependent and reversible reduction in motor activity 24 h later, suggestive of a caffeine withdrawal syndrome. Utilizing quantitative immunoblotting methods, we found that hippocampal G iα1,2 and G iα3 subunits were significantly reduced by 20.2% and 11.1%, respectively, in caffeine tolerant/dependent mice (caffeine 125 mg kg −1 day −1 vs. vehicle controls). Decreases in inhibitory G protein subunit concentrations in hippocampus were accompanied by a significant increase (by 21%) in hippocampal G protein function, as measured by guanine nucleotide-stimulated adenylyl cyclase activity, in caffeine-treated mice. This same caffeine treatment also produced significant decreases in cortical G sα subunits of 14.0%. Since short-term caffeine treatment has been shown to reduce adenylyl cyclase activity, chronic caffeine treatment could produce adaptive increases in G protein-stimulated adenylyl cyclase to oppose this effect via G protein regulation.

Postnatal caffeine effects on copper, zinc, and iron concentrations in mammary gland, milk, and plasma of lactating dams and their offspring.

Beginning on the day of delivery and until the 15th or 22nd day of lactation, one group of dams received a 20% protein diet as a basal diet and one group received the basal diet supplemented with caffeine (4 mg/100 g body weight). A correlation between caffeine concentrations in the dams' plasma and milk was observed. In the caffeine group, levels of Fe and Cu in the dams' mammary glands at day 22 were decreased. Copper levels in the milk at day 15 and Fe and Zn levels in the milk at day 22 showed a significant decrease. Copper concentration in the plasma of 15-day-old pups showed a significant decrease also, but Zn and Fe concentration showed no difference between caffeine and noncaffeine control groups. The present study shows that the dams' consumption of a caffeine-containing diet influences trace elements of mammary glands, milk, and pups' plasma.

Absorption rate of methylxanthines following capsules, cola and chocolate.

To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study.

To examine the association of plasma caffeine concentrations during pregnancy with fetal growth and to compare this with relations with reported caffeine intake. Prospective population based study. District general hospital, inner London. Women booking for delivery between 1982 and 1984. Stored plasma was available for 1,500 women who had provided a blood sample on at least one occasion and for 640 women who had provided a sample on all three occasions (at booking, 28 weeks, and 36 weeks). Birth weight adjusted for gestational age, maternal height, parity, and sex of infant. The exposures of interest were reported caffeine consumption and blood caffeine concentration. Cigarette smoking was assessed by blood cotinine concentration. Caffeine intake showed no changes during pregnancy, but blood caffeine concentrations rose by 75%. Although caffeine intake increased steadily with increasing cotinine concentration above 15 ng/ml, blood caffeine concentrations fell. Caffeine consumption was inversely related to adjusted birth weight, the estimated effect being a 1.3% fall in birth weight for a 1,000 mg per week increase in intake (95% confidence interval 0.5% to 2.1%). The apparent caffeine effect was confined to cigarette smokers, among whom the estimated effect was-1.6%/1000 mg a week (-2.9% to -0.2%) after adjustment for cotinine and -1.3% (-2.7% to 0.1%) after further adjustment for social class and alcohol intake. Adjusted birth weight was unrelated to blood caffeine concentrations overall (P = 0.09, but a positive coefficient), after adjustment for cotinine (P = 0.73), or among current smokers (P = 0.45). Smokers consume more caffeine than non-smokers. Blood caffeine concentrations during pregnancy are not related to fetal growth, but caffeine intake is negatively associated with birth weight, with this effect being apparent only in smokers. The effect remains of borderline significance after adjustment for other factors. Prudent advice for pregnant women would be to reduce caffeine intake in conjunction with stopping smoking.

Effects of exam stress on mood, cortisol, and immune functioning: Influences of neuroticism and smoker-non-smoker status

In a number of studies, neuroticism, depression and stress have been reported to be positively correlated with each other, with serum cortisol concentration and with smoking. The same factors are inversely related to measures of immune system functioning. The present study assessed in smokers and non-smokers the effects of the presumed stress of final examinations on moods, cortisol and immune system functioning. Subjects were college students selected because they reported feeling reliable high degrees of stress during examinations. Immune system functioning (natural killer cell cytotoxic activity [NKCA], and ConA and PHA lymphocyte proliferation), serum cortisol concentration and mood were assessed in 19 smokers and 23 non-smokers. The findings indicate that exam stress was associated with large increases in reported tension and slightly increased symptoms of depression. Further, T lymphocyte proliferation in response to ConA, but not to PHA, was suppressed during the exam period, while changes in NKCA during exams were associated with an interaction of smoker status and neuroticism. There was also a neuroticism by stress interaction for negative mood assessed by the Profile of Mood States such that those individuals who scored high on measures of neuroticism were higher in negative affect at baseline and postexam periods, but not during the exam period. Smokers had higher serum cortisol concentrations than non-smokers across conditions and scored higher in Beck Depression Inventory-assessed symptoms of depression. Cortisol did not vary as a function of stress and was not correlated with changes in immune functioning, with depression or with negative moods. Serum cortisol and beta-endorphin concentrations were not associated with immune functioning or habitual nicotine intake (plasma nicotine and cotinine concentrations). Among smokers, exam stress did not result in elevated plasma nicotine, cotinine or caffeine concentrations.

Caffeine induces ventricular tachyarrhythmias possibly due to triggered activity in rabbits in vivo.

Caffeine induces delayed afterdepolarizations (DADs) and triggered activity in isolated cardiac tissue. We investigated the ability of caffeine to induce triggered ventricular arrhythmias in rabbits in vivo. During continuous infusion of caffeine at doses of 0.3 or 1.0 mg/kg per min, ventricular pacing was performed with 50 stimuli with a cycle length of 220 msec (basic pacing train) every 5 min until ventricular tachycardia (VT) was induced. The effects of programmed stimulation and pharmacologic agents on the induction of ventricular ectopic beats (VEBs) were examined. Pacing protocols were carried out in the presence of vagal-induced slowing of sinus rhythm. VT was induced by a basic pacing train during the infusion of caffeine at 1.0 mg/kg per min, but not at 0.3 mg/kg per min. An increase in the pacing rate or the number of stimuli resulted in 1) a decrease in the first postpacing interval, and 2) an increase in the number of postpacing VEBs. Induction of VT was suppressed by intravenous bolus injections of verapamil, propranolol and adenosine. At the time of the initial induction of VT, the plasma concentration of caffeine was 87 +/- 2 micrograms/ml and the plasma level of norepinephrine increased from 666 +/- 166 pg/ml at baseline to 1121 +/- 245 pg/ml. These results suggest that catecholamine-associated triggered activity may be responsible for caffeine-induced VT.

Use of 3-(1,8-naphthalimido)propyl-modified silyl silica gel as a stationary phase for the high-performance liquid chromatographic separation of purine derivatives

The use of a packing material, 3-(1,8-naphthalimido)propyl-modified silyl silica gel (NAIP), as a stationary phase for high-performance liquid chromatography, has been studied. NAIP behaved like a reversed-phase stationary phase with some π-π interaction. Purine derivatives, i.e., xanthine, hypoxanthine, uric acid, theobromine, theophylline and caffeine, were separated by a column packed with NAIP using an eluent of borate solution (pH 6.4)-MeOH (50:50, v/v). Of these, caffeine was selected as the target of the subsequent investigation and its determination was examined in commercially available medicinal drinks and pharmaceutical preparations. The average recoveries of caffeine were 98.0–107.4% for five drinks and 99.6–107.8% for five tablets and one powder. Subsequently, determination of caffeine and its metabolites in human plasma was examined. In twelve normal human plasma, caffeine levels ranged from 0.24 to 4.26 μ/ml. Time curves of plasma caffeine concentrations and those of its demethylated metabolite, 1,7-dimethylxanthine (1,7-DMX), after an oral ingestion of caffeine (200 mg) were measured by the proposed method and it was found that the maximum concentrations of caffeine and 1,7-DMX were obtained at 1-1.5 h and 3–6 h after ingestion, respectively.

Effects of exercise on plasma concentrations of caffeine and its metabolites in horses.

The effects of exercise on the metabolism of caffeine (CA) were studied 3h after administration of the drug to race horses which then underwent exercise sets (1000-m gallop). Analysis was made of pharmacokinetics of CA, changes in its plasma concentrations, its metabolites, i.e., theophylline (TP), theobromine (TB) and paraxanthine (PX), and the molar concentration ratios of CA to these metabolites. After exercise, AUC and t1/2 tended to decrease, and the concentration of CA decreased, while the concentrations of TP and TB significantly increased. The TP/CA ratio and TB/CA ratio significantly increased from 6 to 74h and from 25 to 50h after drug administration, respectively. This indicated promotion of metabolism of CA into TP and TB. The effects on PX were minimal.

Cerebrospinal Fluid Concentrations of Caffeine Following Oral Drug Administration

Twelve hospitalized adult patients received 300 mg of oral caffeine 1 h before a diagnostic lumbar puncture. Caffeine concentrations were determined simultaneously in saliva, plasma, and cerebrospinal fluid (CSF). Mean caffeine concentrations in plasma, saliva, and CSF were 5.9 +/- 2.1, 4.4 +/- 1.5, and 2.9 +/- 1.1 micrograms/ml, respectively, with coefficients of correlation plasma-saliva, saliva-CSF, and plasma-CSF of 0.89, 0.79, and 0.77, respectively, all statistically significant (p < 0.001).

Caffeine metabolism and epinephrine responses during exercise in users and nonusers

This study compared the caffeine (CAF) metabolism and the catecholamine and metabolic responses of users and nonusers of caffeine after acute ingestion of caffeine (5 mg/kg) during 1 h of steady-state exercise (50% maximal oxygen consumption). Nonusers (n = 7) completed two exercise trials after ingesting either CAF (5 mg/kg) or placebo (PL). Users (n = 7) underwent three trials designed to control caffeine use and abstained from voluntary CAF intake for 18 days. After 4 days they had a PL trial and in the following 14 days they were given random 6 days of CAF (2 x 2.5 mg.kg-1 x day-1) or PL ingestion followed in each case on the 7th day by a CAF exercise trial identical to that of the nonusers. In nonusers CAF increased (P < 0.05) plasma epinephrine (EPI) concentration above PL values during exercise. Users did not exhibit any increased EPI with CAF, but the EPI response to exercise in all three trials was twofold greater than that of the nonusers' PL trial (P < 0.05). In all trials both groups had identical norepinephrine responses. The groups had similar plasma and urinary caffeine concentration, but plasma dimethylxanthines varied; the users had greater (P < 0.05) theophylline concentration, and the nonusers had a greater (P < 0.05) rise in paraxanthine (PX) concentration. The users and nonusers' plasma free fatty acids (FFA), glycerol and respiratory exchange ratio were similar after ingestion of CAF. Although PX may increase FFA in resting subjects, in this study PX concentrations in nonusers varied from that of the users, yet FFA data were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain.

The effect of long-term oral treatment with caffeine on A1 and A2 receptors in the rat brain was studied. Caffeine was added to the drinking water and the animals were sacrificed after a 12 day treatment period. The plasma caffeine concentration was close to 100 microM. A1 receptors were studied using quantitative autoradiography with [3H]cyclohexyladenosine (CHA). Caffeine treatment increased the number of A1 receptors in the CA3 subfield of the hippocampus from 337 to 393 fmol/mg with no change in KD (0.692 vs. 0.675 nM). A1 mRNA was measured using Northern blots and quantitative in situ hybridization. There was no increase in A1 mRNA. A2a receptors, located in dopamine rich regions of the rat brain, were studied with quantitative autoradiography using [3H]CGS 21680 as the ligand, and the A2a mRNA was determined using quantitative in situ hybridization. Caffeine treatment produced no significant change in either receptor number or mRNA, even though the apparent Bmax tended to increase from 322 +/- 8 to 352 +/- 8 fmol/mg. The results show that treatment with caffeine in a dose that causes tolerance to several effects of caffeine and increases some effects of adenosine analogues increases the number of A1 receptors without any change in A1 mRNA, suggesting that the adaptive changes are at a post-translational level. There were no significant changes in A2 receptors indicating that the two types are regulated differently and/or that the amount of endogenous agonist is sufficient to regulate A1, but not A2 receptors.

Pharmacokinetic-pharmacodynamic modeling of caffeine: tolerance to pressor effects.

We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90% reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine.

Is caffeine a factor in subjective insomnia of elderly people?

Subjective insomnia is more prevalent in elderly than in young populations. In order to examine the relationship between caffeine and sleep quality we studied 181 community-dwelling subjects over a wide age range and 53 elderly patients receiving continuing hospital care. Subjects completed a sleep questionnaire and data concerning smoking, alcohol, use of hypnotics and caffeine-containing substances were recorded. Late afternoon plasma caffeine concentrations were measured in a sub-group of 87 of the community-dwelling subjects and in the hospitalized patients. For the group as a whole, there was a significant negative correlation between age and coffee but not tea consumption (p < 0.001). A global score of sleep quality was significantly inversely related to age (p < 0.001). For the community-dwelling population, the median plasma caffeine concentration was 1.71 micrograms/ml (range 0.10-6.74) and showed a significant correlation with sleep quality (p < 0.05). In contrast, for the hospital dwelling population, median caffeine concentration was higher in patients reporting sleep problems than in those without (p < 0.05). Self-reported consumption of coffee and tea did not correlate with plasma caffeine concentrations. It is possible that people with poor sleep quality, residing in the community, are aware of the stimulatory effects of caffeine and lower their intake accordingly, whereas hospitalized elderly patients, who have less control over their environment, do not.

The effect of brassica vegetable consumption on caffeine metabolism in humans.

Ten healthy volunteers were used in two studies investigating the effect of short-term Brassica consumption on caffeine metabolism. In the first study volunteers were given three Brassica-containing meals, the last one 3 h prior to caffeine administration. In the second study volunteers were given two Brassica-containing meals and then fasted overnight before caffeine administration. In both studies the mean plasma half-life of caffeine was reduced by approximately 20% following a Brassica diet, suggesting that Brassica vegetables stimulate caffeine metabolism. When caffeine was given 3 h after the last meal, plasma caffeine concentrations over 6 h, were increased by up to 27% on the Brassica diet compared to controls. This may be due to a transient increased permeability of the intestine to caffeine, immediately following Brassica consumption. This effect was not seen in the second study where there was a 12-h period between the last meal and caffeine administration. There was large interindividual variation in the effect of the Brassica diet on caffeine metabolism.

Application of microdialysis for study of caffeine distribution into brain and cerebrospinal fluid in rats.

The usefulness of microdialysis was examined for the chronological determination of caffeine concentration in the brain and cerebrospinal fluids (CSF) following intravenous administration of caffeine in rats. The recovery percent of caffeine by microdialysis, the concentration ratio of caffeine in the dialysate against that in the brain tissue or CSF was determined. The recovery percent was proved to be constant at 5 different steady-state plasma concentrations of caffeine (0.1-280 nmol/ml) and in different collecting periods of dialysate ranging from 30 s to 10 min. The mean recovery percent in the brain and CSF were 10.9 and 13.1%, respectively. Thus, microdialysis was proved useful for determination of drug concentration in the tissue and biological fluids with time resolution of more than 30 s. The microdialysis method was then applied for the chronological determination of caffeine concentration in the brain and CSF following intravenous bolus administration. The estimated caffeine concentration in the brain and CSF was the same as those obtained by direct determination in isolated brain and CSF, respectively. Transfer of caffeine from plasma to brain and CSF were further pharmacokinetically analyzed using a modified 2-compartment model. In this kinetic model, the transfer of caffeine between the CSF and brain was neglected, since the mutual transfer of caffeine was not detected in in vivo experiments. Calculated curves were well fitted on observed caffeine concentrations in the plasma, brain and CSF.

Caffeine restriction: effect on mild hypertension.

To determine the effects on blood pressure of modifying dietary caffeine intake in patients with mild and borderline hypertension by monitoring ambulatory and clinic blood pressure. Four way, randomised, crossover trial of four consecutive two week dietary regimens: normal diet, caffeine free diet alone, caffeine free diet with decaffeinated instant coffee, caffeine free diet with caffeinated instant coffee (instant coffee phases conducted double blind). Hospital hypertension clinic, Scotland. 52 patients (23 men; aged 26-67 years) with untreated borderline or mild hypertension (diastolic blood pressure 90-105 mm Hg) who normally drank a minimum of three cups of coffee daily. Mean ambulatory blood pressure over 24 hours; mean morning, daytime, and night time ambulatory blood pressure; sitting clinic blood pressure at 1700; plasma caffeine concentration at 1700 on the last day of each regimen. Mean 24 hour ambulatory blood pressure was not different between regimens. There was no difference in blood pressure variability between regimens. During the caffeine free diet alone morning ambulatory diastolic blood pressure was higher (2.8 mm Hg) than during the caffeine free diet with caffeinated coffee. Mean sitting clinic systolic blood pressure was higher at 1700 (4.7 mm Hg) with a caffeine free diet than with the caffeine free diet with caffeinated coffee (p less than 0.05). Dietary compliance as assessed by plasma caffeine concentration was excellent. There was no significant correlation between plasma caffeine concentration and blood pressure. Drinking caffeinated instant coffee over a two week period does not adversely influence blood pressure in patients with borderline or mild hypertension; abstinence is of no benefit.

Steady‐state population pharmacokinetics of sustained release theophylline in adult asthmatic patients

The steady-state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained-release theophylline as armophylline or euphylline. A total of 92 steady-state plasma theophylline concentration-dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one-compartment open model with single path Michaelis-Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with beta-agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (Vm) and Michaelis constant for theophylline metabolism (Km) were investigated. Hypothesis testing produced a final model in which Km = 0.42 (mg/l), and Vm (mg/kg per day) was based on cigarette smoking and dosage form, with Vm = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in Km and Vm were 162.6% and 48.1%, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.

A comparison of the central nervous system effects of caffeine and theophylline in elderly subjects.

1. The effects of oral administration of 250 mg caffeine or theophylline and placebo on subjective ratings and psychological test performance were studied in a double-blind crossover experiment in 20 healthy elderly subjects. 2. Performance on the continuous attention task showed a significant improvement compared with placebo with both active treatments. Performance with caffeine was significantly better than with theophylline. Mean error index scores (normalised AUCs) were: placebo--0.130; caffeine--0.083; theophylline--0.093. No other objective measure shows significant treatment effects. 3. Subjective ratings showed that subjects felt significantly more alert on caffeine than on either theophylline or placebo. Subjects also rated themselves as more energetic and interested on caffeine than on placebo. 4. Plasma concentrations of caffeine were lower than those of theophylline (mean 5.76 and 8.72 mg l-1 respectively at 2 h post-drug. 5. These results suggest that caffeine is a more potent CNS stimulant than theophylline.

Validity of Self‐Reports of Caffeine Use

The relationship between self-reports of caffeine ingestion on two occasions and measured plasma concentrations of caffeine and its major metabolites was examined. A subject population [25 men and 25 women, age 20-45 years (mean: 28.7 yr)] that was enrolled in a benzodiazepine pharmacokinetic study underwent general medical screening on two occasions, each including detailed caffeine histories. Before beginning their scheduled study, plasma samples were obtained and evaluated by HPLC for caffeine, paraxanthine, theophylline, and theobromine. These values were compared with estimates of caffeine consumption in mg/day generated from both histories. There was no significant difference between plasma levels of caffeine, metabolites, or caffeine plus metabolites for categories corresponding to reports of low, intermediate or high caffeine use. A self-reported caffeine consumption of greater than 300 mg/day (high) did correlate, however, with a significant smoking history. The authors conclude that self-reports of caffeine ingestion do not accurately reflect acute exposure, and that if caffeine use is of importance in a given setting, reports should be confirmed by biochemical means.