Residual Drug Effects Research Articles

The Human Carotid Body

Hypoxia is a common cause of adverse events in the postoperative period, where respiratory depression due to residual effects of drugs used in anesthesia is an important underlying factor. General anesthetics and neuromuscular blocking agents reduce the human ventilatory response to hypoxia. Although the carotid body (CB) is the major oxygen sensor in humans, critical oxygen sensing and signaling pathways have been investigated only in animals so far. Thus, the aim of this study was to characterize the expression of key genes and localization of their products involved in the human oxygen sensing and signaling pathways with a focus on receptor systems and ion channels of relevance in anesthesia. Six CBs were removed unilaterally from patients undergoing radical neck dissection. The gene expression and cell-specific protein localization in the CBs were investigated with DNA microarrays, real-time polymerase chain reaction, and immunohistochemistry. We found gene expression of the oxygen-sensing pathway, heme oxygenase 2, and the K channels TASK (TWIK-related acid sensitive K channel)-1 and BK (large-conductance potassium channel). In addition, we show the expression of critical receptor subunits such as γ-aminobutyric acid A (α2, β3, and γ2), nicotinic acetylcholine receptors (α3, α7, and β2), purinoceptors (A2A and P2X2), and the dopamine D2 receptor. In unique samples of the human CB, we here demonstrate presence of critical proteins in the oxygen-sensing and signaling cascade. Our findings demonstrate similarities to, but also important differences from, established animal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic drugs and human CB chemoreception.

Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study

The effects of hypnotic drugs on driving performance are most often evaluated on young healthy subjects by using a monotonous motorway driving test. The effects of drugs in urban driving situations have not yet been evaluated in any age group. Our objectives were to assess residual effects of the most prescribed hypnotics, zolpidem and zopiclone, on older middle-age drivers' capacities in an urban situation. Sixteen healthy subjects aged 55 to 65 years underwent this double-blind, balanced, cross-over study. Zopiclone (7.5 mg), zolpidem (10 mg), and flunitrazepam (1 mg; used as positive control) or a placebo were administered at each subject's home at 11:00 PM: under the supervision of an investigator. The next morning, the subjects had to drive in a simulated urban environment where accident scenarios were introduced. Accident scenarios were implemented using data from real accident cases. Hypnotics did not significantly increase the number of collisions. However, significantly higher speeds were found with zopiclone and flunitrazepam; moreover, zolpidem and zopiclone induced modifications of the lateral position of the car on the road. This study did not reveal any major residual effects of the hypnotics studied on driving performance in aging drivers. However, the urban driving situations used here for the first time in the evaluation of drugs revealed some modifications in driving habits which could lead to risky behavior. It thus appears that urban driving simulations are useful for gaining knowledge about the effects of drugs on driving behavior.

Comparison of various tests designed to assess the recovery of cognitive and psychomotor function after ambulatory anesthesia

Background: Few studies have been conducted to evaluate the reliability of the various tools used to assess cognitive and psychomotor recovery after ambulatory anesthesia. Therefore, this study was conducted to compare the sensitivity and reliability of simple, standard tests used to measure postoperative cognitive and psychomotor functions. Methods: Twenty-seven patients admitted for same day surgery were included in this prospective, randomized study. While in the preanesthetic unit, each patient was asked to perform three different standard psychometric tests, the digit symbol substitution test (DSST), digit span test (DST), and perceptual speed test (PST), to evaluate cognitive and psychomotor functions. The results were then used as baseline values that were subsequently compared to results obtained when patients repeated the tests at 15, 30 and 60 min after extubation. In addition, the observer’s assessment of alertness and sedation was evaluated. Results: The DSST scores were significantly lower than the baseline scores at 15 and 30 min after extubation, with a performance ratio of 64.9 and 89.2, respectively (P ＜ 0.05). The DST scores had returned to preanesthetic levels at 30 min post-anesthesia and the PST scores were found to be significantly higher than the baseline scores at 30 and 60 min post-anesthesia. Conclusions: DSST is a more sensitive indicator of residual drug effect following anesthesia than the other tests evaluated in this study. In addition, a learning effect was obvious when the PST was administered. (Korean J Anesthesiol 2008; 55: 291～7)

Residual effects of intranasal methamphetamine on sleep, mood, and performance

Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers ( n = 11) completed this two-week, in patient, within-participant, double-blind study. The study consisted of four two-day blocks of sessions; each block was separated by at least 48 h. At approximately 10:00 h, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50 mg/70 kg). Lights were turned out at 23:00 h that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50 mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50 mg) dose decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days.

Residual effects of zolpidem, zopiclone and flunitrazepam on the processing of visual information in driving context

Drivers who had taken hypnotic medications such as benzodiazepines are over-represented in road accidents. Experimental studies show that, even the day after, these drugs induce an impairment of real or simulated driving. To remedy the undesirable side-effects of hypnotics, new families of such drugs have been developed, their residual effects on visual information processing functions are poorly documented. We therefore compared the residual effects of two hypnotics, zopiclone (7.5 mg) and zolpidem (10 mg), and those of an old one, flunitrazepam (1 mg), versus a placebo on the capacities of subjects to estimate their own speed of movement and to anticipate a situation of collision with another vehicle parked along their trajectory. We found no modification in the processing of visual information the day after taking an active molecule. As these perceptive tasks have been demonstrated to be sensitive to environmental and individual factors, we can conclude that own speed perception and time to collision estimation are not affected by the residual effects of the hypnotic drugs studied. Thus, the behavioural impairments observed in previous studies result from the alteration of other functions solicited when driving a vehicle.

Response of Trypanosoma vivax and Trypanosoma congolense in zebu cattle in North Cameroon to prophylactic treatment with two formulations of isometamidium

We tested the efficacy of two formulations of isometamidium in a tsetse-infested farm in North Cameroon from 20 August 2000 to 5 January 2001. A total of 90 adult cattle were used in three groups of 30 each corresponding to two treated and one untreated control. Drug efficacies were evaluated in terms of reduction of parasite incidence in the host's blood, maintenance of packed-cell volume (PCV) and weight gains. Both drugs reduced the incidence of parasites even though re-infections 2 weeks after treatment were common. PCV values were similar in both treated groups but higher than in the untreated control. Body weight changes followed a similar trend with the control losing weight from a mean of 427 ± 119 kg at the beginning to 398 ± 93 kg in 4 months. Weights increased from 375 ± 76 and 396 ± 110 to 396 ± 69 and 418 ± 112 kg in the Veridium ® and Trypamidium ® groups, respectively. Efficacy was similar between the two formulations of isometamidium in the prophylaxis of bovine trypanosomosis. However, the presence of parasites in some animals barely 2 weeks after treatment suggested that either infections were not cleared or residual drug effects were not sufficient to prevent re-infections.

MAC Should Stand for Maximum Anesthesia Caution, Not Minimal Anesthesiology Care

MAC Should Stand for Maximum Anesthesia Caution, Not Minimal Anesthesiology Care

Ascaris Lumbricoides: Post Operative Hypoxia

Post operative airway obstruction may be due to anaesthesia related factors such as residual anaesthetic or sedative effects of drugs, inadequate antagonism of neuromuscular block or secondary to several physical factors such as compression of airway due to haematoma, bilateral recurrent laryngeal nerve palsies, massive tongue swelling, paradoxical vocal cord motion or simply obstruction by mucous plug. The case reported highlights the possibility of unusual airway obstruction in post operative period due to obstruction caused by regurgitation of round worm (Ascaris Lumbricoides).

Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring

Most studies that investigated the next-day residual effects of hypnotic drugs on daytime driving performances were performed on healthy subjects and after a single drug administration. In the present study, we further examine whether the results of these studies could be generalised to insomniac patients and after repeated drug administration. Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8+/-2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia. Driving tests were performed 9-11 h post-dose. Results showed that treatment effects were evidenced for subjective sleep, for driving abilities, and for electroencephalogram (EEG) recorded before (resting EEG) and during the driving simulation test (driving EEG). Compared to placebo, zopiclone increased the number of collisions and lormetazepam increased deviation from speed limit and deviation from absolute speed, whereas zolpidem did not differentiate from placebo on these analyses. EEG recordings showed that in contrast to zolpidem, lormetazepam and zopiclone induced typical benzodiazepine-like alterations, suggesting that next-day poor driving performance could relate to a prolonged central nervous system effect of these two hypnotics. The present results corroborate studies on healthy volunteers showing that residual effects of hypnotics increase with their half-lives. The results further suggest that drugs preserving physiological EEG rhythms before and during the driving simulation test 9-11 h post-dose, such as zolpidem, do not influence next-day driving abilities.

The early recovery of cognitive function after total-hip replacement under hypotensive epidural anesthesia

Recovery of cognitive function immediately after major surgery has not been previously reported, partly because of residual drug effects and pain. Changes in cognitive function were assessed using the Stroop Color and Word Test (SCWT), which was performed preoperatively, and 1 and 2 hours after total-hip replacement performed under hypotensive epidural anesthesia. In this case series, patients were sedated with propofol alone and had a lumbar plexus block performed at the end of surgery. The SCWT was completed in 52 of 55 patients at either 1 or 2 hours after surgery. A significant reduction in cognitive function was noted 1 hour after surgery but a return toward baseline occured 2 hours after surgery. Age older than 70 years adversely affected recovery of cognitive function, but neither the preoperative diagnosis of hypertension nor the degree or duration of intraoperative hypotension (mean arterial pressure less than 45 mmHg) influenced cognitive function. The Stroop Color and Word Test can be used to assess change in cognitive function immediately after surgery. Total-hip replacement performed under regional anesthesia with propofol sedation enables recovery of cognitive function (as assessed by SCWT) 2 hours after surgery.

Fármacos no meio ambiente

Pharmaceutical drugs have been detected in sewage treatment plants, surface waters, underground waters and potable waters. Some investigations have been conducted in several countries such as Germany, Brazil, Canada, United States, The Netherlands, England and Italy. Patients and animals excrete part of pharmaceuticals used for human and veterinary medicine after administration in domestic sewage or on the soil. Drugs residues which have not been completely removed during passage through a sewage treatment plant (STP) enter the aquatic environment. The effects of such residual drugs in terrestrial and aquatic organisms are scarcely known.

Effects of veterinary drugs on beta-hexosaminidase release from rat basophilic leukemia cells (RBL-2H3)

Little is known about the effects of residual veterinary drugs on the allergic reaction, except for the antigenicity of antibiotics and synthetic antimicrobials. Therefore, 59 kinds of veterinary drugs were investigated for their effects on the IgE receptor-mediated beta-hexosaminidase release from RBL-2H3 cells as an index of immediate allergic reaction. We found that the antibiotics chlorotetracycline, doxycycline, monensin, the synthetic antimicrobial pyrimethamine and the steroid hormone testosterone inhibited beta-hexosaminidase release. Most of the veterinary drugs showed no action, though the ionophores lasalocid, salinomycin and the steroid hormone hexestrol promoted beta-hexosaminidase release from injured cells. Based on the residual levels of these drugs and the frequencies of detection in actual food samples, it seems unlikely that these drugs have any immediate allergic effect in practice.

Effects of d-AP5 and NMDA microiontophoresis on associative learning in the barrel cortex of awake rats

Experiments involving single-unit recordings and microiontophoresis were carried out in the barrel cortex of awake, adult rats subjected to whisker pairing, an associative learning paradigm where deflections of the recorded neuron's principle vibrissa (S2) are repeatedly paired with those of a non-adjacent one (S1). Whisker pairing with a 300 ms interstimulus interval was applied to 61 cells. In 23 cases, there was no other manipulation whereas in the remaining 38, pairing occurred in the presence of one of three pharmacological agents previously shown to modulate learning, receptive field plasticity and long-term potentiation: N-methyl- d-aspartic acid (NMDA) ( n=8), the NMDA receptor antagonist AP5 ( n=17) or the nitric oxide synthase inhibitor l-nitro-arginine- N-methyl-ester ( l-NAME) ( n=13). Non-associative (unpaired) experiments ( n=14) and delivery of pharmacological agents without pairing ( n=14) served as controls. Changes in neuronal responsiveness to S1 following one of these procedures were calculated and adjusted relative to changes in the responses to S2. On average, whisker pairing alone yielded a 7% increase in the responses to S1. This enhancement differed significantly from the 17% decrease obtained in the non-associative control condition and could not be attributed to variations in the state of the animals because analysis of the cervical and facial muscle electromyograms revealed that periods of increased muscular activity, reflecting heightened arousal, were infrequent (less than 4% of a complete experiment on average) and occurred randomly. The enhancement of the responses to S1 was further increased when whisker pairing was performed in the presence of l-NAME (27%) or NMDA (35%) whereas AP5 reduced it to 1%. During the delivery period, NMDA enhanced both neuronal excitability and responsiveness to S1 whereas AP5 depressed them. However, the effects of both substances disappeared immediately after administration had ended. l-NAME did not affect the level of ongoing activity and responses to S1 significantly. From these data, we concluded that, since the changes in the responses to S1 lasted longer than the periods of both whisker pairing and drug delivery, they were not residual excitatory or inhibitory drug effects on neuronal excitability. Thus, our results indicate that, relative to the unpaired controls, whisker pairing led to a 24% increase in the responsiveness of barrel cortex neurons to peripheral stimulation and that these changes were modulated by the local application of pharmacological agents that act upon NMDA receptors and pathways involving nitric oxide. We can infer that somatosensory cerebral cortex is one site where plasticity emerges following whisker pairing.

Microtremors During a Sustained Concentration Task from Boys Previously Exposed to Opiates In-Utero

ABSTRACT Fourteen boys who were exposed to opiates in-utero (drag exposed) maintained their index finger in a static, weight-forced position while attempting to maintain a stylus at a fix point producing intentional microtremors. After 2.5 minutes, significant increases in tremor were recorded in mean peak (6 Hz) amplitude while accuracy of sustaining this response was significantly reduced. Age matched boys (ages 7–12) who were raised in an environment in which drags were used but were not directly exposed in-utero (lifestyle group N = 13) or a standard control group (N = 12), did not show similar changes over time. Resting or postural-extended tremor did differ among groups. Alcohol, marihuana, or tobacco usage by the mother or birth weight of the child did not predict subsequent group differences in tremor. Both biological and environmental variables plus type and sensitivity of measurement used are critical elements for describing long-term, potential residual drug effects in children, especially as they relate to sustained attention.

Failure to Awaken After General Anesthesia Due to Cerebrovascular Events

Failure to awaken after general anesthesia is a rare complication that may be caused by residual drug effect, systemic abnormalities, or neurologic injury. Failure to awaken often is initially attributed to residual drug effect, potentially delaying correct diagnosis. Three cases of failure to awaken because of neurologic injury are reviewed. Differential diagnosis of failure to awaken is discussed, and the importance of distinguishing pathologic causes from residual anesthetic is stressed.

Pharmacokinetics and Pharmacodynamics of 4-Aminopyridine in Awake Guinea Pigs

ABSTRACTThe selective blockade of potassium channels on excitable membranes by 4-aminopyridine (4-AP) leads to facilitation of neurotransmitter release at a wide variety of synapses. This compound has been shown to be efficacious against lethality induced by saxitoxin (STX) and tetrodotoxin (TTX) in guinea pigs. To characterize the actions of 4-AP in guinea pigs we have investigated its pharmacokinetics (PK) and pharmacodynamics following a 2 mg/kg, intramuscular (im) dose in awake chronically instrumented (IN) animals. Animals were chronically instrumented for electrophysiologic recordings of diaphragmatic electromyogram (DEMG), lead II electrocardiogram (ECGII) and electro-corticogram (ECoG). Also, PK studies were carried out in uninstrumented (UN) guinea pigs. Blood and electrophysiologic data were collected at predetermined time intervals up to 4 hours post 4-AP administration. High performance liquid chromatography was used to determine plasma 4-AP concentrations. For IN and UN animals, plasma concentration-time data best fit a one-compartment model, and PK parameter estimates were similar for both groups. Peak plasma levels were found to occur between 16 and 17 min, and the half-lives of elimination were 65 and 71 min for IN and UN animals respectively. Heart and respiratory rates were elevated as early as 5 and 15 min respectively in response to 4-AP administration. The duration of action was approximately 1–1.5 half-lives of elimination beyond peak plasma levels. Maximum ECoG responses were observed between 12–15 min after 4-AP injection; some residual drug effects were still apparent at 240 min. The difference between the heart and respiratory rates and ECoG profiles suggests that these different physiological systems respond with varying degrees of sensitivity to plasma 4-AP concentrations. The stimulation of these systems is consistent with the action of 4-AP in reversing STX- and TTX-induced cardiorespiratory depression and decreased ECoG power in guinea pigs.

Sleep in schizophrenia: A polysomnographic study on drug-naive patients

A slow wave sleep (SWS) deficit and a shortened rapid eye movement (REM) sleep latency are commonly reported in schizophrenic patients. However, most of these patients have been off neuroleptic medication for only a short period of time. Therefore, the reported sleep alterations may be due to residual drug effects. We polysomnographically investigated 22 drug-naive patients with a schizophrenic disorder, paranoid type, and 20 normal controls. In addition, we assessed the ventricular brain ratio (VBR) by means of computed assisted tomography. Except for a prolonged sleep onset latency, increased wake time and decreased stage 2 sleep, the patients showed a sleep pattern, i.e., of SWS and REM sleep, comparable with that of controls. The VBR was increased in 71% of the patients but was not associated with the patients' clinical characteristics or their SWS and REM sleep patterns. Our results indicate that the commonly reported SWS and REM sleep changes in schizophrenia reflect the remnant of prior neuroleptic treatment rather than the pathophysiology of the disorder itself.

Reply

Ian Gilron, M.D., F.R.C.P.(C), Pain Research Fellow, Departments of Neurology/Neurosurgery and Anaesthesia, McGill University.Terence J. Coderre, Ph.D., Director, Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.In Reply:-Goto et al. continue an interesting discussion regarding conflicting results among the cited studies. As they reiterate, evidence exists to support the dose dependency of barbiturates on nociceptive behavior. This phenomenon appears to be due to a dose-related progression starting from suppression of descending inhibitory systems (hyperalgesic effect) to suppression of spinal nociceptive mechanisms (analgesic effect). For this reason, differences in behavioral effects of GABAminergic anesthetics that have variable pharmacokinetic/pharmacodynamic (PK/PD) profiles must be interpreted with caution. Goto et al. suggest that, in our study, the lack of analgesic effect with pentobarbital may be due to the possibility that the dose used produced roughly equal suppression of both descending inhibitory and spinal nociceptive systems. Although this is a feasible hypothesis, it should be noted that the purpose of our study paradigm is to measure persistent pain during phase 2, which is thought to be an expression of spinal sensitization produced by noxious stimulation during phase 1. The timing and dosing of drugs used in our study was designed to maximize drug effect during phase 1, in an attempt to prevent spinal sensitization while allowing for anesthetic recovery, so as to eliminate or at least minimize residual drug effect during phase 2. With this in mind, phase 2 pain behavior is interpreted as how effectively the study drug prevented sensitization during phase 1 and less dependent on whether the drug dose was hypnotic or subhypnotic.Although flinch counting and weighted scores behavioral measurement have both been validated and widely used, Goto et al. emphasize the value of qualitative distinction between different pain behaviors in the rat formalin test. This is an interesting idea, because each of these behaviors may be an expression of diverse subjective sensations and may respond differentially to pharmacologic manipulations.Given the obvious difficulties in interpreting pharmacologic effects on experimental pain behavior, it is of vital importance that we enhance such behavioral studies with other concomitant measures, such as PK/PD analyses, electrophysiology, molecular biology, and receptor binding assays. Such strategies may provide additional information regarding specific mechanisms of drug action and further aid in clarifying equivocal behavioral findings.Ian Gilron, M.D., F.R.C.P.(C.), Pain Research Fellow, Departments of Neurology/Neurosurgery and Anaesthesia, McGill University.Terence J. Coderre, Ph.D., Director, Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.(Accepted for publication October 31, 1996.)

Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats

The development of tolerance to the anticonvulsant effects of clonazepam, clobazam, and diazepam were studied in genetically epilepsy-prone rats following intraperitoneal (IP) or oral administration. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz). All compounds showed 60 min after IP injection antiseizure activity with ED 50 against clonus of 0.24 μmol kg −1 for clonazepam, 0.72 μmol kg −1 for diazepam, and 3.9 μmol kg −1 for clobazam. After 120 min of oral administration the ED 50 against clonus of 2.37 μmol kg −1 for clonazepam, 15.8 μmol kg −1 for diazepam, and 30 μmol kg −1 for clobazam. The dose chosen for the chronic treatment were 2.5 μmol kg −1 for clonazepam, 15 μmol kg −1 for diazepam, and 30 μmol kg −1 for clobazam. The animals were treated three times daily for 4 or 6 weeks. Auditory stimulation was administered 60 min after drug IP injection on various days. During treatment, tolerance was observed as a loss of drug anticonvulsant effects. No changes of occurrence of audiogenic seizures was observed in rats treated with vehicle. Tolerance to the anticonvulsant activity developed most rapidly during clobazam treatment, less rapidly following diazepam treatment, and most slowly during clonazepam treatment. Sixty minutes after IP injection on various days of chronic treatment the motor impairment induced by these benzodiazepines was also studied by means of a rotarod apparatus. The tolerance to the motor impairment developed more rapidly than the anticonvulsant effects. The response to auditory stimulation to benzodiazepines was stopped 24 and 48 h after chronic treatment with these compounds, showing no residual drug effects and that rats were still tolerant. The genetically epilepsy-prone rats is a reliable and sensitive model for studying long-term effects of anticonvulsant drugs.

Twenty-Four-Hour Antihypertensive Efficacy of Felodipine 10 mg Extended-Release: The Italian Inter-University Study

We assessed the 24-h antihypertensive efficacy of an extended-release (ER) 10-mg formulation of the dihydropyridine felodipine in mild-to-moderate essential hypertension [World Health Organization (WHO) stage I-II]. Thirty patients, 23 men and 7 women, aged 37-70 years (mean 53 +/- 9 years) participated in a double-blind, randomized, cross-over study of felodipine 10 mg ER versus placebo. An ambulatory daytime diastolic blood pressure (DBP) >90 mm Hg at the end of a 4-week run-in period was necessary to enter the 10-week treatment phase. Twenty-nine patients completed the treatment phase. Twenty-two underwent a 2-day single-blind placebo follow-up to assess residual drug effects. All patients underwent ambulatory BP monitoring (ABPM) by Spacelabs 90207 recorders. Recorders were programmed to make automatic BP and heart rate (HR) measurements every 15 min throughout the 24 h. Felodipine 10 mg ER significantly (p < 0.01) reduced ambulatory systolic BP (SBP) and DBP values throughout the 24-h, day (7 a.m. to 11 p.m.) and night (11 p.m. to 7 a.m.) periods, but not influencing average ambulatory HR values. Trough-to-peak (T/P) ratios, calculated on the average ambulatory BP values measured in the 7-9 a.m. 2-h interval of the second day of ABPM (before the new drug administration: trough) and in the 10 a.m. to 12 noon 2-h interval of the first day of ABPM (peak BP-lowering effect), were 0.71 and 0.58 for SBP and DBP, respectively. Individual T/P calculations, after post hoc selection of nonresponders, gave superimposable results, the consistency of which was judged on mean, median, and confidence intervals (CI). However, the wide variability of the individual T/P ratios suggests that this method cannot be the only means to evaluate the duration of action of an antihypertensive drug by ABPM. The long-acting BP-lowering drug effect was clearly shown by the ABPM performed in the follow-up when SBP and DBP average values of the 24-h, day, and night periods were still reduced. Felodipine 10 mg ER effectively reduced BP in patients with mild-to-moderate hypertension, showing prolonged duration of its antihypertensive action beyond the time of the next dose.