Plasma Clonidine Concentrations Research Articles

Safety and Efficacy of Novel Epidural Clonidine Micropellets for Lumbosacral Radiculopathy

Background: Chronic low back and leg pain is a leading cause of disability driving significant health care expenditure and lost productivity. Treatment options such as physical therapy, corticosteroids epidural injections (ESI) or spine surgery have limited long term effectiveness, are costly, and may cause significant morbidity. Clonidine has well-known anti-neuropathic pain (analgesic) with anti-inflammatory properties. A novel, targeted-delivery formulation of slow-release biodegradable polymer (Poly (D, L-lactide) clonidine has the ability to deliver sustained, high clonidine levels in tissues to provide prolonged pain relief while minimizing systemic exposure and side effects. Methods: A pilot multicenter study was performed to investigate safety, pharmacokinetics (PK) and activity of clonidine micropellets in patients with chronic lumbosacral radiculopathy. Three sequential cohorts of 18 subjects each received a single epidural injection of clonidine 0.325 mg, 0.975 mg or 1.95 mg (1, 3 or 6 micropellets, respectively) at the interlaminar epidural level that corresponds to the painful dermatomes. Clonidine PK was evaluated at multiple time points for 84 days. Paired t-tests were performed to examine changes from baseline within each cohort, and analysis of covariance evaluated differences between dose levels. Numeric Rating Scale (NRS) and Roland Morris Disability Scale (RMS-Q) were recorded at baseline and followed up to one year postinjection. Results: The peak plasma clonidine concentration was observed 24 hours following the injection in each cohort. The mean elimination half-life ranged from 13 to 20 days. There was a statistically significant reduction in leg pain from baseline at all time points up to 1 year, in all cohorts with similar improvement in each group. All cohorts showed statistically significant improvement in the RMS-Q at all timepoints. Adverse events and rescue medications were also recorded. Conclusion: Results of this trial support the hypothesis that Clonidine Micropellets would safely and slowly deliver clonidine over a prolonged period. Clonidine’s anti-neuropathic and anti-inflammatory effects could treat the radicular pain process at the nerve root resulting in long term pain relief. Trial Registration: ClinicalTrials.gov (NCT01917825). Funding Statement: Phase II trial was funded by Medtronic Inc. Declaration of Interests: Nagy A. Mekhail: Consultant: Boston Scientific, Sollis Therapeutics, and Relievant Medsystems, Inc. Receiving research support from Mallinckrodt, Mesoblast, Halyard, and Neuros Medical Independent medical monitor for Closed-loop SCS “Evoke study” sponsored by Saluda Medical Pty. Ltd., HF10 for PDN “Senza-PDN study” sponsored by Nevro Corp. and Mild for LSS “Motion study” sponsored by Vertos Medical. Ali R. Rezai: Equity position: Sollis Therapeutics and Neurotechnology Innovation Management Board of Directors: Sollis Therapeutics Pragya B. Gupta: Nothing to disclose W Porter McRoberts: Consultant: Nalu, Abbott, Bioness, Sollis, BGT Shareholder of Nalu Gregory J. Fiore: Consultant to Sollis Therapeutics Bryan A. Jones: Employee of Sollis Therapeutics Lou-Anne G. Acevedo-Moreno: Nothing to disclose Chris J. Gilligan: Funded Research: Sollis Therapeutics, Mainstay Medical Consulting: Medtronic, Abbott, Saluda, Nuvectra Ramsin M. Benyamin: Consultant: Medtronic, Avanos, Vertiflex Ethics Approval Statement: This study was approved by the institutional review boards at 6 participating sites. The study was conducted in compliance with the Declaration of Helsinki principles for human medical research, and the principles of good clinical practice and data management. Written informed consent was obtained from all study participants.

The use of clonidine in elderly patients with delirium; pharmacokinetics and hemodynamic responses

BackgroundThe Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is an RCT investigating the effect of clonidine in medical patients > 65 years with delirium. To assess the dosage regimen and safety measures of this study protocol, we measured the plasma concentrations and hemodynamic effects of clonidine in the first 20 patients.MethodsPatients were randomised to clonidine (n = 10) or placebo (n = 10). The treatment group was given a loading dose (75μg every 3rd hour up to a maximum of 4 doses) to reach steady state, and further 75μg twice daily until delirium free for 2 days, discharge or a maximum of 7 days. Blood pressure (BP) and heart rate (HR) were measured just before every dose. If the systolic BP was < 100 mmHg or HR < 50 beats per minute the next dose was omitted. Plasma concentrations of clonidine were measured 3 h after each drug intake on day 1, just before intake (day 2 and at steady state day 4–6) and 3 h after intake at steady state (Cmax). Our estimated pre-specified plasma concentration target range was 0.3–0.7μg/L.Results3 h after the first dose of 75μg clonidine, plasma concentration levels rose to median 0.35 (range 0.24–0.40)μg/L. Median trough concentration (C0) at day 2 was 0.70 (0.47–0.96)μg/L. At steady state, median C0 was 0.47 (0.36–0.76)μg/L, rising to Cmax 0.74 (0.56–0.95)μg/L 3 h post dose. A significant haemodynamic change from baseline was only found at a few time-points during the loading doses within the clonidine group. There was however extensive individual BP and HR variation in both the clonidine and placebo groups, and when comparing the change scores (delta values) between the clonidine and the placebo groups, there were no significant differences.ConclusionsThe plasma concentration of clonidine was at the higher end of the estimated therapeutic range. Hemodynamic changes during clonidine treatment were as expected, with trends towards lower blood pressure and heart rate in patients treated with clonidine, but with dose adjustments based on SBP this protocol appears safe.Trial registrationClinicalTrials.gov NCT01956604, 09.25.2013. EudraCT Number: 2013–000815-26, 03.18.2013. Enrolment of first participant: 04.24.2014.

Enteral Absorption and Haemodynamic Response of Clonidine in Infants Post-cardiac Surgery

Background Clonidine is a useful analgesic-sedative agent; however, few data exist regarding its use in infants after congenital heart disease surgery. We thus aimed to assess the absorption and safety of enterally administered clonidine in this setting. Methods Sixteen infants (median age 6.7 months) received a single nasogastric dose of 3 μg kg −1 clonidine 2–6 h after surgery. Blood samples were obtained at seven time intervals (up to 480 min). Plasma concentration profiles were obtained, and then pooled with a previous study (137 samples, 30 infants) for estimation of population pharmacokinetic parameters (NONMEM version 7.2). Results Enteral absorption showed considerable inter-individual variability, with clonidine C max ranging from 0.15 to 1.55 ng ml −1 (median 0.73), and T max from 12 to 478 min (median 190). Although therapeutic sedative plasma concentrations were achieved in 94% of patients, only half had attained this by 70 min post-dose. Patients who did not receive inotropes exhibited a positive association between cumulative morphine dose and T max (interaction effect P =0.03); this was not seen among those receiving inotropes. The haemodynamic profile was favourable; few patients required fluid boluses, and this bore no relationship to plasma clonidine concentration. Population pharmacokinetic parameter estimation yielded results similar to previous paediatric studies: clearance 13.7 litre h −1 70 kg −1 and V d 181 litre 70 kg −1 . Conclusions Early postoperative enteral clonidine produces favourable haemodynamic profiles and therapeutic plasma concentrations in the majority of cardiac surgical infants; however, the time to achieve this can be erratic. Thus, parenteral administration may be preferable if rapid analgo-sedative effects are needed.

Development of an LC-MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound.

Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO-HCT-high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine.

Enteral absorption and haemodynamic response of clonidine in infants post-cardiac surgery

Clonidine is a useful analgesic-sedative agent; however, few data exist regarding its use in infants after congenital heart disease surgery. We thus aimed to assess the absorption and safety of enterally administered clonidine in this setting. Sixteen infants (median age 6.7 months) received a single nasogastric dose of 3 μg kg(-1) clonidine 2-6 h after surgery. Blood samples were obtained at seven time intervals (up to 480 min). Plasma concentration profiles were obtained, and then pooled with a previous study (137 samples, 30 infants) for estimation of population pharmacokinetic parameters (NONMEM version 7.2). Enteral absorption showed considerable inter-individual variability, with clonidine Cmax ranging from 0.15 to 1.55 ng ml(-1) (median 0.73), and Tmax from 12 to 478 min (median 190). Although therapeutic sedative plasma concentrations were achieved in 94% of patients, only half had attained this by 70 min post-dose. Patients who did not receive inotropes exhibited a positive association between cumulative morphine dose and Tmax (interaction effect P=0.03); this was not seen among those receiving inotropes. The haemodynamic profile was favourable; few patients required fluid boluses, and this bore no relationship to plasma clonidine concentration. Population pharmacokinetic parameter estimation yielded results similar to previous paediatric studies: clearance 13.7 litre h(-1) 70 kg(-1) and Vd 181 litre 70 kg(-1). Early postoperative enteral clonidine produces favourable haemodynamic profiles and therapeutic plasma concentrations in the majority of cardiac surgical infants; however, the time to achieve this can be erratic. Thus, parenteral administration may be preferable if rapid analgo-sedative effects are needed.

Clonidine as an adjuvant to prolong local analgesia in conventional scleral buckle surgery.

The aim of this study was to determine the effect of a single dose of 150 μg of clonidine as an adjuvant to levobupivacaine (Chirocaine(®)) in retrobulbar block on postoperative safety and analgesia. This was a prospective, randomized, controlled, double-blind trial. One hundred twenty patients with a rhegmatogenous retinal detachment scheduled to undergo external buckling surgery and cryocoagulation were asked to participate. Participants were randomly assigned either to receive 3-5 mL Chirocaine (22.5-37.5 mg) or 3-5 mL Chirocaine and 1 mL clonidine (150 μg) before surgery. Main outcome measures were postoperative pain, use of analgesics, blood pressure, and plasma clonidine concentration. Nine nonrandomized patients consented to give blood samples for pharmacokinetic analysis. There was no significant difference in pain score between both groups. On average, the use of analgesic medication occurred later in the clonidine group (P=0.0004), but there was no statistical difference in the first time that postoperative medication was taken (P=0.13). Blood pressure was reduced by clonidine (systolic: P=0.02, diastolic: P=0.006). Clonidine levels could be demonstrated during the 24-h postoperative period, with an average half-life of 22 h. Administration of clonidine as an adjuvant to conventional retrobulbar block is safe, and delays the postoperative use of analgesics. The reduction of postoperative pain and the time of first use of analgesic medication, however, were not significantly different between groups. Further, pain scores in both study groups remained low. Therefore, the beneficial effect of clonidine in conventional scleral buckle surgery appears to be limited.

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial

BackgroundThis pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.FindingsFive adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.ConclusionClonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

Clonidine Clearance Matures Rapidly During the Early Postnatal Period: A Population Pharmacokinetic Analysis in Newborns With Neonatal Abstinence Syndrome

The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnatal age, PNA) and weighing 2.1 to 3.9 kg, were enrolled to take multiple oral doses of clonidine. The population PK model of clonidine was developed by NONMEM, and significant covariates were identified, followed by nonparametric bootstraps (2000 replicates) and simulation experiments. A 1-compartment open linear PK model was chosen to describe plasma concentrations of clonidine, and body weight and PNA were significant covariates for apparent clearance (CL/F) as follows: CL/F (L/h) = 15.2 × [body weight (kg)/70](0.75) × [PNA (day)(0.441)/(4.06(0.441) + PNA (day)(0.441))]. Furthermore, CL/F of clonidine increased rapidly with PNA during the first month of life after body weight was adjusted. Any optimal dosage regimen for clonidine in term neonates should be based on infant's age and body weight, and 1.5 µg/kg every 4 hours is proposed starting the second week of life based on the simulation results.

Implication of enterohepatic re-circulation on single dose bioequivalence evaluation of two brands of clonidine hydrochloride tablets in healthy human volunteers

A single dose, crossover bioequivalence study of two different brands of clonidine hydrochloride 25 μg tablets was conducted in 24 (+2 stand by) healthy, adult, male, Indian subjects under fasting conditions to check the implication of enterohepatic re-circulation on assessment of bioequivalence. After an overnight fasting of at least 10 h, the subjects received single oral dose of test or reference product with either of the product as per randomization schedule in each period with a washout period of 10 days. The pre-dose blood sample was collected within a period of one h before dosing. The post-dose blood samples were collected at specified time intervals up to 96 h. The plasma concentrations of clonidine were quantified by validated LCMS/MS method and pharmacokinetic parameters were computed. The 90% confidence intervals of test/reference ratios for Cmax and area under the plasma-concentration- time-curve AUC under 0-t were found to be between 0.80 and 1.25 for log-transformed data. Analysis of variance did not show significant difference to these parameters. No meaningful values of Kel and therefore AUC under 0-infinity could be calculated for significant number of subjects due to enterohepatic re-circulation. Based on the results obtained, two different brands of clonidine 25 μg tablets have comparable rate and extent of absorption after oral administration but failed to show bioequivalence as per regulatory requirement of Food and Drugs Administration-united states.

Clonidine Pharmacokinetics in Pregnancy

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

The Effect of Clonidine Infusion on Distribution of Regional Cerebral Blood Flow in Volunteers

Through their action on the locus coeruleus, alpha2-adrenoceptor agonists induce rapidly reversible sedation while partially preserving cognitive brain functions. Our goal in this observational study was to map brain regions whose activity is modified by clonidine infusion so as to better understand its loci of action, especially in relation to sedation. Six ASA I-II right-handed volunteers were recruited. Electroencephalogram (EEG) was monitored continuously. After a baseline H2(15)O activation scan, clonidine infusion was started at a rate ranging from 6 to 10 microg x kg(-1) x h(-1). A sequence of 11 similar scans was then performed at 8 min intervals. Plasma clonidine concentration was measured. Using statistical parametric mapping, we sought linear correlations between normalized regional cerebral blood flow (rCBF), an indicator of regional brain activity, and plasma clonidine concentration or spindle EEG activity. Clonidine induced clinical sedation and EEG patterns (spindles) comparable to early stage nonrapid eye movement sleep. A significant negative linear correlation between clonidine concentration and rCBF or spindle activity was observed in the thalamus, prefrontal, orbital and parietal association cortex, posterior cingulate cortex, and precuneus. The EEG patterns and decreases in rCBF of specific brain regions observed during clonidine-induced sedation are similar to those of early stage nonrapid eye movement sleep. Patterns of deactivated brain regions are also comparable to those observed during general anesthesia or vegetative state, reinforcing the hypothesis that alterations in the activity of a common network occur during these modified conscious states.

Improved Sensory Blockade by Clonidine Added to Axillary Block Solution. Resulting Plasma Clonidine Concentration

Improved Sensory Blockade by Clonidine Added to Axillary Block Solution. Resulting Plasma Clonidine Concentration

Clonidine added to bupivacaine enhances and prolongs analgesia after brachial plexus block via a local mechanism in healthy volunteers

Background and objective: The addition of clonidine to local anaesthetics enhances pain relief after peripheral nerve block, but the site of action is unproven. Methods: Seven healthy volunteers underwent three brachial block procedures using bupivacaine 0.25% 1 mg kg−1 + epinephrine 1 : 200 000 (=local analgesic) in a randomized, double-blind cross-over fashion: (a) control treatment: local analgesic with 0.9% sodium chloride solution for the block and an intramuscular injection of saline; (b) intramuscular treatment: local analgesic with 0.9% NaCl for block and an intramuscular injection of clonidine 2 μg kg−1 and (c) block treatment: local analgesic with clonidine 2 μg kg−1 for block and an intramuscular injection of saline. Results: The onset and duration of complete blockade (sensory/motor/temperature) was evaluated in the four nerve regions of the hand and forearm. Additionally, sedation score, blood pressure, heart rate and plasma clonidine concentrations were determined. The median duration of complete sensory blockade was 270 min (range 0-600) for block treatment compared to 0 min (range 0-480) for intramuscular treatment (P < 0.05) and 0 min (range 0-180) for control treatment (P < 0.05). Motor and temperature blockade exhibited similar results. Administration of clonidine was associated with sedation and a decrease in heart rate and blood pressure independent of the route of administration. Plasma clonidine concentrations were lower for block compared to the intramuscular treatment. Conclusions: The admixture of clonidine to bupivacaine plus epinephrine prolongs and enhances brachial plexus blockade. Lower clonidine plasma concentrations for block treatment strongly suggest a local effect.

Plasma Concentrations Following Application of Whole versus Cut Transdermal Clonidine Patches To Critically Ill Children

Clonidine is used for hypertension and narcotic withdrawal prophylaxis in adults and children. This study described plasma absorption of clonidine from whole and cut transdermal clonidine patches. This was a retrospective descriptive study in an 18 bed multidisciplinary pediatric intensive care unit, evaluating 15 critically ill children with a median age of 1.1 years (range 0.3-11 years) treated with transdermal clonidine for narcotic withdrawal prophylaxis, and who had plasma clonidine concentrations measured. An assessment of the relationship between clonidine dose and patch integrity (whole vs. cut) with plasma concentrations was performed, with further analysis by Spearman Correlation Coefficient. Clonidine doses averaged 7.5±4.2 μg/kg/day (range 2.3-20 μg/kg/day) for 9.8±4.3 days (range 4-20 days). There were 9 cut patches and 6 whole patches. The average prescribed dose delivered by cut patches was 6.4±3 μg/kg/day, resulting in a mean plasma concentration of 1±1.1 ng/ mL (range <0.05-3.3 ng/mL). The average prescribed dose delivered by whole patches was 7±1.7 μg/kg/day, resulting in a mean plasma concentration of 0.55±0.3 ng/mL (range 0.13-1.5 ng/mL). The Spearman Correlation Coefficient was calculated to evaluate the correlation between dose and concentration. For whole and cut patches the correlation coefficient was 0.94 (P=0.005) and 0.72 (P=0.002), respectively. Doses ranging from 1.7 to 20 μg/kg/day using whole patches resulted in no plasma concentrations >2 ng/mL. However, a plasma concentration >2 ng/mL was achieved with a dose of 8.8 μg/kg/day delivered by a cut patch. In addition, the 2 samples that resulted in undetectable concentrations were taken from patients who were treated with cut patches. The results from this pilot study suggest that critically ill children absorb clonidine from transdermal patches, but the rate and extent of absorption appears to be more predictable with the use of whole patches compared to patches that have been cut.

Clonidine-induced vasoconstriction in awake volunteers.

We evaluated the vasomotor effects of clonidine in awake subjects with an intact central cardiovascular regulatory system. To determine the lower limit of the vasoconstrictive effect of clonidine in awake volunteers, we blocked sympathetic innervation to the left arm by anesthetizing the brachial plexus. We then measured arterial blood pressure and vasoconstriction via finger volume plethysmography measuring infrared light transmitted through a fingertip (LTF). LTF values obtained from the left arm were compared with those from the neurally intact right arm during four progressively increasing IV doses of clonidine, targeting plasma clonidine concentrations of 0.3, 0.45, 0.68, and 1.0 ng/mL. Clonidine decreased systolic blood pressure (P < 0.004) from 135 +/- 8 mm Hg to 115 +/- 8 mm Hg and heart rate (P = 0.0017) from 68 +/- 7 mm Hg to 61 +/- 10 mm Hg. Clonidine decreased LTF by -12% +/- 11% (P < 0.0001) less than preinfusion values at the 0.68 ng/mL target concentration in the right hand. In contrast, in the left hand, clonidine increased LTF significantly more than (P < 0.0001) preinfusion values at all target concentrations, with a maximal increase of 30% +/- 7%. We conclude that IV clonidine, at doses that decrease arterial blood pressure, causes arterial vasoconstriction in awake subjects. IV clonidine, at doses that decrease blood pressure, causes arterial vasoconstriction in awake subjects. These data suggest that an alpha-2 agonist with a high alpha-2a/alpha-2b selectivity should provide more profound sedative and analgesic effects with less undesirable vasoconstrictive effects.

Absorption of Clonidine from a Halved Transdermal System — A Pilot Study

Objective: To assess whether clonidine bioavailability is compromised when a transdermal system is cut in half. Methods: Seven healthy volunteers were enrolled in this prospective crossover study. In phase I, an intact clonidine 0.1 mg/24 h transdermal system (TS-1) was applied and plasma clonidine concentration was obtained 72 hours after application, after steady-state (48–72 hours) was purported to have been reached. After a minimum seven-day washout period, half of a clonidine 0.2 mg/24 h transdermal system (½TS-2) was applied in phase II, with plasma clonidine concentrations obtained at 24, 48, 72, 120, and 192 hours following application. Results: Mean plasma clonidine concentrations at 72 hours with TS-1 in phase I were 0.17 ± 0.07 ng/mL. Mean plasma clonidine concentrations at 24, 48, 72, 120, and 192 hours with ½TS-2 in phase II were 0.16 ± 0.11, 0.15 ± 0.06, 0.15 ± 0.05, 0.19 ± 0.4, and 0.20 ± 0.8 ng/mL, respectively. There was no statistically significant difference between mean concentrations at 72 hours in phases I and II, but individual clonidine concentrations between phases varied 50–286%. Individual concentration versus time curves obtained from subjects in phase II lacked a consistent pattern. Conclusions: Although there was no statistically significant difference in mean concentrations at 72 hours, individual clonidine concentration variations may have a clinically significant impact. The lack of a consistent plasma concentration versus time pattern may also be of clinical concern. Based on these results, cutting the clonidine transdermal system may compromise its integrity, and is therefore not recommended.

Clinical uses of alpha2 -adrenergic agonists.

Clinical uses of alpha2 -adrenergic agonists.

The Effects of Clonidine on Human Digital Vasculature

Large concentrations of alpha(2) agonists cause vasoconstriction. However, the threshold of the vasoconstrictive effect in humans is not known. We studied seven volunteers to determine the lower limit of the vasoconstrictive effect of clonidine. Subjects were studied while they were awake, and they were anesthetized with propofol/alfentanil/N(2)O. Arterial blood pressure was continuously monitored via radial arterial catheter and vasoconstriction via finger volume plethysmography measuring infrared light transmitted through a fingertip (LTF). Clonidine was administered, targeting plasma clonidine concentrations of 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL. The maximum change from preclonidine values for systolic blood pressure (SBP) and LTF was analyzed by using repeated measures analysis of variance. In awake subjects, clonidine (2.25 ng/mL) decreased LTF by 14%+/-13% and SBP from 141+/-7 to 110+/-15 mm Hg (P<0.0001). In contrast, clonidine (2.25 ng/mL) increased LTF in anesthetized subjects by 21%+/-16% and SBP from 91+/-7 to 106+/-19 mm Hg (P<0.0001). We conclude that the same dose of clonidine that decreased blood pressure and caused vasodilation in awake subjects had the opposite effect in anesthetized subjects with reduced sympathetic tone, increasing blood pressure and causing vasoconstriction in human digital vasculature. Our findings suggest that the lower threshold for clonidine-induced vasoconstriction in human digital vasculature is 1.0 ng/mL.

150. Cognitive function and QEEG: Stimulant effects among ADHD children

200p,gPO.When given in slow infusionsover 80 or 120 minutes, clonidine 1.5~glkg produced concentrationdependentreductions in SEMpeakvelocity,accelerationanddeceleration.Thereweresignificant linearrelationshipsbetweenthe administeredclonidinedose,or plasma clonidineconcentration, andtheirSEMeffectsin mostsubjects.In a pilot analysis,femalepatients,recoveredfroma majordepressiveepisodeand still taking SSRIS, showed reduced dose-responsescompared with controls(depressed= –43*29”/seclpgikg; controls = –93*26°1secl I@g; r = 3.3; d~= 12; p=O.006).These results supportthe further developmentof this approachas a challengetest of central a2-adrenoceptorfunctionin humans.

Plasma concentrations and disposition of clonidine following a constant 14-day epidural infusion in cancer patients

Epidural administration of clonidine, a partial alpha 2-adrenergic agonist, provides effective relief for patients with intractable cancer pain. However, clonidine's long plasma elimination half-life suggests a potential for plasma accumulation following repeated doses or constant infusion. Adult male and female cancer patients experiencing severe, intractable pain were administered a continuous epidural infusion (30 μg/h) of clonidine hydrochloride for 14 days. Plasma clonidine concentrations were determined for 31 patients using a radioimmunoassay with a limit of quantitation of 0.062 ng/mL. Mean (± SD) plasma clonidine concentration and calculated total body clearance after 7 days of infusion (respectively, 2.19 ± 1.17 ng/mL, n = 24; 279 ± 184 mL/min, n = 27) were comparable to those following 14 days of infusion (2.50 ± 1.51 ng/mL, n = 19; 272 ± 163 mL/min, n = 21). Clonidine does not appear to accumulate in the plasma compartment during prolonged (14-day) continuous epidural infusion in cancer patients.