Clonidine transdermal patches for use in outpatient opiate withdrawal

We conducted a study to assess the clinical usefulness of transdermal clonidine for heroin detoxification in an outpatient drug treatment clinic. Twenty-two young otherwise healthy heroin addicts participated. Outcome was assessed on the basis of (a) hypotension and other side effects of clonidine; (b) patient retention; (c) concomitant drug use; (d) subjective symptoms of withdrawal; and (e) objective signs of withdrawal. Side effects were present but in no case necessitated discontinuation of treatment. Drop-out rates were equal to conventional treatment offered at the clinic. The availability of clonidine broadens the therapeutic options available to patients and clinicians in treating the opiate-addicted patient. Transdermal clonidine offers several advantages over the oral form: patches can be applied weekly, fewer supplemental medications are required, and patches supply an even blood level of medication. A protocol for use is recommended.     

Rate and extent of absorption of clonidine from a transdermal therapeutic system

The in-vivo performance of a clonidine transdermal therapeutic system (TTS 3.5 cm2, 2.5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4.32 micrograms h-1 over a 7-day period.     

In vitro and in vivo characterization of a newly developed clonidine transdermal patch for treatment of attention deficit hyperactivity disorder in children

The aim of this study was to characterize a newly developed clonidine transdermal patch, KBD-transdermal therapeutic system (TTS), for the treatment of attention deficit hyperactivity disorder in children. In vitro release, penetration, and in vivo pharmacokinetics in rabbits were investigated. The smaller size of KBD-TTS (2.5 mg/2.5 cm2) showed a similar in vitro penetration to those of Catapres-TTS (2.5 mg/3.5 cm2, a clonidine transdermal patch used for the treatment of hypertension, Alza Corporation, U.S.A.). The transdermal penetration rate of clonidine was mainly controlled by the ethylene vinylacetate membrane used in the patch. The skin layer may be only a minor rate-limiting barrier after the topical skin layer at the dosing site is saturated with penetrating clonidine in the initial phase (0 to 12 h). A sensitive liquid chromatography-mass spectrometry method for the quantification of clonidine in rabbit plasma was developed using solid-phase extraction and gradient elution on LC combined with the selected-ion monitoring (SIM) mode. A single dose of clonidine transdermal patch (KBD-TTS) or Catapres-TTS was transdermally administered to rabbits (n=6 each) and removed after 168 h. The average half-life, Tmax, Cmax and Css values of clonidine in rabbits following administration of KBD-TTS were 19.27+/-4.68 h, 52.56+/-25.77 h, 27.39+/-9.03 ng/ml, and 25.82+/-9.34 ng/ml, similar to those of Catapres-TTS, respectively. The clonidine plasma concentration of KBD-TTS reached a steady state at 24 h through 168 h. The in vitro release rate of the clonidine from KBD-TTS significantly correlated with the in vivo absorption rate (p<0.001).     

Clinical pharmacokinetics of clonidine

Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5 cm2) until the desired pharmacological effect has been obtained.(ABSTRACT TRUNCATED AT 400 WORDS)     

Drug delivery to the eye with a transdermal therapeutic system

A matrix-type transdermal therapeutic system was developed for treating diseases of the eye where it is difficult for drug molecules to reach with conventional topical instillation. Prednisolone was employed as a model drug. An in vivo study using rats showed that the daily application of the patch maintained a constant plasma concentration of the drug, which was equivalent the therapeutic plasma level following three times daily oral administration (30 mg), for approximately 24 h. Transdermal delivery provided equivalent to or higher bioavailability (drug distribution) to the eyeball of topical administration. Moreover, pharmacokinetic analysis indicated that the present transdermal therapeutic system may be clinically effective as a new treatment for ocular diseases.     

Effects of clonidine on aortic diameter and aortic baroreceptor activity

Effects of clonidine (Catapres) on aortic baroreceptors and diameter of ascending aorta were studied in anesthetized rabbits. Baroreceptor activity was recorded from the whole aortic nerve; aortic diameter was measured by an ultrasonic technique, inside the intact thorax. Blood pressure was controlled by alterations in blood volume. At diastolic pressures of 50–90 mm Hg, clonidine, 20–30 μg/kg, increased aortic nerve activity by 90-30% and aortic diameter by about 5%. These effects were abolished by pretreatment with piperoxane, an α-adrenergic blocking drug. Clonidine did not alter the aortic response to large concentrations of noradrenaline. Effects of clonidine on aorta and aortic baroreceptors occurred a few min after injection, while sympathetic activity, recorded in the renal nerve, decreased abruptly. The results suggest that the relaxation of aortic smooth muscle — and hence aortic dilatation and increased receptor activity — was due to an α-adrenergic blocking effect of clonidine, rather than to suppression of sympathetic nervous activity. The experiments indicate that the central hypotensive actions of clonidine are aided by increased baroreceptor activity at all blood pressures.     

Pharmacokinetics and efficacy of phenazepam after transdermal and enteral administration in rats

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.     

Alinidine pharmacokinetics following acute and chronic dosing.

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.     

Transdermal administration of clonidine: a new approach to antihypertensive therapy

This study assessed the antihypertensive efficacy and side effects of clonidine administered transdermally. Twenty-five patients with mild to moderate essential hypertension (seated diastolic blood pressure 95-120 mm Hg with diuretic therapy alone) controlled with oral diuretic plus oral clonidine were enrolled. Transdermal clonidine was substituted for oral clonidine and titrated until adequate blood pressure control (seated diastolic blood pressure less than 90 mm Hg) was attained. At the end of titration, seated morning blood pressure averaged 129/90 +/- 15/5 mm Hg (mean +/- standard deviation) compared to 136/96 +/- 13/7 mm Hg (p less than 0.01/0.001) during oral clonidine administration. Standing morning blood pressure was also lower during transdermal than oral therapy (131/94 +/- 16/5 vs 136/99 +/- 14/7, p less than 0.05/0.001). Afternoon blood pressures (at peak effect of oral dose) were virtually identical during oral and transdermal therapy in both seated and standing positions. Typical side effects of oral clonidine, including dry mouth, drowsiness, and sexual dysfunction, were reduced during transdermal therapy. There was less morning-to-afternoon variability of blood pressure control and plasma clonidine concentrations during transdermal than during oral therapy. One patient left the study because of drowsiness and two because of skin reactions to the transdermal skin patch. Mild transient local skin irritation occurred frequently. Transdermal clonidine plus a diuretic is an effective treatment for mild to moderate essential hypertension, improves compliance and reduces side effects of therapy.     

Pharmacokinetics of clonidine following intravenous administration of high doses for the treatment of delirium tremens

Concentrations of clonidine (CAS 4205-09-7. Catapresan) were measured in the plasma and the urine of 6 patients with delirium tremens who received 1.8-13.8 mg clonidine on the third treatment day. There was a linear correlation between the daily dose of clonidine and the steady state concentration of clonidine in the plasma, even with the high doses of clonidine used in this study. The total clonidine clearance was 29-62% lower than in normal volunteers. The renal clearance were 49-75% lower than normal. The renal excretion of the non-metabolized clonidine was significantly lower than the normal range. The creatinine clearance on the other hand was only slightly reduced. The present study gives first hints that the metabolic clearance of clonidine in patients with delirium tremens is not decreased remarkably.     

血药浓度监测下大剂量甲氨蝶呤24h滴注疗法延迟排泄分析

目的:研究非霍奇金淋巴瘤患者大剂量甲氨蝶呤(HD-MTX)24 h滴注疗法延迟排泄影响因素、不良反应和解救措施。方法:收集某院2009-2014年之间122个患者的377次疗程的HD-MTX 24 h滴注疗法的资料,运用统计学方法分析延迟排泄和疗程、年龄、性别、剂量、血药浓度及不良反应的相关关系,探讨了延迟排泄的解救措施。结果:延迟排泄发生率与疗程、年龄、性别无关,但与剂量相关,当剂量大于4.0 g时发生率高。延迟排泄患者滴注完12 h以后的MTX血药浓度明显升高,高浓度MTX延迟排泄的可引起肾功能损伤。结论:延迟排泄更多发生在低浓度点,但高浓度的延迟排泄肾功能损伤大,因此血药浓度监测是实施HD-MTX疗法必不可少的安全保证措施。在及时的亚叶酸钙(CF)解救和充分的水化碱化下,延迟排泄的不良反应完全可以很好地预防和控制。     

Transdermal therapeutic systems

Transdermal therapeutic systems (TTS) gain continuously increasing importance in therapy due to their advantageous properties. They assure constant concentration of the active substance in the blood, a lower amount of the drug compared to the orally administered dose is sufficient, side effects decrease, and the therapy is painless. Since the appearance of the first products many TTSs have been developed containing a wide variety of active substances including hormonal, antihypertensive, antianginal, and analgesic plasters. Nowadays TTSs belong to the most advanced formulations. There is ongoing research in the field of regulating the active substance release with electric current or ultrasound. There are systems containing insulin, cytostatics, antiparkinsonians, contraceptives, and anxiolytics under development.     

Transdermal clonidine compared with hydrochlorothiazide as monotherapy in elderly hypertensive males

Sixteen of 22 elderly male patients (aged 60-74 years) who had previously taken only hydrochlorothiazide 50 mg completed a study evaluating the safety, efficacy, and tolerability of 12-20 weeks of transdermal clonidine (Catapres TTS) as monotherapy for mild hypertension. Thirteen of the sixteen patients (81%) responded to transdermal clonidine which was begun after 28 days of placebo. Five patients discontinued transdermal clonidine therapy because of intolerable skin irritation, and one because of daytime fatigue. Clonidine caused none of the metabolic effects we observed with hydrochlorothiazide: no change in serum potassium, uric acid, cholesterol, or triglyceride. Eleven of the 22 patients (50%) who began the study experienced a skin reaction under the transdermal clonidine patch. The incidence of dry mouth and fatigue in patients using transdermal clonidine was dose-related and similar to reports of dry mouth and fatigue in patients taking oral clonidine tablets. Rebound hypertension occurred in one patient upon withdrawal of transdermal clonidine. There was no effect of transdermal clonidine or hydrochlorothiazide on cognitive function or emotional state tested with three questionnaires. Overall, transdermal clonidine, in various doses, was as effective as hydrochlorothiazide in elderly male hypertensive patients. The effectiveness of both was inversely proportional to the level of untreated blood pressure. The high incidence of skin reactions limited prolonged use of transdermal clonidine in our patients.     

Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl

Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same adverse effects as other opioids, mainly sedation, nausea, vomiting and constipation. In comparison with oral morphine, TTS fentanyl causes fewer gastrointestinal adverse events. The risk of hypoventilation is comparatively low in cancer patients. Sufentanil and buprenorphine may also be suitable for transdermal delivery, but clinical results are not yet available. Transdermal morphine is only useful if applied to de-epithelialised skin. However, iontophoresis may allow transdermal administration of opioids, including morphine, with a rapid achievement of steady state concentrations and the ability to adjust delivery rates. This would be beneficial for acute and/or breakthrough pain, and initial clinical trials are in progress.     

Comparison of effects of guanfacine and clonidine on blood pressure, heart rate, urinary catecholamines, and cyclic nucleotides during and after administration to patients with mild to moderate hypertension

In a random trial, the effects of treatment and withdrawal of guanfacine were compared with those of clonidine in 20 uncomplicated hypertensive patients. Elevated blood pressure returned to normal or responded well in all the patients given either guanfacine once daily or clonidine thrice daily. The pulse rate was reduced comparably by both treatments after 12 weeks, but the effect of guanfacine developed more gradually. Both guanfacine and clonidine significantly inhibited urinary noradrenaline, dopamine, and cyclic nucleotide excretion, while urinary adrenaline levels were unaffected. Side effects occurred earlier during treatment with clonidine. After sudden withdrawal, all the parameters tended to increase gradually in the guanfacine group, reaching base line by days 4-6. In the clonidine group the increase was more rapid, with pretreatment values reached within the 2nd day, and sometimes these values were surpassed. After withdrawal of clonidine all the patients had one or more side effects, most of them occurring within 48 h, while only 60% of the patients in the guanfacine group reported the appearance of unwanted symptoms, on days 3-6. It is concluded that there are close similarities between the effects of guanfacine and clonidine on the parameters evaluated, except for dopamine excretion, which was significantly less affected by guanfacine. Marked differences were found after abrupt withdrawal, with guanfacine less likely to produce the "discontinuation syndrome," probably due to its long half-life.     

Dermal Drug Delivery Systems: A Review

Abstract

Systems that deliver drugs through intact skin at a controlled rate are now in routine clinical use. They include a nitroglycerin system for the prophylaxis of angina, and a scopolamine system for the prevention of motion sickness. In addition, there are also published reports on rate-controlled transdermal forms of clonidine and estradiol. Since the trans-dermal mode of drug administration can provide continuity of delivery and precise control of drug plasma concentrations, it offers particular advantages for drugs with short half-lives or narrow therapeutic indices. It is also useful when the oral route is unsuitable. Transdermal rate-controlled therapy appears on the brink of rapid expansion for the administration of potent, nonirritating, nonallergenic agents with suitable physi-cochemical properties. In the case of new agents, rate-controlled transdermal administration may render some drugs routinely usable that otherwise would produce unacceptable side effects or require impractical regimens. Some older agents will gain an increased margin of safety and convenience—as well as expanded therapeutic usefulness—compared with their administration in conventional dosage forms. Owing to constraints arising from drug potency, skin permeability, and/or topical reactions, however, transdermal administration is not expected to become the preferred dosage form for a high percentage of drugs.     

Pharmacokinetics and side-effects of clonidine

Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p<0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.     

The pharmacokinetic profile of lithium in rat and mouse; an important factor in psychopharmacological investigation of the drug

The pharmacokinetic characteristics of lithium and the profile of plasma lithium concentration at steady state in both the mouse and the rat have been determined. The half life of lithium in both rodents was shorter (3.5 h and 6 h) than that found during maintenance therapy in man. Following a loading dose (10 mmol/kg s.c.) and twice daily maintenance injections (3 mmol/kg s.c.) of lithium chloride the plasma concentration remained above the accepted human therapeutic minimum (0.4 mM) for 16 of every 24 h in the mouse and throughout the entire 24 h period in the rat. Maximum concentrations in both species were below the range at which toxic effects might be expected to occur.     

Studies on the transdermal delivery of nimodipine from a menthol-based TTS in human volunteers

The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 microg/cm2/h to 167.53+/-3.69 microg/cm2/h with the addition of 8%w/w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w/w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w/w vinyl acetate content) was 152.05+/-2.68 microg/cm2/h, and this flux decreased to 132.69+/-1.45 microg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/ rat skin composite was found to be 116.05+/-2.39 microg/cm2/h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2%w/w HPMC gel as reservoir containing 8%w/w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated menthol-based TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.