skin pretreatment and the use of transdermal clonidine

Skin Pretreatment and the Use of Transdermal Clonidine MATTHEW K. ITO, PHARM.D., ~tochton, ca/iiornia, DANIEL T. O’CONNOR, M.D., La b//a, Ca//forn/a

Although therapy with transdermal clonidine is effective in bringing elevated blood pressure under control, this mode of delivery has been associated with localized dermal reactions in a small percentage of patients. Because anecdotal information suggests that a number of physicians have resorted to various dermal pretreatment strategies in an effort to alleviate or eliminate these dermal reactions, we decided to investigate the two most commonly used pretreatment strategies, to determine if they af- fected the pharmacokinetics and pharmacodynamics of transdermally administered clonidine. Specifically, we examined the effect of dermal pretreatment with 0.5% hydrocortisone cream and with an over-the-counter antacid, magnesium-aluminum hydroxide suspension, on the pharmacokinetics of transdermal clonidine in 10 adult hypertensive males. Patients were randomized to receive one of the two pretreatment regimens or therapy with the patch alone, and after 7 days of treatment and a 14- day washout period, patients were crossed over to receive one of the other therapies. All patients ultimately received all three therapies.

We present here the results from the 10 patients enrolled in our study. Our study found a statistical difference detected in maximum plasma concentration (C,,,), steady-state plasma concentration (C,,), and apparent clonidine dose delivered (Dose,,,) following dermal pretreatment with hydrocortisone compared with the transdermal patch alone. The mean -C SD relative extents of absorption (F,,,) of clonidine following dermal pretreatment with hydrocortisone and magnesium-aluminum hydroxide in respect to the transdermal patch alone were 94.84 + 45.69% and 97.65 f 59.65%, respectively. No significant difference was detected in this parameter. Supine and sitting blood pressures and pulse rates were similar

From the University of the Pacific School of Pharmacy, Stockton, California (MKI). the University of Callfornla San Diego School of Medicine, La Jolla, Call-

Request; for reprints should be addressed to Matthew K. Ito, Pharm.D., VA Medical Center (119), 3350 La Jolla Village Drive, San Dlego, California 92161.

during treatment with clonidine alone, following dermal pretreatment with hydrocortisone cream, and following pretreatment with magnesium-aluminum hydroxide suspension. In addition, systemic side effects were evenly dis- tributed among treatments. However, dermal side effects were less frequent following pretreatment with hydrocortisone compared with magnesium-aluminum hydroxide and the patch alone. The results of this study suggest that dermal pretreatment with 0.5 percent hydrocortisone cream may significantly alter the plasma concentrations of transdermally administered clonidine without adversely altering the pharmacodynamics.

C lonidine is an alpha-adrenoceptor agonist used for the treatment of mild to moderate hyper-

tension. Clonidine is available as oral or transder- ma1 therapy (Catapres-TTS, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT). Clinical trials indicate that clonidine has comparable efficacy when administered by either route [l-3]. A single transdermal system will deliver clonidine in a zero- order fashion over a 7-day period [4]. Available studies have demonstrated a relationship between clinical response-gauged by reduction in blood pressure-and steady-state plasma concentrations of clonidine in both normotensive and hypertensive subjects [5-81.

Therapy with trandermal clonidine has been associated with localized dermal reactions-which include pruritis, erythema, allergic contact dermatitis, and hyperpigmentation. The reported frequency of these skin reactions ranges from 16% to 42% in studies lasting from 6 to 10 months [2-4, g-121. Both sex and race appear to influence the incidence of contact sensitization. Cumulative expe- rience in clinical trials with transdermal clonidine suggests that the incidence of contact dermatitis will be approximately 18% in white males and 34% in white females, compared with 8% in black males and 14% in black females [13].

In an effort to alleviate or eliminate adverse der- ma1 reactions to transdermal clonidine, clinicians have resorted to various dermal pretreatment strategies. One of the most commonly used strategies involves pretreating the patient’s skin with

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SYMPOSIUM ON HYPERTENSION / IT0 and O’CONNOR

0.5% hydrocortisone cream before applying the transdermal clonidine system. Another strategy, also reportedly used, is to swab the skin with magnesium-aluminum hydroxide suspension, a common over-the-counter antacid, before attaching the transdermal system [14].

The effectiveness of these two dermal pretreatment strategies on the incidence of adverse events has not been established, although anecdotal re- ports suggest that both pretreatments reduce the frequency and severity of dermal reactions, at least in some patients.

Because these two pretreatment strategies are being used by a number of clinicians, it is important to assess the effects of these pretreatment modalities on the pharmacokinetics and pharmacodynam- its of transdermal clonidine. The main purpose of our study was to compare the pharmacokinetics of transdermal clonidine, administered without skin pretreatment, with the pharmacokinetics of the transdermal clonidine when used following dermal pretreatment with either 0.5% hydrocortisone cream or magnesium-aluminum hydroxide suspension. We also assessed the influence of dermal pretreatment on hemodynamic parameters.

Although we did take note of the incidence of localized skin reactions to all three treatment modalities, the purpose of this study was, first and fore- most, to assess the effects of dermal pretreatment on the pharmacodynamies and pharmacokinetics of transdermal clonidine. It was our conviction that the results of our study would help determine if a larger trial, designed to determine the effectiveness of various dermal pretreatment strategies, is warranted.

METHODS Experiment Design

For this prospective, open label, randomized, three-way crossover study we enrolled patients over 18 years of age with diastolic blood pressures greater than 90 mm Hg who were receiving treatment for mild to moderate essential hypertension. Patients meeting the study criteria who expressed a willingness to participate were randomized to one of three treatment sequences. Although the order of treatments differed, all 10 patients enrolled received all three treatments. These were:

0 Treatment A: Catapres-TTS 7.0 cm2 system (5 mg total content, programmed to deliver 0.2 mg per day) applied 15 minutes after dermal pretreatment with approximately 0.25 grams (i.e., a l-inch bead) of 0.5% hydrocortisone cream (Hydroskin, Rugby; Rockville Centre, NY).

* Treatment B: Catapres-TTS 7.0 cm2 system applied 15 minutes after dermal pretreatment with

TABLE I

Concurrent Antihypertension Medications

Patient No. Medication(s)

Metoprolol, hydrochlorothlazide Metoprolol, hydrochlorothlazide, captopril Metoprolol, hydrochlorothiazide, hydralazine Metoprolol, hydrochlorothiazide, hydralazine Hydrochlorothiazideir~amterene, metoprolol Verapamil Metoprolol, hydrochlorothlazide, enalaprll Enalaprll Clonldine (discontinued 5 weeks prior) Enalaprll

2 mL of magnesium-aluminum hydroxide suspension (Aloxgel, Vans; Los Angeles, CA). This suspension was applied with a 2-inch by 2-inch gauze dressing, allowed to dry, and lightly brushed until it formed a thin haze on the skin.

0 Treatment C: Catapres-TTS 7.0 cm2 system applied without any dermal pretreatment.

The 10 patients in our study were taking at least one other antihypertensive agent concurrently with transdermal clonidine. All subjects continued to take the other antihypertensive agents without altering their regimen during the study (Table I).

Exclusion Criteria Patients were excluded from our study for the

following reasons: pregnancy or breast feeding; exposure to clonidine within 2 weeks prior to enroll- ment; type 1 allergic reactions to oral or transder- ma1 clonidine, hydrocortisone, magnesium-aluminum hydroxide suspension, or any of their compo- nents; severe hypertension (diastolic 2115 mm Hg); anergy; treatment with oral steroids, antihis- tamines, or any other immunosuppressive medications; fungal infections; tuberculosis of the skin; herpes simplex; impaired renal function (serum creatinine greater than 2.0 mg/dL); hepatic dysfunc- tion (SGOT or SGPT >200 IU or total bilirubin >3.0 mg/dl); congestive heart failure (New York Heart Association functional class 3 or 4), myocar- dial infarction, or serious arrhythmias; resting diastolic blood pressure <90 mm Hg and systolic blood pressure ~140 mm Hg prior to treatment with clonidine; or cerebrovascular disease such as cerebral ischemia or hemorrhage.

Treatment Protocol Prior to dermal pretreatment and application of

the transdermal system, each subject’s skin was cleaned with a hypoallergenic soap (Cuticura, Dep Corporation, Los Angeles, CA) and allowed to dry.

Each clonidine transdermal treatment was applied to a hairless area of intact skin on the upper

July 18, 1991 The American Journal of Medicine Volume 91 (suppl 1A) lA43S

arm or torso. The adhesive overlay that is provided with each system was applied directly over the patch. Each system was removed after 7 days, and a 14-day washout ensued. Following each washout period, patients were crossed over to receive one of the alternative treatments, with each patient receiving all three treatments over a period of 52 days. During the washout periods, all subjects continued to take the other antihypertensive agents in their regimen without change.

At each visit, three supine and three sitting blood pressure readings, as well as three pulse rates, were obtained with an automatic digital sphygmo- manometer (Pipeer #246, NelkiniPiper Interna- tional; Kansas City, MO). The average of the three readings was used to determine the blood pressure and pulse values for any given visit. Venous blood samples (of 5 ml) were drawn in heparinized tubes immediately prior to the application of each system, and venous blood samples were then drawn daily for the next 11 days.

Assay Methodology All blood samples were centrifuged and the

plasma removed. Plasma, urine, and removed transdermal systems were immediately frozen at approximately -20°C until analysis of clonidine levels could be made by radioimmunoassay [15].

Pharmacokinetic Analysis Pharmacokinetic parameters for clonidine were

estimated using the following equations. The area under the concentration (AUC) versus time curves from 0 to 11 days (AU&,,) and 4 to 7 days (AUGm7) were calculated for each treatment with linear-trapezoidal methods 1161. The AUCp7 was used to determine the steady-state plasma concentration using the following relationship:

C,, = AUG-& - tY where t4 - t7 is the time difference between the plasma samples collected on days 4 and 7. The percent fluctuation (Fl) during steady-state was calculated from the following equation:

Fl xz C maxo - Gain x 1oo uss

where C,,, and Cmin are the maximum and mini- mum plasma clonidine concentration determined by visual inspection of the concentration time plots between days 4 and 7.

The relative extents of absorption (F,,,) of treatments A and B, relative to C, were determined by the following expression:


where ptAUCc,-,,, and AUC,,-,, are each subject’s AUC values for dermal pretreatment (treatments A and B) and no pretreatment (treatment C), re- SpeCtiVely. DoseApp and ptdoseApp are the apparent delivered dose with no dermal pretreatment and with pretreatment, respectively. The doseApp was calculated from the difference between the ini- tial total labeled content of the patch and the resid- ual content of each transdermal patch, assayed following removal of the transdermal system.

To determine clonidine urinary excretion rates, renal clearance, and creatinine clearance, urine was collected for 24 hours, beginning on the fourth day of each of the three treatment regimens.

Statistical Analysis Mean blood pressure, pulse, and pharmacokinetic

indexes generated from the different treatments were analyzed using the Friedman two-way analysis of variance test. Differences between two means were analyzed using the Wilcoxon sign rank test [17]. A sample size of 10 was deemed necessary in order to conclude correctly a 30% change in clonidine C,, with dermal pretreatment at an alpha level set at 0.05 and the power of the test (1-p) of 0.80.

ASSESSMENT OF SIDE EFFECTS During and following each treatment phase, pa-

tients were questioned daily about the systemic side effects commonly associated with clonidine therapy, including dry mouth, sleepiness, fatigue, constipation, dizziness, and impotence.

Following removal of each transdermal system, the application site was observed for signs of edema, hyperpigmentation, erythema, vesicula- tion, or contact dermatitis. Complaints of pruritis were also noted.

RESULTS The demographic characteristics of our patients

are shown in Table II. Patients tended to be slightly obese, with an average body weight ex- ceeding lean body weight by 23%. Four patients had moderate renal insufficiency based on an average of three measured creatinine clearance determinations. Patients number 2, 3, 7, and 9 had mean measured creatinine clearance values of 60.0 (? 4.7), 70.5 (+- 7.3), 49.0 (* 12.7), and 70.4 (* 1.9) mlimin, respectively.

Hemodynamics Mean reduction in blood pressure on day 4 (pre-

sumed steady-state) and day 7 were compared to baseline for each treatment (Figure 1). Baseline mean ? SD systolic and diastolic blood pressures



TABLE II

Individual Patient Demographic Characteristics

Patient Sex and Age Weight Actual Weight* Lean Height Creatininet Clearance Number Race (years) (kd (kg) (inches) (mlimin)

M/C M/C M/C

ii 73

M/B 61 110.9 66.1 67.0 117.2 z Ml6 M/B 2 115.5 88.9 59.2 63.8 64.0 66.0 107.3 94.3

; M/C M/C iii 91.5 82.7 63.8 70.7 66.0 69.0 82.0 49.0

PO M/B M/C z: 85.9 76.8 66.0 70.7 69.0 63.8 90.6 70.4

Mean 62 SD 11

*Lean body weight = 50 kg + 2.3 kg for every Inch over 5 feet. tMean of three determinations by 24.hour urine collections.

90.4 14.8

69.8 9.7

67.4 2.9

84.4 22.0

for treatments A, B, and C were, respectively: 159.8 (? 17.7) over 97.5 (? 15.5); 156.9 (i 14.6) over 93.2 (+ 9.0); and 152.3 (2 16.2) over 88.8 (k 8.1) mm Hg.

Baseline blood pressure prior to treatment C appeared to be lower than those pressures obtained prior to treatments A and B; however, no statistical differences were noted. Reductions in both systolic and diastolic blood pressure compared to baseline were observed on days 4 and 7 following dermal pretreatment with hydrocortisone and magnesium- aluminum hydroxide suspension (p ~0.05). Follow- ing treatment with transdermal clonidine alone a significant reduction in blood pressure was observed on day 4, but this reduction was only for systolic blood pressure (p ~0.05).

Pharmacokinetics The mean plasma concentration-time profiles

(Figure 2) and pharmacokinetic indexes are pre- sented in Tables III and IV. The calculated mean

AUC~o-ll, for treatment A (patch plus hydrocortisone cream) was larger than the AUC,,-,,, for treatments B (patch plus magnesium-aluminum hydroxide suspension) and C (patch alone). How- ever, these differences were not statistically significant (p = 0.12). The observed C,, and C,, following treatment A were significantly greater than those during treatment C. No significant differences in C,,, and C,, were observed between treatments B and C.

Urinary excretion rates of clonidine within and among patients were relatively constant. More- over, mean urinary excretion rates between treatments were not statistically different. An average percent fluctuation was calculated to measure the stability of plasma clonidine concentrations at steady-state. No detectable differences in percent fluctuation were observed among the various treatments. The apparent doses delivered to each subject by the various treatment modalities are listed in Table IV. The mean apparent doses delivered

L

-40

t Systolic Diastolic Systolic Diastolic

-45 (day 4) WY 4) (day 7) WY 7)

Figure 1. Mean reduction in systolic and diastolic blood pressures on days 4 and 7 relative to baseline for each treatment. Filled bars = with hydrocortisone; white bars = with magne- sum-aluminum hydroxide suspension; gray bars = with TK patch alone.

July 18, 1991 The American Journal of Medlclne Volume 91 (suppl 1A) lA4S


g 1.4

E 6 1.2 li; s 1.0 E : 0.8 8 g 0.6 3 6 0.4 5

2 0.2 3 Q 0 5 0 1 2 3 4 5 6 7 8 9 IO 11

r” t System Applied

Time (days) t System Removed

Figure 2. Mean plasma clonidine concentration- time profile in 10 patients. TX A and TX I3 are transdermal clonidine therapy following dermal pretreatment with hydrocortisone cream and magnesium-aluminum hydroxide suspension, respectively. TX C refers to transdermal clonidine therapy alone. l = TX A; H = TX 6; A=TxC.

TABLE III

Individual and Mean (2 SD) Pharmacokinetic Parameters of Transdermally Administered Clonidine, Alone and Following Dermal Pretreatment

Patient No. Treatment* AUC (ng + hrlml) C,, (rigid C,,, (ns/mL) C7Gn MmL)

1 A 153.95 1.01 1.15 0.88 8 158.83 0.86 1.01 0.74

2

3

! 144.75 142.89 0.83 0.80 0.87 1.22 0.59 0.73 4 A 205.82 1.28 1.53 1.30

F 120.65 153.73 0.68 0.99 0.73 1.07 0.64 0.71 5 A 61.90 0.54 0.73 0.17

CB 53.34 27.68 0.42 0.14 0.58 0.17 0.17 0.11

6 A 178.56 1.26 1.49 1.09 F 181.51 13286 0.81 1.27 0.93 1.52 0.59 1.00

7 A 137.37 0.85 0.89 0.79

F 64.06 49.31 0.39 0.32 0.47 0.36 0.17 0.24 8 A 310.09 1.93 2.12 1.81

c” %T 1.16 1.21 1.25 1.32 0.85 1.12

9 A 49.75 0.47 0.53 0.22 43.17 0.37 0.52 0.24

103.11 0.55 0.76 0.46 10 80.58

69.60 32.44

Mean (2 SD) A 166.17 1.05 1.23 0.87 8 186.04) 128.84 ‘;:;;I

c

p-value

‘;:J;’ (0.34) 0.045t

reatments A, 6, and C refer to dermal pretreatment with hydrocortisone, magnesium-aluminum hydroxide, and no dermal pretreatment, respectively. ignificant difference; treatment A compared with treatment C; other comparisons = nonsignificant.



TABLE IV

individual and Mean (k SD) Pharmacokinetic Parameters of Transdermally Administered Clonidine, Alone and Following Dermal Pretreatment

No. Treatment* Percent Fluctuation

(“4 Urine Excretion Rate

(mcgihr) Renal Clearance

b’hr)

Apparent Dose Delivered

(md

Relative Extent of Absorptiont

(%I - 1 94.40

130.99 -

25.79 2.64 2.42 2.38 44.25 5.67 2.96 2.63 2.04 1.95 2.49 1.91

14.29 3.64 3.52 2.58 46.40 4.03 6.10 2.99 9.33 4.15 5.35 2.30

19.92 11.16 7.75 2.99 18.33 7.10 3.63 3.85 4.44 5.48 2,13 2.18

34.44 2.85 6.35 3.02 20.07 39.08 3.25 1.92 12.37 13.33 2.94 2.46

18.02 13.28 11.45 4.42 19.49 13.97 13.41 4.29

79.76 86.22

119.35 60.37

121.54 98.98

9ii3 43.43

lT1.37 122.93

10.76 40.40 65.96 76.58 54.99 29.22 49.92 41.06

7.58 3.86 2.89 2.20 2.80 0.56 5.50 0.15 5.88 1.55 5.79 6.59 4.42 3.11 4.02 5.84 9.97

11.56

1.17 0.97 3.10 1.22 2.11 2.01 1.31 1.45

18.99 34.80

90.36 79.85

354 72.42

179.22 237.52

- Mean (i SD]

94.84 (45.69) 97.65

(59.03) -

p-value “$3’ ‘;:;;I (;:;;I (1.02)

0.0033t reatments A, B, and C refer to dermal pretreatment with hydrocortlsone, magnesium-aluminum hydroxide, and no dermal pretreatment. respectively. Determined in respect to therapy without dermal pretreatment (Treatment C). Nlgntflcant difference, treatment A compared with treatment C: other comparisons = nonslgnlflcant.

0.88

and following treatments A, B, and C were, respectively: 2.81 (2 0.86), 2.20 (Z!Z 1.13), and 2.03 (t 1.02) mg. The doseApp was significantly greater when treatment A was compared to treatment C. No difference in the doseApp was noted between treatments B and C. Mean relative extents of absorption following treatments A and B, relative to C, were 94.84% (+- 45.69%) and 97.65% (+ 59.03%). No statistical differences were observed in these indexes.

DISCUSSION Transdermal clonidine has certain obvious advan-

tages over orally administered antihypertensive medications: It delivers drug at more even levels, and it is easier to administer. This convenience of dosing, coupled with its established efficacy, is thought to improve compliance, especially in those

patient groups least likely to take their medications as scheduled.

For all its advantages, however, this mode of therapy is hampered by a small but significant number of dermal reactions, which lead to discontinua- tion in approximately 16% of patients [9,10,12]. Cli- nicians have therefore tried using various prophy- lactic measures-the most common of which are pretreatment with 0.5% hydrocortisone or magnesium-aluminum hydroxide suspension-to alleviate this problem. Our study sought to characterize the effects of the two most frequently used dermal pretreatment strategies on the pharmacokinetics and pharmacodynamics of transdermally administered elonidine.

Results in 10 patients indicate that dermal pretreatment with 0.5% hydrocortisone cream alters the systemic availability of transdermal clonidine. The C,,,, C,,, and the apparent dose delivered fol-

July 18, 1991 The American Journal of Medicine Volume 91 (supp! 1A) IA47S

lowing dermal pretreatment with hydrocortisone were statistically higher compared to those generated without dermal pretreatment. Dermal pretreatment, relative to the patch alone, did not adversely affect the normal fluctuation in clonidine concentration-time profiles. The steady-state clonidine concentrations achieved for all treatments, following an average dose delivered of approximately 2.3 mg over a 7-day period, were within the defined therapeutic window of 0.2 to 2 ng/mL [5-81.

In a recent study, MacGregor et al assessed the dose linearity of increasing sizes of transdermal clonidine systems (3.5, 7.0, and 10.5 cm2 size) in six subjects without dermal pretreatment [18]. The mean urinary excretion rate in that trial, following application of a 7.0 cm2 system, was 5.56 (? 3.08) mcg/hr. This value is consistent with the urinary excretion rate determined in the present study. The mean clonidine C,, without dermal pretreatment in our study (0.73 +- 0.34 ng/mL) is consistent with the mean clonidine C,, (0.84 +- 0.31 ng/mL) reported by MacGregor. However, when clonidine therapy was preceded by hydrocortisone treatment, mean clonidine C,, (1.05 ? 0.47) exceeded the aforementioned concentration by approximately 32% (0.73 ng/mL compared to 1.05 ng/mL).

The mechanism for this increased systemic availability of clonidine following dermal pretreatment with hydrocortisone cannot be addressed by the current study; we can only speculate on the reasons for the changes we observed. In general, the drug vehicles used for topical steroid applications are designed to increase spontaneous penetration of the active medication. A variety of substances, some of which are contained in the brand of 0.5% hydrocortisone cream used in this study, have been identi- fied as promoters of percutaneous absorption. These include such substances as dimethylsulfoxide (DMSO), propylene glycol, oleic acid, and various alcohols. It has been suggested that these compounds may act through both specific and nonspe- cific derangement of barrier function, thus enhanc- ing absorption of selected molecules [19,20]. How- ever, we are not aware of any published data that identify such compounds as enhancers of clonidine penetration.

Another possible, but less likely, hypothesis is that an increased clonidine depot within the stratum corneum-secondary to a decrease in mitotic rate and to turnover of epidermal cells induced by occlusive glucocorticoid administration-may help to explain these observed differences 1211.

Despite the increase in clonidine C,,, and C,, following dermal pretreatment with 0.5% hydrocortisone cream, hemodynamic parameters between


treatments were not statistically different. The in- significant reductions in mean blood pressure, compared to baseline, following therapy without der- ma1 pretreatment could be the result of a type 2 statistical error due to the relatively small sample size.

Although our study was not designed to assess the effect of dermal pretreatment on the incidence of adverse skin reactions, skin reactions observed in these patients were more frequent following der- ma1 pretreatment with magnesium-aluminum hydroxide or with the patch alone. Due to the low expected frequency in each cohort, we were unable to determine, statistically, if the frequency of der- ma1 reactions was influenced by the various treatments.

Our results show that dermal pretreatment with 0.5% hydrocortisone cream does appear to affect the pharmacokinetics of transdermally administered clonidine. Further studies are needed to elu- cidate the mechanism by which absorption is en- hanced through pretreatment with hydrocortisone and to determine if pretreatment modalities can reduce or prevent skin reactions to transdermal clonidine.

ACKNOWLEDGMENT The authors acknowledge the assistance of Thomas R. MacGregor, Ph.D., of the Department of Research and Development at Boehringer lngelheim Pharmaceutr- cals for assaying clonidine; Brigitte To, Pharm.D., and Justine Cervenka, R.T., of the VA Medical Center; and Mrchael Mergener, Ph.D., of the University of the Pacific.

REFERENCES 1. Breimer DD. Ratronale for rate-controlled drug delivery of cardiovascular drugs by the transdermal route. Amer Heart J 1984; 108: 196-200. 2. Popli S, Stroka TS, Daugrrdas JT, et al. Transdermal clonidine for hypertensive patients. Clin Ther 1983; 5: 624. 3. Weber MA, Drayer JIM, McMahon GF, et al. Transdermal administrabon of clonidine for treatment of high blood pressure. Arch Intern Med 1984; 144: 1211-3. 4. Transdermal clonidine for hypertension. Med Lett 1985; 27: 95-6. 5. Arndts D, Arndts K. Pharmacokinetics and pharmacodynamics of transdermally admrristered clonidine. Eur J Clin Pharmacol 1984; 26: 79-85. 6. Frisk-Holmberg M, Paalzow L, Wibell L. Relationship between the cardiovascular effects and steady-state kinetics of clonrdrne in hypertension. Eur J Ciin Pharmacol 1984; 26: 309-13. 7. Boekhorst JC, Lustermans F, van Tol R. Transdermal administration of clonidine for treatment of mild-to-moderate essential hypertension. Current Therapeutic Re- search 1987; 41: 215-25. 8. Burris JF, Mroczek WJ. Transdermal administration of clonidine: A new approach to antihypertensive therapy. Pharmacotherapy 1986; 6: 30-4. 9. Maibach H. Clonidine: Irritant and allergic contact dermatitis assays. Contact Dermatitrs 1985; 12: 192-5. 10. Boekhorst JC. Allergic contact dermatitis with transdermal clonidine. Lancet 1983; 2: 1031-2. 11. DickJB, eta/. Skin reactions to long-term transdermal clonidrne. Lancet 1987; 1: 516. 12. Groth H, Vetter H, Knuesel J, et a/. Allergic skin reactions to transdermal clonidine. Lancet 1983; 2: 850-l. 13. Matzek, KA. Boehringer Ingelherm. Wrrtten communication. December 2, 1988. 14. Matzek, KA. Boehringer Ingelheim. Personal communication. 1989.

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15. Farrna PR, Homon CA, Chow CT, ei al. Radroimmunoassay for clonidrne rn 19. Vlckers CFH. Stratum corneum reservorr for drugs, In: Montagna W, Van Slott EJ, human plasma and urine usrng a solid phase second antibody separation. Ther Drug Stoughton RB, eds. Pharmacology and the skin. New York: Appleton-Century-Crofts, Monitorrng 1985; 7: 344-50. 1972: 177-89. 16. Gibaldr M, Perrier D. Pharmacokrnetics. New York: Marcel Dekker, 1982: 409- 17. 17. SOLO. Los Angeles, CA: BMDP Statistical Software, 1989. 18. MacGregor TR, Matzek KM, Keirns JJ, et a/. Pharmacokrnebcs of transdermally delivered clonrdrne. Ckn Pharmacoi Ther 1985; 38: 278-84.

20. Guy RH, Hadgraft J. The effect of penetration enhancers on the kinehcs of percutaneous absorption. J Controlled Release 1987; 5:43-51. 21. Barry SW, Southwell D, Woodford R. Optimization of broavarlability of topical steroids: Penetration enhancers under occlusron. J Invest Dermatol 1984 82:49- 52.

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