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Nitrate tolerance in angina therapy. How to avoid it.

Tolerance is the attenuation, or loss, of one or several of the effects of organic nitrates after long term administration. All organic nitrate regimens using frequent doses of long-acting nitrates (3 or more times daily), continuous delivery systems [transdermal nitroglycerin (glyceryl trinitrate) patches or continuous intravenous infusions of nitroglycerin] or long-acting (sustained release) preparations will result in partial or complete nitrate tolerance. There are several proposed mechanisms which may contribute to the development of tolerance including activation of neurohormonal mechanisms, plasma volume expansion and depletion of intracellular sulfhydryl cofactors. To avoid tolerance to long term nitrate therapy, regimens should be tailored to provide a 10- to 12-hour nitrate-free interval when possible. This means that antianginal prophylaxis can only be provided by nitrate therapy for some portion of each day, and that some patients will develop an increase in angina in the nitrate-free intervals which will necessitate short term therapy with sublingual nitroglycerin or a similar preparation.

Administration, Sublingual↗

Different impact of carvedilol and transdermal scopolamine on cardiovascular performance of mild-moderate chronic heart failure patients: evidence of useful effects of scopolamine on tolerance to work load.

OBJECTIVES: To verify and compare the effects respectively exercised in chronic heart failure patients by transdermal, slow release scopolamine patch and by the beta and alfa adrenoreceptor blocker carvedilol upon the main indexes derived from maximal cardiopulmonary stress test, as well as from analysis of heart rate variability. METHODS: In each of 14 patients suffering from NYHA class II chronic heart failure, admitted to study, the maximal cardiopulmonary test and heart period power spectrum assessment were performed, firstly during usual therapy, then after 7 days of continuous adjunctive treatment with scopolamine patch, and, finally after 3 months of regular administration of oral carvedilol, added to the basal therapy. The need of time enough to the adaptation of the cardiovascular system against the carvedilol pharmacodynamics, together with the need of slow, progressive dose titration, caused that the onset of therapy with carvedilol was separated from assessment of its effects on ergometric and spectral parameters by an interval period of 3 months. RESULTS: During administration of low doses of scopolamine, the values of VO2max, exercise time and double product were respectively 24 +/- 5.3 ml/kg/min, 12 +/- 3 min and 23630 +/- 3760, and resulted significantly higher than basal (p < 0.05 in all cases) and carvedilol-related readings (p < 0.01 by comparisons with VO2max and double product; p < 0.05 by comparison with exercise time). Again during scopolamine, the total variance, LF and HF powers exhibited the values reported as follows: 1255 msec2 and, respectively, 430 and 250 msec2, thus exceeding significantly the basal levels (p < 0.05 from comparison with total power, p < 0.01 from comparisons with LF and HF bands) as well as the levels reached during adrenergic blockade with carvedilol (LF scopolamine vs LF carvedilol: p < 0.01; total power and HF scopolamine vs corrispective carvedilol values p < 0.05). Compared to the basal findings, the carvedilol induced a significant reduction in VO2max (p < 0.05), double product (p < 0.01), peack of heart rate (p < 0.05) and LF power (p < 0.05), and elicited no significant decreases in exercise time; similarly a weak, not significant surge was product by carvedilol in total and HF powers. CONCLUSIONS: Therefore, in patients with left ventricle asymptomatic dysfunction, the low doses of scopolamine potentiate simultaneously the spontaneous heart rare variability and cardiopulmonary maximal testing; whereas, the carvedilol acts upon LF oscillatory component only, the effects upon total variance and HF band being negligible; moreover, this drug depress the myocardial functional capability; in fact, the carvedilol has been demonstrated to produce a remarkable fall in VO2max, this significant reduction in O2 maximal uptake involving the poor rise in cardiac output during the effort or less effective O2 removal from capillary beds or both.

Administration, Cutaneous↗

[The use of analgesics in Denmark, 2000-2004].

INTRODUCTION: The purpose of this survey was to map the sale of analgesics in the Danish primary care sector from 2000 to 2004. MATERIALS AND METHODS: Data on analgesics and NSAIDs were drawn from the Register of Medicinal Products Statistics. Sales in 2004 and changes from 2000 to 2004 are treated with descriptive statistics. Our focus was on analgesics bought on prescription. RESULTS: In 2004, approximately 580,000 persons bought an analgesic on prescription. Including NSAIDs it is a total of approximately 1.16 million people. Between 2000 and 2004, the number of users increased by 10%. STRONG OPIOIDS: The number of users was almost unchanged from 2000 to 2004. Most people bought ketobemidone and morphine, even though the number of these users decreased. In contrast, the number of oxycodone users increased greatly. Several-time users of oxycodone are often new users of strong opioids. Likewise, the number of users of transdermal fentanyl and buprenorphine patches increased. WEAK OPIOIDS: The number of users increased by approximately 31,000 (10%), due to a greater number of users of tramadol, while the number of users of other weak opioids decreased. Thirty percent of several-time users of tramadol had not previously bought other analgesics on prescription. NSAIDs: The number of users increased by approximately 95,000 (13%). After 2002, the number of coxib users decreased concurrently with an increased usage of other NSAIDs. After coxib treatment, 29% of several-time users did not shift to other analgesics bought on prescription. WEAK NON-OPIOIDS: The number of users increased by approximately 42,000 (15%). The majority were users of paracetamol. CONCLUSION: In 2004, every fifth Danish citizen bought analgesics on prescription. Between 2000 and 2004, the number increased. In particular, the number of users of NSAIDs was large. The number of users of strong opioids did not increase as did the number of users of the other groups of analgesics, but within that group there was a shift to more expensive drugs.

Analgesics, Non-Narcotic↗

Effects of transdermal nicotine delivery on measures of acute nicotine withdrawal.

The effects of transedermal nicotine on acute physiologic, performance and subjective measures of tobacco withdrawal were evaluated in a residential, double-blind, placebo-controlled, crossover study. Ten subjects smoked ad libitum for 4 days and underwent monitored tobacco abstinence for 3 days. On no-smoking days, three transdermal nicotine delivery systems (patches) that delivered a total of 0, 10, 20 or 30 mg of nicotine were applied for 16 hr. Experimental measures were collected 6 hr after the application of the patches. Plasma levels of nicotine and cotinine indicated that the 20- and 30-mg treatment condition fully replaced the nicotine ordinarily obtained from smoking. During nicotine abstinence (0 mg condition) typical signs of tobacco withdrawal were evident including: decreases in pulse rate, increases in electroencephalographic theta power, increases in subjective measures of tobacco abstinence and slowed performance on computer-delivered cognitive tests. Nicotine patch treatment diminished the physiologic and performance changes, but subjective measures of tobacco abstinence (cigarette craving, increases in withdrawal scores) were not significantly reduced. These data indicate that the nicotine patch may be used to diminish aspects of tobacco abstinence that could affect performance even though withdrawal discomfort may persist.

Administration, Cutaneous↗

[The role of nicotinic receptor in memory impairment: a study using event-related potentials and midlatency responses].

To evaluate the efficacy of chronic nicotine administration in dementia, electrical field distributions of event-related potentials (ERPs) and midlatency response (MLR) were recorded and were analyzed in terms of time and space. The study was carried out on 22 normal individuals and 17 patients with dementia (vascular dementia, Alzheimer disease and Parkinson disease). Nicotine was delivered transdermally from a nicotine patch (22.5 to 52 mg/day) for 2 or 4 weeks. Dementing patients showed abnormal ERPs in latency, amplitude and electrical field on the scalp. Decreased amplitude and electrical field abnormality of P1 in MLR was also seen in some patients with dementia. These abnormal ERPs and MLR of the patients improved after administration of nicotine especially in P300 latency of ERPs and P1 amplitude of MLR. These data suggest that nicotine administration might be useful as a cognitive enhancer in memory impairment.

Dementia↗

Quitting chew: results from a randomized trial using nicotine patches.

The authors examined the efficacy of transdermal nicotine replacement for cessation in 410 adult nonsmoking chewing tobacco users. Participants were randomly assigned to 6 weeks of 15-mg nicotine patch plus behavioral treatment or placebo patch plus behavioral treatment. All participants received the same behavioral treatment of 2 pharmacy visits, 2 support calls, and self-help materials. At 6 months after treatment, biochemically confirmed point-prevalence rates (no chewing in the last 7 days) in the active (38%) and placebo (34%) groups were high and not significantly different. The difference in relapse (no chewing for 7 consecutive days) between the active patch group (33%) and placebo group (48%) was significant at 6 months (p = .003). Nicotine dependence and age predicted nonrelapse at 6 months. The results suggest that nicotine replacement may improve chewers' chances of abstinence.

Administration, Cutaneous↗

Allergic and nonallergic reactions to nitroglycerin.

Allergic and nonallergic reactions to nitroglycerin occur. The aims of this study were to review the different manifestations of nitroglycerin allergy, to explain how to evaluate for it, and to discuss its treatment. We reviewed relevant literature in peer-reviewed journals, computerized databases, and references identified from relevant bibliographics. Nitroglycerin's most common side effects are headache, facial flushing, head throbbing, fainting, hypotension, tachycardia, and syncope. The majority of reported skin reactions to topical and transdermal nitroglycerin products are irritant contact dermatitis, allergic contact dermatitis, and urticaria. Five cases of presumed allergic reactions to oral, sublingual, intravenous, or perianal nitroglycerin products have been described. Patch testing may be helpful in subjects with skin reactions to topical or transdermal nitroglycerin. In subjects with positive patch tests to nitroglycerin (allergic contact dermatitis), transdermal nitroglycerin patches and other topical nitroglycerin products should be avoided. Most patients with contact dermatitis to nitroglycerin have tolerated oral nitroglycerin, sublingual nitroglycerin, or oral isosorbide challenges.

Diagnosis, Differential↗

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine.

The alkaloid L-(-)-scopolamine [L-(-)-hyoscine] competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar to atropine (racemate of hyoscyamine), is used in conditions requiring decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands, and in special circumstances for a CNS action. Therefore, scopolamine is most suitable for premedication before anesthesia and for antiemetic effects. This alkaloid is the most effective single agent to prevent motion sickness. Scopolamine was the first drug to be made commercially available in a transdermal therapeutic system (TTS-patch) delivering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liquid chromatographic-tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM injection). Scopolamine has a limited bioavailability if orally administered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmetabolized L-(-)-scopolamine is excreted in urine, a first-pass metabolism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 microg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 microg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (Cmax) of approximately 100 pg/mL (range 11-240 pg/mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56-245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion. Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with beta-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these results from enzymatic hydrolysis of scopolamine metabolites, the glucuronide conjugation of scopolamine could be the relevant pathway in healthy volunteers. However, scopolamine metabolism in man has not been verified stringently. An elucidation of the chemical structures of the metabolites extracted from human urine is still lacking. Scopolamine has been shown to undergo an oxidative demethylation during incubation with CYP3A (cytochrome P-450 subfamily). To inhibit the CYP3A located in the intestinal mucosa, components of grapefruit juice are very suitable. When scopolamine was administered together with 150 mL grapefruit juice, the alkaloid concentrations continued to increase, resulting in an evident prolongation of tmax (59.5 +/- 25.0 minutes; P < 0.001). The AUC0-24h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (P < 0.005). Consequently, the related absolute bioavailabilities (range 6% to 37%) were significantly higher than the corresponding values of the drug orally administered together with water (range 3% to 27%). The effect of the alkaloid on quantitative electroencephalogram (qEEG) and cognitive performance correlated with pharmacokinetics was shown in studies with healthy volunteers. From pharmacokinetic-pharmacodynamic modeling techniques, a direct correlation between serum concentrations of scopolamine and changes in total power in alpha-frequency band (EEG) in healthy volunteers was provided. The alkaloid readily crosses the placenta. Therefore, scopolamine should be administered to pregnant women only under observation. The drug is compatible with nursing and is considered to be nonteratogenic. In conclusion, scopolamine is used for premedication in anesthesia and for the prevention of nausea and vomiting associated with motion sickness. Pharmacokinetics and pharmacodynamics of scopolamine depend on the dosage form. Effects on different cognitive functions have been extensively documented.

Humans↗

High local endometrial effect of vaginal progesterone gel.

Our objective was to investigate the first-pass effect to the uterus of progesterone gel administered vaginally. This was a prospective, randomized study of 32 postmenopausal women, attending our menopause clinic. All women used transdermal estradiol (50 microg/day, a patch each week) for 2 weeks. They used either vaginal progesterone gel or intramuscular progesterone in oil 50 mg after 24 h to oppose the transdermal estradiol. Serum progesterone levels and endometrial tissue progesterone levels were determined. Serum progesterone levels were higher in women who used the intramuscular rather than the vaginal route. Although serum progesterone levels in the vaginal group were lower than in the intramuscular group, the endometrial tissue concentration of progesterone was higher. It is concluded that progesterone gel, used vaginally, has a high local effect on the endometrium, without any systemic side-effects due to high plasma progesterone levels.

Administration, Cutaneous↗

Time and dose effect of transdermal nicotine on endothelial function.

Nicotine patches are available as an over-the-counter medication for aid in smoking cessation. This study was designed to determine how nicotine patch therapy over time and dose ranges used in smoking cessation programs in humans affects endothelium-dependent relaxations. Dogs were treated with nicotine patches (11, 22, or 44 mg/day) for 2 and 5 wk. Circulating nicotine and oxidized products of nitric oxide (NOx) were measured. Coronary arteries were prepared for measurement of isometric force and aortic endothelial cells were prepared for measurement of mRNA or NO synthase (NOS) activity. Circulating nicotine increased with increasing concentrations of nicotine patches. After 5 wk of treatment with 22 mg/day patches, circulating NOx was reduced but NOS activity was increased. NOS mRNA was similar among groups. Only after 5 wk of treatment with 22 mg/day patches were endothelium-dependent relaxations reduced to alpha(2)-adrenergic agonists, ADP, and the calcium ionophore A-23187. These results suggest a time and biphasic dose effect of nicotine treatment on endothelium-dependent responses that may be related to bioavailability of NO. This complex relationship of duration and dose of nicotine treatment may explain, in part, discrepancies in effects of nicotine on endothelium-dependent responses.

Adenosine Diphosphate↗

Comparison of transdermal and oral estrogen therapy in girls with Turner's syndrome.

Eight girls with Turner's syndrome were given low dose oral ethinyl estradiol or transdermal 17 beta-estradiol in order to compare the effect of the route of administration on selected markers of hepatic metabolism, and various hormonal concentrations. Oral estrogen was given at a dose of 100 ng/kg/day and transdermal estrogen via adhesive skin patch at 0.0125 mg/kg/day. The subjects received one form of estradiol for one month, and after a one month washout period, received the other form. Both oral and transdermal estradiol caused a significant decrease in FSH while only transdermal resulted in a significant decrease in LH. Oral estradiol, though not transdermal estradiol, increased serum high density lipoprotein, thyroxine binding protein and growth hormone binding protein. Urinary growth hormone excretion increased after both forms of therapy, while insulin-like growth factor-I and insulin-like growth factor binding protein-3 remained unchanged. Thus, in girls with Turner's syndrome, estrogen replacement by the transdermal route may have less deleterious effect on hepatic metabolism than oral estrogen.

Administration, Cutaneous↗

Transdermal nicotine: reduction of smoking with minimal abuse liability.

Cigarette consumption as well as the physiologic, performance and subjective effects of the nicotine patch were evaluated in ten subjects who smoked ad libitum while residing on a residential research ward for 30 days. Nicotine transdermal systems ("patches") delivering a total of 0, 22 or 44 mg per 24 h were applied daily at a constant dose during each 7-day condition; the order of dosing conditions was varied according to a randomized, double-blind, crossover design. Nicotine patches significantly but modestly reduced spontaneous smoking and significantly increased venous plasma nicotine levels. Self ratings of patch liking, satisfaction with cigarettes and the ability to identify the patch condition did not change as a function of the nicotine dose, indicating minimal abuse liability. There were no consistent changes in the puffing pattern measures; however, in all patch conditions, subjects with extensive histories of illicit drug use smoked cigarettes faster than subjects with histories of occasional drug use. Small changes in resting heart rate, pulse and blood pressure occurred when the nicotine patch was worn. Thus large changes in venous plasma nicotine levels engender only modest changes in ad libitum cigarette consumption, measures of abuse liability and cardiovascular effects. These findings are consistent with the notion that the addictive and toxic effects of nicotine are partially determined by the rate of drug administration.

Administration, Cutaneous↗

The transdermal contraceptive system.

The transdermal contraceptive system or contraceptive patch (Ortho EVRA, Ortho-McNeil Pharmaceuticals, Raritan, NJ), approved by the Food and Drug Administration in November 2001, is a novel combination hormonal contraceptive that contains the hormones norelgestromin and ethinyl estradiol. In clinical trials, the contraceptive patch was shown to have comparable safety and efficacy with that of oral contraceptives (OCs), and results indicated that the women who used the patch did so more correctly and consistently than those who used OCs. The enhanced patient compliance may be due to the once-a-week dosing and relative ease of use of this system. The transdermal delivery approach minimizes the "peaks and troughs" of hormone concentrations associated with daily oral administration and avoids hepatic first-pass metabolism. Side effects are similar to those seen with OCs with the exception of application site reactions that are obviously unique to transdermal delivery.

Administration, Cutaneous↗

Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men.

OBJECTIVE: Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD. DESIGN: This was a prospective, randomized, multicentre, parallel clinical trial where 227 hypogonadal men, mean age 51 years (range: 19-68 years) were studied in 16 academic and research institutions in the USA. Subjects were randomized to apply 1% T gel containing 50 or 100 mg T (delivering approximately 5-10 mg T/day) or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment occurred in the T patch group. MEASUREMENTS: Serum T, free T and oestradiol, bone turnover markers and BMD were measured on days 0, 30, 90 and 180 before and after treatment. RESULTS: Application of T gel 100 mg/day resulted in serum T concentrations 1.4 and 1.9-fold higher than in the T gel 50 mg/day and the T patch groups, respectively. Proportional increases occurred in serum oestradiol. Urine N-telopeptide/creatinine ratio, a marker for bone resorption, decreased significantly (P = 0.0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to baseline thereafter. BMD increased significantly both in the hip (+1.1 +/- 0.3%) and spine (+2.2 +/- 0.5%) only in the T gel 100 mg/day group (P = 0.0001). CONCLUSIONS: Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblastic activity markers for a short period, which resulted in a small but significant increase in BMD. Ongoing long-term studies should answer whether the observed increases in BMD are sustained or continue to be dependent on the dose of testosterone administered.

Administration, Cutaneous↗

Evaluation of mathematical models describing drug release from estradiol transdermal systems.

The in vitro release profiles of 13 patches of estradiol (from five marketed products) were determined by the paddle-over-disk method. The transdermal systems were membrane-controlled type or matrix diffusion-controlled type. The estradiol content of test aliquots of the dissolution medium was determined by HPLC. To analyze the release mechanism, several release models were tested such as zero order, first order, Higuchi, Weibull, Korsmeyer-Peppas, and Makoid-Banakar. The release profiles showed that the drug was released at a constant rate for three patches. The drug-release rate from the other 10 patches was not constant, and diminished with the square-root of time (Higuchi model).

Administration, Cutaneous↗

Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain.

Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrome beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.

Administration, Cutaneous↗

[Opioid intoxication. Inappropriate administration of transdermal fentanyl].

A 22-year-old male suffering from neuropathic pain in his right leg had sufficient analgesia with oral tilidin 300 mg per day. Nevertheless, the general practitioner decided to change the therapy to transdermal fentanyl. Having cut a fentanyl patch (50 micrograms/h) into pieces, he applied one-fourth of the patch; 60 min later the patient developed signs of opioid intoxication, including heavy sedation, nausea and respiratory depression. After the patch was removed another 60 min later, the patient made a complete recovery. The risks following inappropriate application of transdermal fentanyl are discussed.

Administration, Cutaneous↗

Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens.

OBJECTIVE: The aim of this study was to evaluate the impact of different hormone replacement therapy (HRT) regimens on mammographic breast density. STUDY DESIGN: Mammographic density was recorded in women participating in a population-based screening program. At first mammogram, all women were non-users of HRT, and thereafter reported continuous use of the same HRT regimen. The study population comprised 158 women: a total of 52 women were using continuous combined HRT (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 5 mg); 51 women were using low-dose oral estrogen alone (estriol 2 mg daily); and 55 women were using unopposed transdermal estrogen given as a patch (estradiol 50 micrograms/24 h). Films were coded and analyzed for mammographic density by an independent radiologist blinded to treatments. Mammographic density was classified according to Wolfe. RESULTS: An increase in mammographic density was much more common among women taking continuous combined HRT (40%) than for those using oral low-dose estrogen (6%) and transdermal (2%) treatment. The increase in density was already apparent at the first visit after starting HRT. During long-term follow-up, there was very little change in mammographic status. CONCLUSION: HRT regimens were shown to have different effects on the normal breast. There is an urgent need to clarify the biological nature and significance of a change in mammographic density during treatment and, in particular, its relation to symptoms and breast cancer risk.

Administration, Cutaneous↗