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PubMed1998

Acute effects of a transdermal nitric oxide donor on perifollicular and intrauterine blood flow.

BACKGROUND: Nitric oxide is a potent vasodilator and is involved in several physiological events during the female reproductive cycle. OBJECTIVE: The aim of this study was to determine the acute effects of a nitric oxide donor on ultrasound-derived indices of blood flow in the intact human uterus and ovaries during the follicular phase of the normal menstrual cycle. STUDY DESIGN: The plan was to perform an observational study of six healthy volunteers, recruited during days 9-12 from day 1 of the last menstruation. Subjects were scanned transvaginally, with B-mode and color Doppler imaging around 12.00, and 2 h after the application of a transdermal glyceryl trinitrate (GTN) patch 10 mg/24 h. The patch was then removed and the subjects were rescanned 2 h later. END-POINTS: The main outcome measures were the peak systolic velocity (PSV), time-averaged maximum velocity (TAMV) and the pulsatility index (PI) derived from flow velocity waveforms, in the left and right main uterine arteries, a radial artery and subendometrial vessels, and from vessels at the rim of the dominant ovarian follicle. RESULTS: One woman was scanned on day 9, two on day 10 and three on day 12 of the cycle. The median pretreatment values for endometrial thickness and follicular volumes were 7.2 mm (range 6.0-10.0 mm) and 3.1 ml (range 0.3-6.8 ml), respectively. GTN induced a significant (p < 0.05) increase in the PSV and TAMV in the subendometrial vessels in all subjects. There was a corresponding decrease in the PI in four cases. Changes in blood flow were reversible (50% of the changes in PSV, TAMV and PI were essentially reversed 2 h after the patch had been removed). In the uterine arteries, PSV and TAMV were significantly (p < 0.01) and progressively decreased with a concomitant significant (p < 0.01) increase in PI. There was also a tendency for the mean PI to decrease progressively in the vessels at the rim of the dominant follicle with decreased post-treatment values in four out of six subjects. CONCLUSIONS: GTN induces a reversible increase in subendometrial blood flow velocity during days 9-12 of the menstrual cycle. The expected circadian decrease in uterine artery blood flow seemed to be partly interrupted by GTN treatment. IMPLICATIONS: These data justify the implementation of randomized controlled studies to determine the potential beneficial effects of transdermal GTN on ovarian and uterine blood flow and function.

Administration, Cutaneous↗
PubMed2006

Current developments using emerging transdermal technologies in physical enhancement methods.

Transdermal drug delivery using patches offers many advantages, but is limited primarily by the stratum corneum barrier. Amongst the various methods to overcome this barrier, physical methods are gaining in popularity and commercial devices development. Macroflux, MTS and Silex are based on microporation, involving use of microneedles that pierce thereby bypassing the stratum corneum. Intraject , Powderject and Helios are based on needleless jet injectors wherein very fine, solid particulate drug, is fired directly into the skin, using high-pressure gas. Med- Tats incorporate use of modified drug-containing tattoos, which bind to the skin, wherein the drug is absorbed. CHADD is based on use of heat, which increases skin - permeation of drugs. High-power, pulsed lasers transmit positive mechanical forces to the skin and create intercellular channels into the skin transiently. Sonophoresis involves use of ultrasound, which transiently disrupts the stratum corneum barrier. This technique offers a non-invasive transdermal extraction of interstitial fluids of sampling body fluids. Modified Liposomes include Ethosomes (containing alcohol) and Transferosomes (containing surfactants), which have enhanced skin permeability. Pulsed magnetic fields may create transient pores in cell membranes, including skin, resulting in increased permeation. Iontophoresis is based on application of electric potential for enhancing the movement of substances to and from the body. Dupel, Ionzyme, Liposite, ETrans, Phoresor and Drionic are based on iontophoresis. GlucoWatch offers non-invasive blood glucose monitoring, based on reverse iontophoresis. This review outlines recent commercial developments in physical transdermal drug delivery technology and the specific devices and applications being targeted by the pharmaceutical industry.

Adjuvants, Pharmaceutic↗
PubMed2004

Augmentation of growth hormone secretion after testosterone treatment in boys with constitutional delay of growth and adolescence: evidence against an increase in hypothalamic secretion of growth hormone-releasing hormone.

The increase in pituitary GH secretion that occurs during mid-late puberty in boys follows an increase in circulating testosterone (T) concentration; the direct mechanism by which this occurs is unknown. We hypothesized that T increases GH secretion during puberty by augmenting hypothalamic output of GHRH. Using constant infusions of a GHRH antagonist, we tested this hypothesis in six early pubertal boys with constitutional delay of growth and adolescence who had a mean chronological age of 14.0 +/- 0.3 yr and mean bone age of 11.4 +/- 0.2 yr. Blood samples were obtained from subjects every 15 min for 24 h during the overnight infusion of normal saline (2000-0600 h) and again during the overnight infusion of GHRH antagonist (0.33 microg/kg/h) the following night. Subjects then received transdermal T (5-mg patch) for 12 h nightly and were studied again after 4 wk of treatment. Serum samples were assayed for GH and total ghrelin; the percent suppression of GH during GHRH antagonist infusion was calculated. Morning serum T rose from 0.44 +/- 0.09 to 4.43 +/- 0.74 microg/liter (P = 0.005). T treatment was associated with a 92.6% increase in mean nocturnal GH secretion area under the curve (830 +/- 177 to 1599 +/- 340 microg/24 h.liter). Infusion of GHRH-antagonist suppressed mean nocturnal GH area under the curve by 29.1% before T treatment (830 +/- 177 to 621 +/- 168 microg/24 h.liter), and by 29.4% after T treatment (1599 +/- 340 to 1182 +/- 249 microg/24 h.liter; P = 0.99). Somatotroph sensitivity to GHRH was tested with 0.1- and 1.0-microg/kg doses of GHRH-44 iv; GH response did not change with regard to T treatment. The mean 24-h concentration of total ghrelin was unchanged with regard to T treatment. In summary, nightly transdermal T administration in six boys with constitutional delay of growth and adolescence increased GH output almost 2-fold, whereas the degree of GH suppressibility by GHRH antagonist remained unchanged. We conclude that the T-associated augmentation of GH secretion during early puberty in boys is unlikely to involve an absolute increase in hypothalamic GHRH output.

Adolescent↗
PubMed1997

The effect of continuous versus intermittent treatment with transdermal nitroglycerin on pacing-induced preconditioning in conscious rabbits.

1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.

Administration, Cutaneous↗
PubMed1992

[Transdermal nitroglycerin in patients with stable angina].

PURPOSE: To evaluate the nitroglycerin patches efficacy and tolerability in patients with stable angina pectoris. METHODS: One thousand and five hundred and thirty nine patients with stable angina pectoris, mean age 61.0 +/- 10.3, 891 men and 648 women were prospectively evaluated by five hundred and thirty five specialists after 5 mg or, posteriorly, if clinical necessary, 10 mg of nitroglycerin patches during 12 weeks. Clinical evaluation, electrocardiogram (ECG) and treadmill exercise were obtained on study entry and at weeks 2, 4, 8 and 12 for clinical evaluation, and at week 12 for ECG and treadmill exercise. RESULTS: A significative reduction was observed in the number of angina crisis, sublingual nitrates consumption, arterial blood pressure and on the percentage of positive treadmill exercise tests. The heart rate and nitroglycerin patches dose did not show statistical differences. The compliance of transdermal administration was excellent. CONCLUSION: The nitroglycerin patches administration was effective for stable angina pectoris with excellent patient's compliance.

Administration, Cutaneous↗
PubMed1991

Pharmacokinetics of nicotine after application of a 30 cm2 nicotine patch under steady-state conditions.

Transdermal nicotine systems (Nicotinell 30) were applied daily to the skin of healthy nicotine-dependent smokers for 4 days. Blood samples were taken for the measurement of nicotine and cotinine in plasma using capillary gas chromatography with nitrogen detection. The plasma concentration-time profiles of nicotine and cotinine and the pharmacokinetic parameters cmax, tmax, AUC and the elimination half-life were determined under steady-state conditions. Nicotine levels after application of the 30 cm2 patch were in accord with published values for 10, 20 and 2 x 20 cm2 patches. The elimination half-life of nicotine after removal of the patch was longer than reported values obtained after i.v. application.

Administration, Cutaneous↗
PubMed2001

Effects of a single transdermal nicotine dose on cognitive performance in adults with Down syndrome.

Subjects with Down syndrome exhibit various types of cognitive impairment. Neuropathological and neurochemical studies revealed similarities between Down syndrome and Alzheimer's disease, cholinergic deficits being the most consistent findings. To explore the potential for cognitive enhancement utilizing nicotinic stimulation, 8 patients with Down syndrome (aged 18.5-31 years) received placebo and a single dose of transdermal nicotine (5 mg patch) over 2h in a single-blind, within-subjects repeated measures design. Auditory event-related potentials (ERPs) and neuropsychological tests, comprising digit symbol performance subtest from WAIS-R and the Frankfurt Attention Inventory (FAIR) were performed. Effects of nicotine administration in Down syndrome individuals were a decrease of ERP-P3 latency in 7 of 8 subjects (electrode position Cz: 386.9+/-24.0 ms vs. 363.1+/-26.9.2 ms, placebo vs. nicotine, respectively; P = 0.058) and an increase of ERP-P3 amplitude in 6 of 8 subjects (electrode position Cz: 17.4+/-5.5 vs. 18.0+/-4.5 microV, placebo vs. nicotine respectively; P = 0.725). Neuropsychological tests exhibited improvements in digit symbol performance subtest in 4 of 8 subjects and 7 of 8 subjects in the Frankfurt Attention Inventory. These results suggest that stimulating central nicotinic receptors might have an acute cognitive benefit in young adult Down syndrome subjects.

Administration, Cutaneous↗
PubMed1990

An economic evaluation of transdermal glyceryl trinitrate in the prevention of intravenous infusion failure.

A common cause of peripheral intravenous infusion failure is due to the patient developing phlebitis or extravasation. Recent clinical trials indicate that the use of transdermal glyceryl trinitrate (GTN patches) can reduce the incidence of infusion failure and hence the costs of re-infusion. In this study we conduct an economic evaluation of this new pharmaceutical application to determine whether the use of such patches results in hospital resource cost savings. Time-to-first infusion failure probabilities from a placebo-controlled trial are used to model the sequential failure problem as a Markov process. Using estimated staff and materials costs for first and subsequent infusions, we calculate the expected cost per infused patient to time t for treatment and control groups. Using this simple comparative cost method, results indicate that the net impact on hospital resources from patch usage is dependent upon the total required length of infusion time. Analysis of infusion time thresholds indicates that for patients requiring long-term (t greater than 50 hours) periods of infusion the use of patches is likely to generate resource savings. We conclude that to realize such resource savings clinical decisions to infuse with GTN patches should incorporate the prior probability that the total required length of infusion time exceeds 50 hours.

Administration, Cutaneous↗
PubMed2006

Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study.

OBJECTIVE: Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD). METHODS: Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter. RESULTS: Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2-4) compared to the women receiving sertraline with placebo. CONCLUSIONS: Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response.

Adult↗
PubMed2003

The use of long-acting opioids in chronic pain management.

The consensus statement from the American Pain Society and American Academy of Pain Medicine states that the undertreatment of pain is unjustified [6]. It has been suggested that opioid therapy can be used effectively to treat noncancer pain in a subset of patients [26], and this is becoming more acceptable [3]. Providing sustained analgesia is an important aspect of therapy, and medications should be administered on an around-the-clock basis, because regular administration of doses maintains a constant level of drug in the body and helps prevent recurrence of pain. Ideal treatment for persistent pain is a long-acting opioid administered around the clock to prevent baseline pain, with the use of short-acting opioids as supplemental agents for breakthrough pain. Controlled-release formulations can lessen the inconvenience associated with around-the-clock administration of short-acting opioids. Sustained analgesia also can be achieved with transdermal fentanyl, which combines a strong opioid with a 72-hour release profile and the benefits of a parenteral route, avoiding first-pass metabolism. Controlled-release formulations of morphine and oxycodone are available in the United States, and hydromorphone preparations are being reviewed for approval. Clinical experience with these formulations and transdermal fentanyl indicates that these agents are equally effective in controlling pain. Studies have demonstrated improved quality of life with the transdermal route and with controlled-release morphine and oxycodone. Because of patch reapplication every 72 hours, the transdermal route also enhances compliance. Use of an opioid without the need for oral or intravenous administration and the opportunity to improve compliance are among the advantages of the transdermal route in clinical practice. The nurse has an important role in the management of patients receiving long-acting opioids for chronic noncancer pain, Facilitation of the conversion from short-acting to long-acting opioids may be the initial step. Individualization of therapy to determine which route and product best suits the patient's needs and lifestyle can be accomplished through a comprehensive nursing assessment. Titration of dose along with institution of a short-acting opioid for break-through pain may require frequent interventions that a nurse familiar with the patient can provide. Prevention and management of opioid-related adverse events are essential for effective opioid therapy. Providing patient and family education regarding administration, monitoring, and management of opioid therapy is an important nursing role. Lastly, documentation of pain level, functional status, and opioid-related adverse events is required for each contact with the patient, to make this information available to all who assist in the management of the patient's pain. Chronic noncancer pain is an experience that affects all aspects of a patient's life. Effective pain management with long-acting opioids may help the patient to focus on the positive aspects of life, decreasing the focus on pain.

Administration, Cutaneous↗
PubMed2000

Monitoring individual response to hormone replacement therapy with bone markers.

Hormone replacement therapy (HRT) induces a rapid decrease in biochemical markers of bone turnover that correlate with a subsequent increase in bone mineral density (BMD). To determine the utility of bone markers in the management of postmenopausal women receiving HRT, we analyzed the relationship between changes in four markers (serum osteocalcin and bone alkaline phosphatase [BAP], serum and urinary C-telopeptide of type I collagen [CTX]) and changes in spine BMD in 569 women treated for 2 years with different doses of a matrix transdermal 17beta-estradiol patch in two placebo-controlled trials. Using a logistic regression model, we found that both the percent change from baseline and the actual value of resorption markers at 3 and 6 months of treatment were predictive of BMD response at 2 years. Comparable results were obtained with formation markers at 6 months only. We determined the sensitivity, probably of positive BMD response, and corresponding cutoff value of markers at 3 and 6 months with a specificity set at a level of 0.90, so that <10% of women classified with markers as responders, i.e., as having a subsequent increase in BMD at 2 years >/=2.26%, would be false positive. All markers provided a high probability of positive BMD response ranging from 0.82 to 0.91, with a sensitivity higher for resorption than for formation markers, and sometimes improved in a model combining the percent change and the actual value of marker under HRT. For example, a decrease in serum CTX >/= 33% at 3 months of HRT provided a 68% sensitivity and 87% probability of positive BMD response at 2 years for a 90% specificity. At 6 months, a decrease in urinary CTX >/= 53% provided a 68% sensitivity and 91% probability of a positive BMD response for a 90% specificity. Half of false-negative cases at 3 months will be correctly identified by a subsequent urinary CTX measurement at 6 months. We conclude that the short-term change in bone markers reflects long-term changes of BMD in postmenopausal women treated with HRT. Our data suggest that bone turnover markers can be used to monitor the BMD response to HRT at the individual level. Whether such monitoring could improve long-term compliance to HRT should be tested prospectively.

Alendronate↗
PubMedDate not supplied

Transcutaneous delivery of levodopa: enhancement by fatty acid synthesis inhibition.

The present investigation aimed at evaluating the role of fatty acid synthesis inhibition in enhancing transcutaneous delivery of levodopa (LD). Rat epidermis was treated with ethanol and various doses of cerulenin (an inhibitor of fatty acid synthase enzyme system) for reducing the normal level of fatty acids. Calcium chloride (0.1 mM) and/or verapamil (1 microM) were coapplied to cerulenin treated skin in order to modulate duration of epidermal perturbation. These treated skin portions were used for estimation of altered triglyceride content (an indicator of fatty acid synthesis), differential scanning calorimetry (DSC) analysis, and in vitro permeation of LD. Plasma concentration of LD was monitored in rats following topical application of various transdermal formulations. Application of cerulenin (0.1 or 0.15 mM/7 cm(2)) to viable rat skin inhibited approximately 60% triglyceride synthesis with respect to control at 2 h. Coapplication of calcium chloride (0.1 mM) significantly increased this inhibition, whereas verapamil application reduced this effect. The decrease in triglyceride content reduced the enthalpy of the lipid endothermic transition. The in vitro permeation of LD was enhanced 3-fold across skin excised after treatment with cerulenin. LD did not permeate across normal skin. The effective plasma concentration (C(eff)) of LD was achieved within 3 h and maintained till 10 h by a single topical application of a carbidopa-levodopa combination (1:4) to ethanol-perturbed cerulenin-treated skin. Coapplication of calcium chloride reduced the time lag to achieve C(eff) to 2 h and maintained it till 24 h. A single transdermal LD (64 mg) patch formulated with calcium chloride (0.1 mM) and cerulenin (0.1 mM) dissolved in a propylene glycol:ethanol (7:3) mixture seems to offer a noninvasive approach for transcutaneous delivery of levodopa.

Administration, Cutaneous↗
PubMed2006

Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002-2004).

In order to characterize fentanyl-related deaths in the province of Ontario, Canada, a retrospective study of all cases in which fentanyl was quantitated in blood was conducted for the time period between 2002 and 2004. A total of 112 fentanyl-related deaths were identified. Decedents ranged in age from 4 to 93 years and comprised 63 men and 49 women. A variety of routes of administration of the drug were identified: transdermal application of Duragesic patches, intravenous injection of patch contents or fentanyl citrate solution, oral/transmucosal administration, and volatilization and inhalation of Duragesic systems. Blood fentanyl concentrations were determined for all modes of drug administration and are provided. There were 54 cases in which death was attributed solely to fentanyl intoxication; the mean blood concentration was 25 microg/L (range: 3.0-383 microg/L). This concentration range overlapped with blood fentanyl concentrations measured among cases where the presence of the drug was considered incidental. For example, a mean blood concentration of 12 microg/L was observed among 12 cases of natural death (range: 2.7-33 microg/L). Detailed case reports of six individuals are also included and provide additional insight into the use of this drug for both therapeutic and illicit means.

Adolescent↗
PubMed2003

Effect of smoking and transdermal nicotine on colonic nicotinic acetylcholine receptors in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a disease largely of non-smokers, in which nicotine is of therapeutic value. The mode of action is unknown, but may involve nicotinic acetylcholine receptors (nAChRs) in the bowel wall. AIM: To investigate the presence of nAChRs in rectal mucosa, and the effect of smoking and nicotine on their expression. DESIGN: Prospective case-control study. METHODS: In situ hybridization (ISH) and immunocytochemistry (ICC) were used to show alpha3 nAChRs in colonic mucosa. Rectal mucosa was examined from controls (n=55) and patients with inactive UC (n=62), both smokers and non-smokers, by ICC, using two antibodies to show the density and distribution of receptors in the mucosa. Non-smokers with UC (n=43) were given transdermal nicotine or placebo patches for 6 months, and rectal biopsies, taken before and after treatment, were examined by ICC to show nAChRs. RESULTS: In normal colon, ISH and ICC showed alpha3 subunit in a wide variety of cells, including mucosal epithelium. In rectal biopsies, neither smoking nor nicotine influenced the expression of alpha3 immunoreactivity in epithelium, either in controls or UC. However, controls had a significantly greater density of immunodetectable mucosal epithelium alpha3 subunit, compared with UC patients. DISCUSSION: The presence of nAChRs in colonic epithelium may be pertinent to the beneficial effect of nicotine in UC, but since neither smoking nor nicotine treatment is associated with any change in the expression of epithelial alpha3 nAChRs, the effect may be due to functional changes in the receptor. The decreased number of alpha3 nAChRs in UC compared with controls may be related to an increased cell turnover in UC.

Administration, Cutaneous↗
PubMedDate not supplied

Transition from estrogen therapy to raloxifene in postmenopausal women: effects on treatment satisfaction and the endometrium-a pilot study.

OBJECTIVE: To compare the effects of transferring from low-dose, transdermal estrogen to raloxifene with a phase of alternate-day raloxifene therapy with or without low-dose transdermal estrogen on patient satisfaction, endometrial changes, and overall safety in healthy, postmenopausal women previously administered hormone therapy. DESIGN: Healthy postmenopausal women were randomized to one of two treatment groups: raloxifene + low-dose, transdermal estrogen (RLX+E) and raloxifene + placebo (RLX+P). The study consisted of four equal phases of 8 weeks each: Phase I (low-dose, transdermal estrogen, 25 microg/day), phase II (double-blind, alternate-day raloxifene 60 mg + low-dose, transdermal estrogen or placebo patch), phase III (alternate-day RLX 60 mg + placebo patch), and phase IV (raloxifene 60 mg/day + placebo patch). Primary endpoints included patient satisfaction, endometrial changes, overall safety, and quality of life. RESULTS: Sixty women were randomized in this study. Baseline characteristics were similar between the two treatment groups. For the primary analysis (phase II to phase IV, inclusive), there were no significant differences between the therapy sequences for patient satisfaction, endometrial thickness, or quality of life. In the therapy comparison phase (phase II), mean change in patient satisfaction score was 3.2 mm (SD = 16.2) for RLX+E and -17.1 mm (SD = 38.7) for RLX+P (P = 0.003), whereas mean change in endometrial thickness was 0.8 mm (SD = 2.7) for RLX+E and -0.9 mm (SD = 1.5) for RLX+P (P = 0.021). The RLX+P group showed a significantly greater increase in vasomotor events, with a mean score change of 1.7 (SD = 1.9) compared with a mean score change of 0.2 (SD = 1.8) in the RLX+E group (P = 0.005). There were no statistically significant differences between the two therapy groups in the reporting of treatment-emergent adverse events. CONCLUSION: Gradual conversion to raloxifene from low-dose estrogen, with a progression from 60 mg every alternate day to 60 mg/day, is a viable option in potentially symptomatic, postmenopausal women.

Administration, Cutaneous↗
PubMed1997

Treatment of menstrual migraine.

Because of its pathophysiological and clinical peculiarities, true menstrual migraine (MM) (i.e. migraine starting exclusively between the days immediately before and immediately after the first day of the menstrual cycle) requires an ad hoc management different from that of other migraines. The paucity of well-conducted, controlled clinical trials and the lack of a universally accepted definition of MM have meant that the treatment of MM is still largely empirical. In our clinical practice, we adopt a sequential therapeutic approach, including the following steps: (i) acute attack drugs (sumatriptan, ergot derivatives, NSAIDs); (ii) intermittent prophylaxis with ergot derivatives or NSAIDs; (iii) oestrogen supplementation with percutaneous or transdermal oestradiol (100 microg patches); (iv) antioestrogen agents (danazol, tamoxifen).

Acute Disease↗
PubMed2001

The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study.

People with type 2 diabetes have a substantially increased risk of coronary heart disease (CHD). Short-term studies with unopposed oral estradiol in women with diabetes have suggested potentially beneficial effects on lipids, thrombotic factors, and insulin sensitivity. However, most (nonhysterectomized) postmenopausal women require combined estrogen-progesterone preparations. We randomized 43 women with type 2 diabetes either to continuous transdermal estradiol (80-microg patches) in combination with oral norethisterone (1 mg daily) or to identical placebos. Blood samples were taken before and after 6 months for measurement of lipoproteins, coagulation factors, and endothelial markers. Total cholesterol and triglyceride concentrations decreased by 8% and 22%, respectively, in those receiving hormone replacement therapy (P < 0.05 relative to change in placebo group after adjustment for baseline concentrations). There was a trend toward a reduction in high density lipoprotein cholesterol concentration (P = 0.06). Factor VII activity decreased by 16% (P < 0.001), and von Willebrand factor antigen decreased by 7% (P = 0.014) with active treatment. Levels of fibrinogen, tissue plasminogen activator, fibrin D dimer, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, lipoprotein(a), and leptin were not significantly altered. No change in glycemic control was detected. Overall, lipid changes may be considered slightly beneficial with respect to CHD risk. The significant decrease in factor VII activity in this study is notable, because elevated factor VII activity has been associated with an increased risk of coronary thrombosis and normally increases with administration of oral estrogen-containing preparations. In addition, a reduction in von Willebrand factor antigen is consistent with an improvement in endothelial function. We suggest that the regimen used in this study may have the potential to reduce CHD risk in women with type 2 diabetes.

Administration, Cutaneous↗
PubMed2004

New Product Review (September 2003). Norelgestromin/ethinyl oestradiol transdermal contraceptive system (Evra).

This new transdermal contraceptive system (contraceptive patch), Evra (Janssen-Cilag), received a UK product licence in 2003. In clinical trials: Consistent doses of norelgestromin and ethinyl oestradiol are released into the systemic circulation daily. Pharmacokinetic data suggest that levels are sufficient to inhibit ovulation for at least 7 days. The overall Pearl index for the contraceptive patch (1.24; 95% CI 0.19-2.33) was similar to that of a triphasic combined oral contraceptive (COC) pill (2.18; 95% CI 0.57-3.8). Self-reported "perfect" compliance was significantly better with the contraceptive patch (88.2%) than with a combined contraceptive pill (77.7%). Patch detachment, requiring replacement with a new patch, with normal daily activity is uncommon (4.6%). Breakthrough bleeding and spotting were significantly more common with the contraceptive patch than with combined oral contraception in the first two cycles but differences were not significant by cycle three. In general, reported side effects were not significantly different with contraceptive patch or combined pill use. However, breast tenderness in the first two treatment cycles was more common with patch use. Symptoms were mild to moderate in 85% of women and were rarely treatment limiting. Currently, there are limited data regarding risk of venous thromboembolism, and cervical or breast cancer with the contraceptive patch. No clinically significant alterations in metabolic or haemostatic parameters were identified with contraceptive patch use. A month's supply of the contraceptive patch costs 7.74 UK pounds. Combined oral contraception prices range from approximately 0.80 to 5.00 UK pounds and hormone replacement therapy patches range from 10.00 to 13.00 UK pounds. The contraceptive patch offers additional choice for women who wish to use a combined hormonal method of contraception.

Administration, Cutaneous↗