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PubMed2000

Modeling adolescent nicotine exposure: effects on cholinergic systems in rat brain regions.

Smoking among teenagers is increasing and the initiation of tobacco use during adolescence is associated with subsequently higher cigarette consumption and lower rates of quitting. Few animal studies have addressed whether adolescent nicotine exposure exerts unique or lasting effects on brain structure or function. Initial investigations with a rat model of adolescent nicotine exposure have demonstrated that the vulnerable developmental period for nicotine-induced brain cell damage extends into adolescence. In the current study, we examined the effect of nicotine on cholinergic systems in male and female adolescent rats with an infusion paradigm designed to match the plasma levels found in human smokers or in users of the transdermal nicotine patch. Choline acetyltransferase activity (ChAT) and [3H]hemicholinium-3 binding (HC-3) were monitored; ChAT is a static marker that closely reflects the density of cholinergic innervation, whereas HC-3 binding, which labels the presynaptic high-affinity choline transporter, is responsive additionally to nerve impulse activity. Measurements were carried out in the midbrain, the region most closely involved in reward and addiction pathways, as well as in the cerebral cortex and hippocampus. During nicotine treatment and for 1 month after the termination of treatment, ChAT activity was reduced significantly in the midbrain but not in the other regions. HC-3 binding showed a substantial increase during the course of nicotine treatment and again, the effect was limited to the midbrain. Midbrain values returned to normal immediately after the cessation of nicotine exposure and then showed a subsequent, transient suppression of activity. Although the cerebral cortex showed little or no change in HC-3 binding during or after nicotine administration, activity was reduced persistently in the hippocampus. The regionally-selective effects of adolescent nicotine treatment on cholinergic systems support the concept that adolescence is a vulnerable developmental period for ultimate effects on behavior.

Aging↗
PubMed2000

Persistent and delayed behavioral changes after nicotine treatment in adolescent rats.

Despite the increasing use of tobacco by adolescents, few animal studies have addressed the neurobehavioral consequences of nicotine exposure during this period. We administered nicotine to adolescent rats via continuous infusion on postnatal days (PN) 30 through 47.5, using a dosage regimen that maintains plasma levels similar to those found in smokers or in users of the transdermal nicotine patch. Behavior in a novel open field and learning a passive avoidance task were assessed during nicotine treatment and for 2 weeks post-treatment. On PN44, during nicotine exposure, female rats showed decreased grooming, an effect not seen in males; this effect is opposite to the effects of nicotine in adult rats. Two weeks after cessation of nicotine administration, females showed deficits in locomotor activity and rearing, whereas males again were unaffected; the behavioral deficits appeared at the same age at which gender-selective brain cell damage emerges. In contrast, nicotine exposure enhanced passive avoidance, with the effect intensifying and persisting throughout the post-treatment period. These results reinforce the concept that developmental vulnerability to nicotine extends into adolescence, with patterns of drug effects different from those in earlier or later periods. The correlation of neurochemical with behavioral effects strengthens the connection between adolescent nicotine exposure and persistent functional changes that may influence drug habituation, learning and memory.

Adolescent↗
PubMed1997

Inhibition of ovulation with transdermal estradiol and oral progestogens in perimenopausal women.

The effects of 6 months of combined hormone therapy with transdermal estradiol (0.05 mg/day x 21 days) and different oral progestogens (10 mg/day medroxyprogesterone acetate [MPA] in the last 12 days, 10 mg/day dihydrogesterone in the last 12 days, and 50 mg/day cyproterone in the first 10 days), on menopausal symptoms and hypothalamo pituitary-ovarian function were studied in normal perimenopausal women. The study included 38 perimenopausal women, aged 43-49 years, with regular cycles of 26-32 days in length and menopausal symptoms. Endocrine status was determined by assay of basal levels of gonadotropins (LH, FSH), E2, and P every week until menstrual bleeding, before and during the first month of therapy. Plasma levels of LH and FSH were suppressed in the first month of therapy while E2 had a mean value of 45 +/- 12 pg/ml. Ultrasound examination and low levels of P indicated a complete block of ovulation and hypothalamo-pituitary-ovarian activity. All women reported the disappearance of vasomotor symptoms and nocturnal sweating. Transdermal estradiol and oral progestogens were well tolerated. This study shows that combined hormone therapy with low doses of transdermal estrogen patches and different oral progestogens reduces menopausal symptoms and also safeguards against unwanted pregnancies in the perimenopausal period.

Administration, Cutaneous↗
PubMed1988

Transdermal estrogen replacement in ovarian failure for ovum donation.

This study examined the efficacy of transdermal estradiol (TE2) replacement versus oral estradiol (OE2) through evaluation of peripheral steroid levels, endometrial morphology, and clinical outcome in six patients with ovarian failure. Patients were begun on sequential E2 and progesterone replacement with transdermal E2 patches. Endometrial biopsies were done on day 21 of the first replacement cycle and day 26 of the second cycle. Controls were 28 cycles on a regular 28-day micronized OE2 protocol. No significant difference was found between E2 levels throughout the cycle of the two respective stimulation protocols, except for days 12 to 14, when the OE2 protocol produced significantly lower E2 than did the TE2 protocol (P less than 0.01). A positive, highly significant correlation was found between estrone (E1) and E2 values in the OE2 group (r = 0.92) (P less than 0.003). During OE2 administration, E1 was significantly higher than E2 (P less than 0.01). E1 was not found to be higher than E2 in the TE2 group, resulting in a significant difference in the E2/E1 ratio of 1.59 +/- 1.6 for TE2 compared with 0.13 +/- .04 for OE2 (P less than 0.05). Early biopsies in patients on TE2 revealed glandular components that were dated as day 18.2 +/- 1.7, while the stroma was dated as day 21.8 +/- 0.8, a statistically significant disparity (P less than 0.01). In patients on OE2, the same significant 3-day glandular/stromal disparity was observed (P less than 0.05). Morphologic evaluation of late biopsy specimens revealed day 25.0 +/- 0.8 and 24.5 +/- 1.5 for TE2 and OE2 groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed2000

Estrogen effects on postural balance in postmenopausal women without vasomotor symptoms: a randomized masked trial.

OBJECTIVE: To assess whether estrogen treatment given to postmenopausal women without vasomotor symptoms improves balance more than placebo. METHODS: Forty healthy postmenopausal women without vasomotor symptoms were randomized to transdermal 17beta-estradiol (E2) 50 microg/day for 14 weeks or identical transdermal placebo patches. Postural balance was measured with dynamic posturography before and after 4, 12, and 14 weeks of therapy. In this test, the visual, vestibular, and somatosensory systems were provoked with increasing difficulty and body sway was measured with a dual forceplate. A low score showed large sway and a score of 100 showed no sway at all. RESULTS: Thirty-eight women completed the study. Both groups had normal balance for their ages and near maximum scores in the three easier balance tests at baseline. In the most difficult test, both groups improved their postural balance significantly (from 13 to 32 and from 22 to 39, respectively) after 4 weeks. Thereafter, no change was seen. One problem was low statistical power, but the relative change in balance did not differ between groups. The comparison did not show even a minute advantage of E2 over placebo, so a study with higher power would probably not have shown a more pronounced effect of estrogen than placebo. The change over time did not differ between groups, which indicates a significant learning effect. CONCLUSION: In women without vasomotor symptoms, estrogen therapy did not seem to increase postural balance significantly more than placebo. However, we could not rule out that estrogens affect postural balance in women with vasomotor symptoms.

Administration, Cutaneous↗
PubMed2003

The effects of corticotropin-releasing factor on the cortical EEG are reduced following adolescent nicotine exposure.

Although smoking is highly prevalent among adolescents, relatively little is known about the lasting neurobehavioral consequences associated with adolescent nicotine exposure. Prior studies from our laboratory suggest that adolescent nicotine exposure induces an anxiogenic profile in adult rats. Corticotropin-releasing factor (CRF) systems are important modulators of anxiety and response to stress. Since acute nicotine administration has been shown to stimulate central CRF activity, the purpose of this study was to examine the effects of adolescent nicotine exposure on CRFs modulation of the cortical and hippocampal EEG in adult rats. Male Sprague-Dawley rats were exposed to nicotine (5 mg/kg/day) between postnatal days 35-40 using transdermal nicotine patches. Six weeks after nicotine exposure ended, the effects of intracerebroventricular administration of CRF (0.01-1.0 microg/5 microl) on EEG activity in the cortex and hippocampus were assessed in nicotine-exposed rats and age-matched control rats. The overall effects CRF were consistent with previous reports. CRF decreased low to moderate frequency EEG activity (1-32 Hz) and increased high frequency EEG activity (32-50 Hz). However, in nicotine-exposed rats the effects of CRF on the frontal and parietal cortical EEG were blunted by 30-50% compared to control rats. A similar pattern of decreased response to CRF was not observed in the hippocampus. These blunted effects of CRF on the cortical EEG suggest that long-term changes in systems responsive to CRF result from adolescent nicotine exposure. Given the role of CRF systems in behavioral responses to stress and anxiety, these data suggest that adolescent nicotine exposure may produce long-term decreases in neurophysiological responses to stress.

Administration, Cutaneous↗
PubMed2001

Adolescent nicotine: deficits in immune function.

Maternal cigarette smoking during pregnancy is known to alter immune function in the offspring and recent studies with animals indicate that prenatal nicotine exposure leads to lasting deficiencies in T-lymphocyte mitogenic responses, likely through excessive cholinergic stimulation during a critical stage of development. The current study was conducted to determine if the vulnerable period for nicotine-induced mis-programming of immune responses extends into adolescence, the stage at which most smokers begin tobacco use. Adolescent rats were given nicotine via osmotic minipump infusions on postnatal days (PN) 30-47.5, using a regimen that produces plasma levels (25 ng/ml) of nicotine similar to those in smokers or in users of transdermal nicotine patches. Toward the end of the infusion period (PN45) and 1 month after termination of nicotine exposure (PN80), we examined the mitogenic responses of splenocytes to Concanavalin A. Although no deficiencies were seen on PN45, there were robust decreases in mitogenic responses on PN80, with deficits apparent at both suboptimal and optimal concentrations of Concanavalin A. These results indicate that the adolescent immune system is vulnerable to nicotine-induced disruption of T-cell function.

Age Factors↗
PubMed1995

Vasoactive effects of smoking as mediated through nicotinic stimulation of sympathetic nerve fibers.

Patients who smoke have higher complication rates than nonsmokers following many surgical procedures. It is not known if the adverse effects of smoking are caused by a nicotine effect or by some other potentially harmful agents that exist in tobacco smoke. It is also not known if these vasoactive effects are mediated through sympathetic nerve fibers (via nicotinic receptors in ganglia) or through elevated circulating levels of vasoactive hormones. We designed a 5-day protocol to measure relative blood flow both before and after a digital sympathetic block in the digits of subjects who were regular smokers following both smoking and wearing of a transdermal nicotine patch. Suitable pulse/wave tracings were recorded on 23 subjects. We also measured serum levels of nicotine, cotinine, vasopressin, norepinephrine, epinephrine, dopamine, and carboxyhemoglobin on each test day. Data for these serum levels were available in 30 test subjects. Digital sympathetic block had a significant beneficial effect in reversing the decreased digital blood flow that occurred after smoking (and also with use of the nicotine patch), despite the elevated circulating levels of vasopressin and norepinephrine seen with smoking. The vasoactive effects of smoking are probably due to the nicotinic effects on sympathetic fibers at the ganglionic levels.

Adult↗
PubMed2001

The effects of transdermal nicotine therapy for smoking cessation on depressive symptoms in patients with major depression.

This study examines the effects of transdermal nicotine patches for smoking cessation on depressive and withdrawal symptoms among 38 non-medicated subjects with Major Depressive Disorder. The study was conducted over a 29-day period, which included a 7 day baseline phase, a 14 day treatment phase, and an 8 day placebo phase. During the treatment phase subjects received either active nicotine patches (N = 18) or placebo patches (N = 20) that were administered in a randomized, double-blind fashion. The target quit date (TQD) was day 8. Significantly, more subjects in the placebo group than in the nicotine group resumed smoking following the TQD (50% vs. 22%). There was little evidence for effects of active nicotine patches on measures of mood (HRSD, BDI, POMS) or withdrawal symptoms among subjects that remained abstinent throughout the study (N = 24). Those who resumed smoking had more severe withdrawal symptoms than those who remained abstinent. One patient in the placebo group (n = 20) became more depressed after 2 weeks of abstinence. None of the patients in the nicotine group (n = 18) became more depressed.

Administration, Cutaneous↗
PubMed1999

Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.

Administration, Cutaneous↗
PubMed1998

Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension.

After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.

Aged↗
PubMed1997

Principles of analgesic drug therapy.

The drugs most often used for pain relief in animals are the nonsteroidal antiinflammatory drugs (NSAIDS) and the opioid analgesics. The NSAIDS are effective, inexpensive, and long-acting drugs, but their degree of analgesia is limited by the adverse effects at high doses. The most common adverse effect from NSAIDS is gastritis and gastrointestinal hemorrhage and ulceration. This is most common from high doses, or from using NSAIDS not appropriate for dogs such as ibuprofen or indomethacin. The NSAIDS used in dogs include aspirin, phenylbutazone, naproxen, piroxicam, ketoprofen, and carprofen. Carprofen is a new drug with a low incidence of side effects and its popularity is increasing at a fast rate. For more acute pain, especially acute pain from surgery or trauma, opioids are frequently administered. Opioids have the advantage of higher efficacy when the dose is increased. The incidence of adverse effects is low, but side effects of sedation are common. An important disadvantage of opioids is their short duration and low oral absorption, which necessitates a frequent injection or i.v. infusion for most patients. Recent studies have established other applications for administration of opioids such as a transdermal fentanyl patch. These applications offer new possibilities for convenient administration.

Analgesics, Opioid↗
PubMedDate not supplied

Contraceptive applications of estrogen.

Estrogens are a primary component of several contraceptive methods: combined oral contraceptive pills, a combined injectable contraceptive, the combined contraceptive vaginal ring, the combination transdermal contraceptive patch, and combined emergency contraceptive pills. Contraceptive formulations that contain estrogen are referred to as combined contraceptives because they also contain some form of progestin. This article reviews the contraceptive methods containing estrogen, beginning with a discussion of combined oral contraceptive pills. Formulations and clinical management, mechanisms of action, noncontraceptive benefits of use, therapeutic uses in addition to contraception, side effects, contraindications to use, and drug-drug interactions are described. Information follows about the newer combined contraceptive products including the injection, vaginal ring, and patch. Finally, combined emergency contraceptive pills are reviewed. Thorough knowledge of the contraceptive methods containing estrogen enables clinicians to provide expert care for women using these products.

Administration, Cutaneous↗
PubMed1997

Differential effects of transdermal nicotine on microstructured analyses of tics in Tourette's syndrome: an open study.

BACKGROUND: The treatment of Tourette's syndrome (TS) is often unsatisfactory. However, there is some evidence that transdermal nicotine patch (TNP) application may improve tics of nonsmoking TS patients who are refractory to haloperidol treatment. METHODS: In this open study we applied two 10 mg TNP for 2 consecutive days to four TS patients whose symptoms were not controlled by haloperidol and to a never-medicated TS patient, all of whom are non-smokers. The Yale Global Tic Severity Scale (YGTSS) and a quantified video-taped micro-structured analysis of tics (head-shake tics, eye-blinks, vocal tics, facial grimace and other body tics) were both carried out to assess the change after the application of TNP. RESULTS: TNP application significantly reduced the YGTSS by an average of 50%, with no reported side-effects, for up to 4 weeks but not 16 weeks, as compared with TNP-free period. Consistent with these results, the total counts of tics also showed a significant decrease for up to 4 weeks after the TNP application. CONCLUSION: TNP application differentially affected individually quantified tics, which may suggest a differential role of nicotinic receptors in the generation of different tics.

Administration, Cutaneous↗
PubMed1990

Transdermal nicotine facilitates smoking cessation.

The efficacy of a transdermal nicotine patch in facilitation of smoking cessation was evaluated in a randomized double-blind trial. Sixty-five smokers who were highly dependent on cigarettes participated in the study, which included a behavioral smoking-cessation program. The rates of continuous abstinence were significantly higher in the nicotine group both initially (55% versus 34%) and at 3 weeks (18% versus 6%). Certain smoking withdrawal symptoms, including negative affect and hypoarousal, were effectively relieved by the nicotine patch. There was a trend toward a reduction in cigarette craving, whereas hunger and habit withdrawal symptoms were not affected. The main side effect associated with the nicotine patch was skin irritation. These findings suggest that a nicotine skin patch may be a useful aid to smoking cessation; however, the combination of other techniques with nicotine replacement may provide a more effective treatment for symptoms such as craving for cigarettes.

Administration, Cutaneous↗
PubMed2001

Cyclic AMP elevating agents and nitric oxide modulate angiotensin II-induced leukocyte-endothelial cell interactions in vivo.

Angiotensin (Ang-II) is a key molecule in the development of cardiac ischaemic disorders and displays proinflammatory activity in vivo. Since intracellular cyclic nucleotides elevating agents have proved to be effective modulators of leukocyte recruitment, we have evaluated their effect on Ang-II-induced leukocyte-endothelial cell interactions in vivo using intravital microscopy within the rat mesenteric microcirculation. Pretreatment with iloprost significantly inhibited (1 nM) Ang-II-induced increase in leukocyte rolling flux, adhesion and emigration at 60 min by 96, 92 and 90% respectively, and returned leukocyte rolling velocity to basal levels. Pretreatment with salbutamol or co-superfusion with forskolin exerted similar effects. When theophylline was administered, leukocyte rolling flux, adhesion and emigration elicited by Ang-II were significantly attenuated by 81, 89 and 71% respectively. Rolipram administration caused similar reduction of Ang-II-induced leukocyte responses. Co-superfusion of Ang-II with the NO-donor, spermine-NO, or 8-Br-cyclic GMP, or pretreatment with a transdermal nytroglycerin patch, resulted in a significant reduction of the leukocyte-endothelial cell interactions elicited by Ang-II. Salbutamol preadministration did not modify leukocyte-endothelial cell interactions elicited by either L-NAME or L-NAME+Ang-II, indicating that the inhibitory leukocyte effects caused by cyclic AMP-elevating agents are mediated through NO release. In conclusion, we have provided evidence that cyclic AMP elevating agents and NO donors, are potent inhibitors of Ang-II-induced leukocyte-endothelial cell interactions. Thus, they could constitute a powerful therapeutical tool in the control of the leukocyte recruitment characteristic of the vascular lesions that occur in cardiovascular disease states where Ang-II plays a critical role.

Analysis of Variance↗
PubMed1995

A case of nicotine psychosis?

A woman attempting to stop smoking using transdermal nicotine patches experienced a variety of transient delusions and hallucinations after smoking a cigarette. Various possible explanations are discussed.

Administration, Cutaneous↗
PubMed2001

Colonic motility in chronic ulcerative proctosigmoiditis and the effects of nicotine on colonic motility in patients and healthy subjects.

BACKGROUND: Nicotine decreases diarrhoea and pain in ulcerative colitis without reducing inflammation. AIMS: (i) To evaluate the effect of ulcerative proctosigmoiditis on motor functions of an uninflamed segment of descending colon; and (ii) to assess nicotine's effects on colonic motor functions in patients and healthy subjects. METHODS: In healthy subjects (n=30) and patients with ulcerative colitis (13; 11 active, two quiescent colitis), we studied the effects of intravenous nicotine on colonic transit of solid residue by scintigraphy (healthy subjects) and on colonic motility in healthy subjects and 11 patients. RESULTS: In ulcerative colitis, fasting colonic motility was increased, whereas motor response to a meal was significantly reduced; compliance was unchanged. In healthy subjects, high-dose nicotine induced transient high amplitude propagated contractions and relaxation of the descending colon followed by decreased phasic contractions. This dose also accelerated colonic transit. Low-dose nicotine (mimicking a transdermal nicotine patch) reduced colonic compliance in healthy subjects, but did not affect motor function in ulcerative colitis. CONCLUSIONS: Ulcerative proctosigmoiditis increases fasting colonic motility and reduces tone response to a meal in the descending colon without affecting colonic compliance, suggesting changes in physiological responses but not intrinsic wall properties. Nicotine has dose-dependent effects on colonic motor activity in healthy subjects.

Adult↗