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Metabolism and biochemical effects of nicotine for primary care providers.

Nicotine is a colorless and volatile liquid alkaloid naturally occurring in the leaves and stems of Nicotiana tabacum and Nicotiana rustica. Nicotine, the primary component of tobacco, is responsible for both tobacco product addiction (with chronic exposure) and the odor associated with tobacco. In addition to cigarettes, nicotine is found in chewing gum, transdermal patches, nasal spray, and sublingual tablets. Following its inhalation and absorption, nicotine and its metabolic products exert diverse physiologic and pharmacologic effects. This article covers the absorption and metabolism of nicotine, nicotine toxicity, pharmacologic effects of nicotine, nicotine-drug interactions, and the use of nicotine for the treatment of disease.

Aryl Hydrocarbon Hydroxylases↗

Acute effects of nicotine on attention and response inhibition.

Smoking is highly prevalent among patients with Attention Deficit Hyperactivity Disorder (ADHD). Previous studies using the reversed continuous performance task (R-CPT) have suggested that nicotine reduces inattention. Since especially adults with ADHD have been claimed to suffer from a core deficit in inhibitory control, this study aimed at determining whether nicotine improves response inhibition in addition to attention. Sixteen healthy regular smokers participated in a pre/post treatment design in which transdermal patches containing 7 and 21 mg nicotine per day were administered in a counterbalanced, double-blind manner. In a second study, patches containing 0 mg (placebo) and 21 mg per day were administered to a different group of regular smokers. For replication purposes, the R-CPT and the profile of mood states (POMS) were administered. Furthermore, a different version of the continuous performance task (CPT-AX) and the stop-signal task, traditionally used to measure response inhibition, were presented. The high dose of nicotine was found to relieve self-reported Depression in Study 1 and Fatigue in Study 2. Performance data indicated acute effects of nicotine on attention-related, but not on inhibition-related measures. Especially the comparison with placebo revealed decreases in reaction time and variability of responding. The results imply that patients with ADHD smoke to reduce inattention.

Adolescent↗

Direct current stimulation for spine fusion in a nicotine exposure model.

BACKGROUND CONTEXT: Decreased effectiveness in spinal fusion procedures in patients who smoke before, during, or after the operation has been noted in several clinical studies. In previous work, direct current (DC) electrical stimulation has been shown to enhance inter-transverse process fusion in a rabbit model. PURPOSE: To test the efficacy of DC stimulation on bone healing in spinal fusion in rabbits exposed to nicotine. STUDY DESIGN/SETTING: A randomized and controlled interventional study. METHODS: Thirty male New Zealand white rabbits received a single level posterolateral, inter-transverse process fusion with autologous iliac crest bone. One group (control) acted as a control without nicotine or electrical stimulation. A second group (Nic) received a continuous dose of nicotine via a transdermal patch to simulate a heavy smoker, and a third group, nicotine/stimulator group (Nic/Stim), additionally received a 100-microamp DC stimulator. The fusion masses (L5-L6) and the adjacent unfused control segment (L4-L5) were evaluated radiographically, manually, and biomechanically. RESULTS: The Nic group showed significantly higher fusion rate compared with the control group. The Nic/Stim group also demonstrated significantly higher fusion rate and X-ray trabeculation compared with the control group. However, the Nic/Stim group was not significantly higher than the Nic group in fusion rate or X-ray trabeculation. CONCLUSIONS: Nicotine significantly improved fusion rate compared with controls, and DC stimulation significantly increased X-ray trabeculation of nicotine treated rabbits compared with controls.

Animals↗

Effect of testosterone supplementation on sexual function in hypogonadal men with erectile dysfunction.

OBJECTIVES: To evaluate the impact of normalization of testosterone levels in men with documented hypogonadism and erectile dysfunction on erectile function and sexual satisfaction. Although the data support the role of testosterone in the preservation of libido and nocturnal erectile function, the evidence supporting the use of testosterone supplementation in hypogonadal men with erectile dysfunction is weak. METHODS: This analysis used two validated questionnaires, the International Index of Erectile Function and the Erectile Dysfunction Inventory of Treatment Satisfaction, in a serial fashion at baseline (before treatment) and 1, 3, and 6 months after the achievement of a therapeutic testosterone level. RESULTS: A total of 32 men met all inclusion criteria; 69% of men achieved therapeutic testosterone levels using transdermal testosterone gel, 19% required a transdermal patch, and 12% required intramuscular delivery. Statistical significance was reached for the difference between the baseline and 1-month International Index of Erectile Function erectile function domain score and all post-treatment International Index of Erectile Function libido scores. A steady decrease occurred in the Erectile Dysfunction Inventory of Treatment Satisfaction scores from the 1 to 6-month values that reached statistical significance. CONCLUSIONS: In men with documented hypogonadism and erectile dysfunction, normalization of serum testosterone levels was associated with only short-term improvement in erectile function and sexual satisfaction. The use of testosterone supplementation in this population for the treatment of erectile dysfunction is questionable.

Administration, Cutaneous↗

Study of myocardial contractility by pulsed wave Doppler tissue imaging does not reveal an inotropic effect of estrogen at physiologic dose.

We studied myocardial contractility by pulsed wave Doppler tissue imaging in 6 postmenopausal healthy women. According to a crossover, double-blind protocol, we randomized patients to treatment with transdermal patches of estradiol-17beta or matched placebo. Estradiol-17beta did not modify local systolic and diastolic functions. Thus, at least when acutely administered, estrogen seems to be unable to determine hemodynamic changes at the myocardial level, in opposition to what occurs in the peripheral vascular system.

Administration, Cutaneous↗

Imidazoline and alpha(2a)-adrenoceptor binding sites in postmenopausal women before and after estrogen replacement therapy.

BACKGROUND: Platelet alpha(2A)-adrenoceptors (alpha(2A)AR) and imidazoline binding sites (subtype I(1)) have been proposed as peripheral markers of brain stem receptors that mediate sympathetic outflow and are reported to be elevated in major depression. METHODS: In our study, p[(125)I]-iodoclonidine was used to assess platelet alpha(2A)AR and I(1) binding sites in healthy postmenopausal women (n = 34) compared with healthy women of reproductive age (n = 26). Receptor determinations were repeated in 19 postmenopausal women following 59-60 days of estrogen replacement therapy (ERT; 0.1 mg estradiol transdermal patches). RESULTS: I(1) binding sites were twofold higher in platelets of postmenopausal women compared with women of reproduction age but were down-regulated (normalized) after 59-60 days of ERT. All other binding parameters, including platelet alpha(2A)AR density, were not different between groups nor were they changed after ERT. Platelet I(1) densities after 59-60 days of ERT were positively correlated with plasma luteinizing hormone concentrations. CONCLUSIONS: It is suggested that increased imidazoline binding sites might be associated with mood and behavioral changes in postmenopausal women.

Adult↗

Endometrial preparation for frozen-thawed embryo transfer with or without pretreatment with gonadotropin-releasing hormone agonist.

OBJECTIVE: To test the efficacy of endometrial preparation with exogenous steroids, without pretreatment with gonadotropin-releasing hormone (GnRH) agonist, in women with normal ovarian function. DESIGN: Prospective randomized study. SETTING: Private outpatient infertility clinic. PATIENT(S): Two hundred ninety-six women undergoing frozen-thawed embryo transfer. INTERVENTION(S): In group 1 (146 patients), depot GnRH agonist was administered in the luteal phase; treatment with 17beta-estradiol transdermal patches at steadily increasing dosage from 100 to 300 microg was then given for at least 12 days. In group 2 (150 patients), endometrial preparation began on day 1 of menstrual cycle. The starting dose was 200 microg; this was increased to 300 microg after 7 days. MAIN OUTCOME MEASURE(S): Pregnancy, abortion, implantation and cancellation rates. RESULT(S): In group 2, six cycles (4%) were cancelled due to evidence of ovulation. Groups were similar in the percentage of embryos that survived freezing-thawing (77.1% in group 1 and 76.6% in group 2) and in the number of embryos transferred per patient (2.1 +/- 0.6 and 2.1 +/- 0.7, respectively). Groups 1 and 2 did not differ significantly in rates of pregnancy (19.7% and 24.1%), abortion (17.8% and 11.7%), and implantation (10.4% and 11.9%). CONCLUSION(S): Endometrial preparation for frozen-thawed embryo transfer based exclusively on steroid administration appears to be as effective as the more conventional protocol involving preliminary desensitization with a GnRH agonist. This simplified protocol reduces costs, minimizes pharmacologic treatment, and increases patient compliance.

Abortion, Spontaneous↗

Prediction of internal standards in reversed-phase liquid chromatography. II. Selectivity optimization and internal standard prediction for the quantitation of estradiol and levonorgestrel in a transdermal drug delivery formulation based on the linear solvation energy relationships.

This paper describes the results of selectivity optimization and internal standard prediction for the quantitation of estradiol and levonorgestrel in transdermal patches by reversed-phase liquid chromatography (RPLC) based on the linear solvation energy relationships (LSERs). The patch samples are prepared by swelling with acetonitrile (ACN) and the separation is performed by Zorbax Eclipse XDB ODS columns. A proper retention range is first determined with a binary mobile phase of ACN and water based on the general resolution equation. The interference to estradiol from a levonorgestrel impurity is then eliminated by a ternary mobile phase of acetonitrile-methanol-water with a composition predicted by LSERs. When the resolution is optimized and the "open window" in the chromatogram for an internal standard is selected, LSERs are used to predict the candidate compounds to be evaluated as the internal standard. The approach described in this study can be used, in general, to considerably improve the efficiency of RPLC method development, particularly for neutral samples. Finally, the LSER approach for the selectivity optimization is compared with a statistical response surface methodology (RSM) based on a central composite design (CCD) in terms of the effectiveness and number of experiments. It is concluded that, although the predicted mobile phase composition to achieve the desired selectivity is about the same, the LSER approach is more efficient and fewer experiments are required.

Chromatography, Liquid↗

Effect of the addition of estrogen to medical castration on prostatic size, symptoms, histology and serum prostate specific antigen in 4 men with benign prostatic hypertrophy.

A total of 4 men with benign prostatic hypertrophy who underwent medical castration therapy with a long-acting gonadotropin-releasing hormone agonist (leuprolide) for more than 6 months elected to add an estrogen transdermal patch (0.05 mg. to the skin biweekly) to the leuprolide regimen. The average prostatic size (transrectal ultrasound), serum prostate specific antigen (PSA) levels and symptoms of prostatism were dramatically decreased with leuprolide alone. The addition of estrogen for 6 months did not result in any change in prostate size, symptoms or serum PSA levels over that seen with leuprolide alone. The development of squamous metaplasia was noted in 1 man with leuprolide alone and in 1 man after the addition of estrogen. Immunohistochemical staining with anticytokeratin 903 antibodies reveals that squamous metaplasia appears to arise from prostatic basal cells. We postulate that the target cell for estrogen action in the prostate is the prostatic basal cell. In the absence of androgen the only direct effect of estrogens is the induction of squamous metaplasia.

Aged↗

Methods of smoking cessation.

Smoking-cessation treatment consists of three phases: preparation, intervention, and maintenance. Preparation aims to increase the smoker's motivation to quit and to build confidence that he or she can be successful. Intervention can take any number of forms (or a combination of them) to help smokers to achieve abstinence. Maintenance, including support, coping strategies, and substitute behaviors, is necessary for permanent abstinence. Although most smokers who successfully quit do so on their own, many use cessation programs at some point during their smoking history. Moreover, many people act on the advice of a health professional in deciding to quit. Some are also aided by a smoking-cessation kit from a public or voluntary agency, a book, a tape, or an over-the-counter product. Still others receive help from mass-media campaigns, such as the Great American Smokeout, or community programs. Counseling, voluntary and commercial clinics, nicotine replacement strategies, hypnosis, acupuncture, and behavioral programs are other methods used by smokers to break the habit. Programs that include multiple treatments are more successful than single interventions. The most cost-effective strategy for smoking cessation for most smokers is self-care, which includes quitting on one's own and might also include acting on the advice of a health profession or using an aid such as a quit-smoking guide. Heavier, more addicted smokers are more likely to seek out formal programs after several attempts to quit. Many people can quit smoking, but staying off cigarettes requires maintenance, support, and additional techniques, such as relapse prevention. Physicians, dentists, and other health professionals can provide important assistance to their patients who smoke. Quit rates can be improved if clinicians provide more help (e.g., counseling, support) than just simple advice and warnings. Clinicians also play an important role in providing nicotine replacement products such as nicotine gum or transdermal patches. These products are particularly useful for smokers who show evidence of strong physiologic addiction to nicotine. Attitudes toward smoking have shifted dramatically. In the 1950s, fewer than 50% of American adults believed that cigarette smoking caused lung cancer. In 1986, this proportion had increased to 92%. A majority of the public favors policies restricting smoking in public places and worksites. Half of all Americans who ever smoked had stopped smoking by 1988. Of those who continue to smoke, more than 70% report that they would like to quit. By increasing their knowledge about smoking-cessation methods, health professionals can support and encourage the large majority of smokers who want to quit.

Acupuncture Therapy↗

Glyceryl trinitrate and ritodrine in tocolysis: an international multicenter randomized study. GTN Preterm Labour Investigation Group.

OBJECTIVE: To compare the efficacy of transdermal glyceryl trinitrate and intravenous (IV) ritodrine as tocolytics. METHODS: Two hundred forty-five women with preterm labor and intact membranes between 24 and 36 weeks' gestation were randomized to transdermal glyceryl trinitrate or intravenous ritodrine. Treatment was continued until contractions stopped or a maximum of 7 days. Glyceryl trinitrate was administered as a 10- or 20-mg transdermal patch. Intravenous ritodrine was administered according to nationally available guidelines. The primary outcome was prolongation of gestation expressed as a percentage of the time from entry to 37 weeks. Secondary outcomes were proportion of women who delivered the same day, next day, or within 7 and 14 days of entry, and by 32, 34, and 37 weeks. Analysis was by intention to treat. RESULTS: Twelve women (5%) were lost to follow-up. Glyceryl trinitrate and ritodrine prolonged gestation by 74% of time to 37 weeks (difference glyceryl trinitrate-ritodrine 0%; 95% confidence interval (CI) -10%, +10%). There was no significant difference in the proportion of women receiving glyceryl trinitrate or ritodrine who delivered within the specified days from study entry or weeks of gestation; however, 42 women who received glyceryl trinitrate and 58 women who received ritodrine delivered by 37 weeks (difference -11%; 95% CI -24%, +2%). No serious maternal side effects were reported for ritodrine or glyceryl trinitrate. CONCLUSION: We found no overall difference between glyceryl trinitrate and ritodrine in the acute tocolysis of preterm labor but a suggested advantage of glyceryl trinitrate over ritodrine in reducing preterm delivery rate. The maternal side effect profile and treatment discontinuation rates were fewer for glyceryl trinitrate, suggesting it was a safer alternative to ritodrine.

Adolescent↗

New perspectives on the overactive bladder: pharmacokinetics and bioavailability.

In the United States alone, approximately 17 million men and women have symptoms of overactive bladder (OAB). For many years, oxybutynin was the drug of choice for treating OAB. Although it provided effective treatment, multiple daily doses were required, and adverse events, such as dry mouth and constipation, were decided drawbacks. Controlled drug delivery systems seen in commercially available OAB formulations alter the pharmacokinetics of antimuscarinic medications in ways that maintain efficacy and allow once-daily dosing and reduction of adverse events. In the future, OAB medications will not only incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but will also use novel drug delivery technologies, including transdermal patches and bladder implants.

Administration, Cutaneous↗

Recently approved and experimental methods of contraception.

The U.S. Food and Drug Administration has recently approved two new contraceptive methods, and others are nearing approval. In addition, several innovative approaches to contraception are under investigation. This paper details the latest information on the following methods: Paragard Copper T 380A intrauterine device, cervical cap, NORPLANT, vaginal pouch, long-acting injectables, hormonal vaginal ring, transdermal patch, experimental male methods, inhibin, and contraceptive vaccines.

Contraception↗

Effects of transdermal nicotine on cognitive performance in Down's syndrome.

Down's syndrome involves age-dependent neuropathological and neurochemical changes similar to Alzheimer's disease, with cholinergic deficits being the most consistent. There is currently no proven treatment for Down's syndrome. We investigated the effect of nicotine-agonistic stimulation with 5 mg transdermal patches, compared with placebo, on cognitive performance in five adults with the disorder. Improvements possibly related to attention and information processing were seen for Down's syndrome patients compared with healthy controls. Our preliminary findings are encouraging, although not generalizable because of small numbers.

Administration, Cutaneous↗

Suppressing sympathetic activation with clonidine on ventricular arrhythmias in congestive heart failure.

This randomized, double-blind, placebo-controlled study examines the effects of clonidine (a centrally acting sympathoinhibitor) on ventricular arrhythmias in 35 patients with congestive heart failure (CHF) by using the 24-h ambulatory electrocardiographic recording. After baseline examination and Holter recording, patients were balanced and 18 patients were randomized to clonidine group and 17 patients to placebo group. After four weeks of clonidine (given as a transdermal patch) or matching placebo therapy, a second Holter recording was obtained. The placebo group showed no change in the frequency of ventricular arrhythmias whereas the clonidine-treated group showed a significant decrease in the frequency of ventricular premature beats by 68% (P<0.01), couplets by 63% (P<0.01) and episodes of non-sustained ventricular tachycardia by 60% (P<0.05). Clonidine also decreased heart rate and arterial blood pressure, but left ventricular ejection fraction was slightly improved. It is concluded that sympathetic suppression with clonidine reduces the frequency of ventricular arrhythmias in patients with CHF, which suggests that sympathetic activation plays a role in arrhythmogenesis in these patients.

Adult↗

Proniosome based transdermal delivery of levonorgestrel for effective contraception.

A proniosome based transdermal drug delivery system of levonorgestrel (LN) was developed and extensively characterized both in vitro and in vivo. The proniosomal structure was liquid crystalline-compact niosomes hybrid which could be converted into niosomes upon hydration. The system was evaluated in vitro for drug loading, rate of hydration (spontaneity), vesicle size, polydispersity, entrapment efficiency and drug diffusion across rat skin. The effect of composition of formulation, amount of drug, type of Spans, alcohols and sonication time on transdermal permeation profile was observed. The stability studies were performed at 4 degrees C and at room temperature. The biological assay for progestational activity included endometrial assay and inhibition with the formation of corpora lutea. The study demonstrated the utility of proniosomal transdermal patch bearing levonorgestrel for effective contraception.

Administration, Cutaneous↗

Prolonged delivery of nicotine in rats via nasal administration of proliposomes.

In order to achieve a prolonged delivery of nicotine to the systemic circulation, proliposomes containing nicotine base (NB-proliposomes) or nicotine hydrogen tartarate salt (NS-proliposomes) and a mixture of powdered nicotine hydrogen tartarate salt and sorbitol (1:9 mixture, MP) were administered intranasally to rats at a nicotine dose of 1 mg/kg. Proliposomes, lipid-sorbitol mixtures that form liposomes upon contact with water, were prepared according to previously established methods, and the mixture (MP) was prepared by mixing NS powder with sorbitol particles (105-350 micrometer in size). Nasal absorption of nicotine from these formulations was very rapid (i.e. less than 10 min was required to reach plasma peaks) and showed substantially sustained plasma nicotine levels compared to saline solutions of NB and NS, and previously reported nasal nicotine sprays. The AUC values from the proliposomes and MP were comparable to those from the saline solutions of NB and NS. However, the mean residence time (MRT) and plasma half-life (T(1/2beta)) of nicotine in the present study were much larger than those from the saline solutions. Thus, a prolonged delivery of nicotine to systemic circulation via the application of proliposomes or MP intranasally appears feasible. NB-proliposomes exhibited the best characteristics in terms of the area under the plasma concentration (AUC), MRT and T(1/2beta) of nicotine, which was followed by NS-proliposomes and MP. Retarded conversion of proliposomes and MP to liposomal emulsions and solution in the nasal cavity seems responsible, in part, for the sustained plasma nicotine concentrations, since the emulsions and solution yielded very short MRT and T(1/2beta) of nicotine. In addition, reduced metabolism to cotinine from the proliposomes and MP was apparently responsible for the sustained plasma nicotine levels. These dosage forms of nicotine appear to circumvent some of the shortcomings of transdermal patches (i.e. long T(max)) and nasal sprays (i.e. short T(1/2beta) and physicochemical instability).

Administration, Intranasal↗

In vivo efficacy and safety of skin electroporation.

This article reviews the studies on skin electroporation carried out in vivo in animals and emphasizes its potential therapeutic applications for transdermal and topical drug delivery. In agreement with in vitro studies, transport across skin due to high-voltage pulses in vivo was shown to increase by orders of magnitude on a timescale of minutes. Increased transdermal transport was measured by systemic blood uptake and/or pharmacological response, and demonstrated for calcein, a fluorescent tracer, fentanyl, a potent analgesic and flurbiprofen, an antiinflammatory drug. Combined electroporation with iontophoresis was shown to provide rapidly responsive transdermal transport of luteinizing hormone releasing hormone ex vivo as well. These data underline the potential of skin electroporation for improving the delivery profile of existing conventional transdermal patches, but also for replacing the injectable route.High-voltage pulses can increase drug permeation within and across skin but are also an efficient tool to permeabilize the membrane of cells of the cutaneous or subcutaneous tissue. This was shown beneficial for targeting cutaneous cells with oligonucleotides or genes and might open new opportunities for gene therapy and DNA vaccination.The safety of the application of high-voltage pulses on skin was assessed in vivo, using histological and visual scores, and bioengineering methods. While changes in skin barrier and function were observed, the irritation was mild and short-lived. Further optimization of the electrode configuration for improved targeting of the stratum corneum should still improve tolerance and levels of sensation.

Journal Article↗