Poisoning with Nicotine Patches

To evaluate potential adverse effects from inadvertent exposure, three marketed TD nicotine products: Nicoderm (drug reservoir and rate-controlling membrane); Nico-tinell (nicotine solution dispersed in cotton gauze between layers of adhesive); and Niconil (nicotine in gel matrix), were administered topically and orally to dogs (133). Topical nicotine doses were 1-2 mg/kg 24 h-1 for all products, with plasma con centrations 43 ng/mL, or less. Of 12 topical exposures (with Nicotinell and Niconil) 2 were associated with clinical signs (excess salivation or emesis). Oral doses (2.8 mg/kg [one patch] to 13.4 mg/kg [two patches] over 25-57 h), were two- to ninefold higher than the oral doses reported to produce severe toxicity in children, and the higher dose was within the known lethal range for dogs. Oral dosing of Nicotinell and Niconil (two patches per dog) produced vomiting in 2 of 12 exposures. No clinical signs were observed with either topical or oral dosing of Nicoderm. Characteristics and outcomes of U.S. poisoning cases, involving dermal human application of multiple nicotine TD systems, were evaluated (134). Nine cases of dermal exposure to 2-20 nicotine TD systems resulted from intentional misuse or suicide attempts and included concomitant exposure to other drugs in 7 of 9 cases. Mean age was 45 years, and 7 of 9 patients were female. All suffered medical complications, including seizures, other CNS changes, cardiovascular effects, and respiratory failure, but plasma nicotine-cotinine levels did not correlate with the severity of illness. Eight patients were hospitalized, but all recovered.

B. Glyceryl Trinitrate and Related Drugs

Measurement of plasma concentrations of glyceryl trinitrate (GTN) is very difficult owing to the unusual pharmacokinetics, with very rapid disappearance from plasma, and large intraindividual and interindividual variations (135). There is extensive firstpass hepatic extraction after oral administration and plasma levels are often undetectable. With controlled-release TD GTN systems, plasma concentrations can be maintained over 24 h, but with fluctuations and important intra- and interindividual variability. After administration of GTN by any route, glyceryl dinitrates and mononitrates are found in plasma. Bioavailability and main pharmacokinetic parameters of the GTN metabolites 1,2- and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) were determined following application of two types of GTN TDS in healthy volunteers

(136). For 1,2-GDN, AUCs(0-rlast) were 23.77 h ng"1 mL"1 (patch A) and 27.83 h ng"1 mL"1 (patch B). Peak plasma levels were 2.45 ng/mL (at 6.4 h) and 2.93 ng/ mL (at 8.3 h), respectively. For 1,3-GDN AUCs(0-rlast) were 3.32 h ng"1 mL"1 (patch A) and 3.81 h, ng"1 mL"1 (patch B). Peak plasma levels were 0.35 ng/mL (at 6.4 h) and 0.41 ng/mL (at 7.9 h), respectively. Statistical comparison showed bioequiva-lence between these TD systems for the metabolites investigated. Typical side effects observed after nitrate therapy also occurred.

The efficacy of lisinopril, TD GTN, and their combination in improving survival and ventricular function after acute myocardial infarction (AMI) was assessed

(137). A total of 19,394 patients were randomized from 200 coronary care units in Italy and assigned 6 weeks of oral lisinopril (5-mg initial dose and then 10 mg daily), or open control, as well as nitrates (intravenous for the first 24 h followed by TD GTN 10 mg/day) or open control. Lisinopril, started within 24 h after AMI symptoms began, produced significant reductions in overall mortality and in the combined outcome measure of mortality and severe ventricular dysfunction. Administration of TD GTN did not show any independent effect on the same outcome measures. Systematic combined administration of lisinopril and GTN produced significant reductions in overall mortality and in the combined endpoint. The effects of a GTN TDS on platelet aggregation was examined in eight normal volunteers (138). A significant effect of TD GTN on platelet aggregation was demonstrated in the presence and absence of iloprost, but the clinical significance of the antiplatelet effect of TD GTN remained unknown.

The anti-inflammatory and analgesic effects of TD GTN was studied in 21 patients with mild to moderate leg varicose veins who underwent vein sclerotherapy in both legs (139). The vein in one leg was treated every 8 h with GTN and compared with a placebo ointment applied to the vein of the other leg. Inflammation signs were observed in all cases 15 min after first application. Intensity of inflammation signs were 26% in GTN-treated veins and 61.5% in placebo-treated veins. One hour later only 63% of cases in the GTN group, but all cases in the placebo group, showed signs of thrombophlebitis. All veins in the GTN group were free of signs of thrombophlebitis in fewer than 48 h, whereas, of the placebo group, 45% required more than 48 h.

Intermittent TD GTN therapy with a 10- to 12-h-patch-free period each day has documented clinical benefits. The antianginal and anti-ischemic effects of three dose levels of TD GTN applied for 12 h daily for 30 days and the development of tolerance and rebound were assessed (140). There was a significant increase in treadmill walking time to moderate angina in each GTN patch group, compared with placebo, at time points up to 12 h throughout the 30-day period. Secondary efficacy parameters supported the primary efficacy results,and there was no evidence of tolerance or rebound. Transdermal GTN is widely used to treat angina pectoris, but development of tolerance is a major problem (141). The effects of short (5 h) and prolonged (3 days) exposure to transdermal GTN patches on the development of tolerance in terms of hemodynamics and vascular reactivity in the conscious rabbit were, therefore, investigated. It was concluded that in the rabbit, prolonged exposure to clinical GTN patches caused hemodynamic compensation and baroreflex resetting, but no evidence of vascular reactivity tolerance.

The efficacy of adding transdermal GTN or oral N-acetylcysteine, or both, to conventional medical therapy was examined (142) in a trial of 200 patients with unstable angina, followed-up for 4 months. Death, myocardial infarction, or refractory angina requiring revascularization occurred in 31% of patients receiving GTN, 42% of those receiving ^-acetylcysteine, 13% of those receiving GTN plus N-ace-tylcysteine, and 39% of those receiving placebo. There was higher probability of no treatment failure when receiving both GTN and N-acetylcysteine than with placebo, N-acetylcysteine, or GTN alone. However, combination of GTN and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache.

The relation between tolerance development, counterregulatory responses, and arterial vasodilating effects were studied in 20 patients with stable angina pectoris who were exercise tested before, after 2 h, and 24 h of nitrate patch treatment (143). Effects observed after 2 h of treatment on exercise duration, ST-segment depression, blood pressure, and heart rate were usually lost by 24 h, although effects on arterial pulse curves persisted after 24 h, with a mean change from baseline of 29%, compared with 33% at 2 h. After 24 h, a significant decrease in hematocrit and an increase in body weight were observed. Hematocrit changes correlated with loss of clinical efficacy. It was concluded that clinical nitrate tolerance may be observed despite maintenance of arterial vasodilating effects, and that tolerance is more related to plasma volume expansion as a counterregulatory mechanism.

A subsequent study (144) examined whether GTN TDS treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Twenty angina patients were exercise-tested after 2 and 24 h of treatment and 2 h after device renewal. The TDS was either renewed at a new skin location or on the previous application site. Clinical efficacy, the effect seen on plethysmography, and GTN plasma concentrations, all tended to increase after TDS renewal, regardless of the application site indicating that cutaneous changes of clinical importance were not demonstrated. The effect of GTN in patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibition was evaluated (145). High-dose (50-100 mg) TD GTN or placebo were given daily for 12 h in 29 patients with CHF. Exercise time (4 h after patch application) showed progressive improvement during GTN administration. GTN decreased left ventricular end-diastolic and end-systolic dimensions and augmented LV fractional shortening.

Clinical efficacy of, and patient tolerance to, sustained-release GTN TDS in the treatment of Raynaud's phenomenon was reported (146). Patients had primary Raynaud's disease or Raynaud's phenomenon secondary to systemic sclerosis. GTN TD (0.2 mg/h) was effective in reducing both number and severity of Raynaud's attacks, but headaches led to withdrawal of 8 patients and occurred in about 80% of remaining patients. A clinical study in 20 patients with shoulder pain syndrome caused by supraspinatus tendinitis was conducted to determine whether TD GTN has analgesic action in this condition (147). One 5-mg GTN (Nitroplast) patch (or placebo patch) was applied per day over 3 days in the most painful area. Follow-up showed a significant decrease in intensity of pain at 24 and 48 h in the GTN group, but no change in the placebo group. It was concluded that GTN could be a useful approach to management of this common condition and other tendon musculoskeletal disorders.

The 24-h effect of TD GTN on splanchnic hemodynamics in nine patients with biopsy-proved liver cirrhosis was evaluated (148). GTN tape, capable of releasing 15 mg of drug in 24 h, was applied to chest skin at 7 am of the second day. After GTN application, the mean portal blood velocity and flow significantly decreased by 18 and 22%, whereas superior mesenteric artery velocity decreased and resistance indices increased. This indicated that GTN, from a transdermal long-acting system, significantly influenced portal hemodynamics in liver cirrhosis, and the use of GTN was proposed for long-term clinical studies to test efficacy in preventing gastrointestinal bleeding.

The role of TD GTN, as a source of exogenous nitric oxide, in the management of primary dysmenorrhea was investigated (149) in a multinational study. Eighty-eight patients from six countries were evaluated during three menstrual cycles while receiving GTN (0.1 mg/h) or placebo patches. The data indicated that TD GTN, as a source of exogenous nitric oxide, was useful as a modulator of uterine contractility and represented a new and mechanistically different therapeutic alternative for management of primary dysmenorrhea.

The maternal and fetal cardiovascular effects of TD GTN compared with ri-todrine for acute tocolysis (150) were studied in 60 women in preterm labor. At doses required for acute tocolysis, TD GTN had minimal effects on maternal pulse, blood pressure (BP), or fetal heart rate, and significantly fewer adverse cardiovascular effects than intravenous ritodrine. It was concluded that TD GTN may be a safer treatment for women in preterm labor.

The efficacy of TD GTN and intravenous ritodrine as tocolytics was also evaluated in an international study (151). A total of 245 women with preterm labor and intact membranes between 24- and 36-weeks gestation were randomized to TD GTN (10 to 20 mg patch) or intravenous ritodrine. GTN and ritodrine prolonged gestation by 74% to 37 weeks. There was no significant difference in the proportion of women receiving GTN or ritodrine who delivered within the specified days from study entry or weeks of gestation, and no serious maternal side effects were reported for either. It was concluded that there was no overall difference between GTN and ritodrine in the acute tocolysis of preterm labor, but there was a suggested advantage of GTN over ritodrine in reducing preterm delivery rate. Maternal side effect profile and treatment discontinuation rates were fewer for GTN, suggesting it was the safer alternative.

The nitric oxide (NO) donor morpholinosydnonmine has been reported to inhibit insulin release in isolated pancreatic islets; accordingly, the effect of TD GTN, an alternative NO donor, on glucose-stimulated insulin release was studied in healthy, young, male volunteers (152). Oral glucose tolerance tests were performed in the presence of placebo or TD GTN (~0.4 mg/h of GTN) in the same patients, with a 2-week intertest interval. Glucose-stimulated maximum increases in plasma insulin immunoreactivity were 36.3 ± 5 and 78.8 ± 6.1 mU/mL in the presence of active and placebo patches, respectively, although both fasting and postload blood glucose levels were equal. Active patches significantly decreased blood pressure with a marginal increase in heart rate. It was concluded that inhibition of glucose-stimulated insulin release by TD GTN without causing hyperglycemia may be a novel component of the antianginal action mechanism of nitrates.

Benzoxazinones are a potent new class of organic nitrates used in cardiovascular therapy that have a coronary vascular selectivity greater than that of GTN and isosorbide dinitrate. The ability of these new derivatives to reach therapeutic steady-state plasma concentrations after TD administration was investigated in vitro using human skin (153). Two members of this class: sinitrodil (ITF 296) and ITF 1129 were compared with GTN, isosorbide dinitrate, and nicorandil at two concentrations (0.08% w/v and saturated solutions). Sinitrodil was considered a good candidate for transdermal administration.

A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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