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Mild serotonin syndrome associated with concurrent linezolid and fluoxetine.

PURPOSE: A case of serotonin syndrome that developed during concurrent linezolid and fluoxetine is presented. SUMMARY: A 23-year-old white male patient was originally admitted to receive intravenous chemotherapy for acute myelogenous leukemia. He had a history of intravenous amphetamine abuse, hepatitis B virus infection, hepatitis C virus infection, depression, and bipolar disorder. The patient's routine medications before admission included methadone, fluoxetine, voriconazole, transdermal nicotine patch, lorazepam, and quetiapine. The patient developed persistent neutropenia and complications from chemotherapy, including mild mucositis. Despite treatment with levofloxacin, acyclovir, and voriconazole, the patient developed high fevers. Levofloxacin was discontinued and aztreonam and vancomycin were started. After a blood culture revealed that the bacteria were likely vancomycin resistant, vancomycin was discontinued and linezolid was initiated. Nine hours later, the patient began complaining of severe pain in his abdomen. After a total of four doses of linezolid, the patient reported further discomfort. Two days after linezolid initiation, a health care team member identified the interaction between fluoxetine and linezolid as the cause of the patient's symptoms, and linezolid was discontinued. All symptoms resolved within 48 hours. While resolution generally occurs within 24-48 hours after discontinuing the offending agent, the time to resolution may be delayed if the agent has a long half-life or active metabolites, in which case admission to an intensive care unit is recommended. Cyproheptadine and chlorpromazine may also be used to treat symptoms. CONCLUSION: Serotonin syndrome developed in a patient taking concurrent linezolid and fluoxetine.

Acetamides↗

Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing the method of administration.

Nitrate usage worldwide is on the increase as the indications for therapy expand. Present indications for nitrate therapy include chronic stable angina pectoris, unstable angina pectoris, complications of acute myocardial infarction, and 'unloading' therapy for acute and chronic congestive heart failure. Nitrates are also being used in the operating suite by anaesthesiologists to control systolic blood pressure during various surgical procedures. New nitrate delivery systems have recently become available which provide considerable dosing flexibility, further increasing the interest in this group of compounds. The dominant action of nitrates is a direct effect on vascular smooth muscle, producing vasodilation of the veins and arteries. These drugs decrease myocardial work by lowering systolic blood pressure, systemic vascular resistance, and reducing intracardiac dimensions. In addition, nitrates have a potent effect on cardiac preload as a result of systemic venodilatation. There is also some evidence that nitrates exert direct effects on the coronary circulation (vasodilatation of coronary arteries and coronary collateral vessels, and direct atherosclerotic stenosis dilatation). These actions may play a role in relieving myocardial ischaemia. Adverse sequelae of nitrate therapy are well known and serious adverse reactions are uncommon. Headache and dizziness are the most frequent side effects. Nitrate tolerance is a definite problem - present evidence indicates that long acting formulations, high doses, or frequent dosing regimens are particularly likely to induce vascular tolerance to nitrates. Consequently, provision of a nitrate-free interval has taken on increasing significance as a strategy to avoid tolerance. Nitrate delivery systems are numerous. Although availability varies from country to country, in most countries there are a wide variety of formulations of glyceryl trinitrate (nitroglycerin) available, including sublingual and oral tablets, oral spray, topical ointment as well as discs or patches for transdermal administration, a transmucosal tablet and an intravenous formulation. Similar formulations of isosorbide dinitrate, except buccal tablets, are available in some countries. Isosorbide 5-mononitrate, a potent metabolite of isosorbide dinitrate, is achieving increasing popularity as an antianginal drug. Optimum nitrate therapy requires a good understanding of the properties of the various formulations, particularly onset and duration of action and propensity to induce tolerance.(ABSTRACT TRUNCATED AT 400 WORDS)

Angina Pectoris↗

Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes.

Increased glucose utilization by aldose reductase (AR) has been implicated in the development of diabetes complications. However, the mechanisms that regulate AR during diabetes remain unknown. Herein we report that several nitric oxide (NO) donors prevent ex vivo synthesis of sorbitol in erythrocytes obtained from diabetic or nondiabetic rats. Compared with erythrocytes of nondiabetic rats, the AR activity in the erythrocytes of diabetic rats was less sensitive to inhibition by NO donors or by AR inhibitors-sorbinil or tolrestat. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, enhanced AR activity and sorbitol accumulation in tissues of nondiabetic rats. Application of transdermal nitroglycerin patches or treatment with L-arginine did not inhibit AR activity or sorbitol accumulation in the tissues of nondiabetic animals. Treatment with L-NAME increased, whereas treatment with L-arginine or nitroglycerine patches decreased AR activity and sorbitol content in tissues of diabetic rats. These observations suggest that NO maintains AR in an inactive state and that this repression is relieved in diabetic tissues. Thus, increasing NO availability may be a useful strategy for inhibiting the polyol pathway and preventing the development of diabetes complications.

Aldehyde Reductase↗

Fatal intravenous misuse of transdermal fentanyl.

The introduction of a transdermal delivery system for fentanyl means that it is now more readily available. We present the first documented fatality after intravenous injection of the contents of a transdermal fentanyl patch. Prescribers need to be aware of the potential for misuse of fentanyl patches.

Administration, Cutaneous↗

Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat.

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ET(A) receptor antagonist ZD2574 to determine whether chronic ET(A) receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC(50) value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ET(A) receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ET(B) receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

Animals↗

A pitfall to avoid when starting a patient on transdermal fentanyl.

BACKGROUND: A woman with advanced carcinoma of the ovary developed fentanyl toxicity while being changed from oral morphine to transdermal fentanyl. OBJECTIVE: To explain the reason for the toxicity and ways to avoid it. DISCUSSION: The transdermal fentanyl patch is proving to be a safe, well tolerated and effective treatment modality in the control of cancer pain, but care has to be exercised when using this drug, especially at the time of initiation, as the consequences may be disastrous for the patient.

Administration, Cutaneous↗

[Serum estradiol levels in early postoperative period after surgical castration--the influence of estrogen replacement therapy].

In 40 premenopausal women who underwent TAH&BSO serum E2 levels were measured by means of RIA in 3 time points: before the operation, in the postoperative day 2 and in the postoperative day 3. In 20 of the subjects the ERT (transdermal estradiol 0.1 g/24 h) was introduced in the 2 postoperative day. In the postoperative day 2 the average serum E2 decreased by nearly 90% as compared to the preoperative values. Twenty four hours after the application of the transdermal E2 patch, the estradiol level returned to the values insignificantly different from the preoperative ones.

Administration, Cutaneous↗

[Acute confusional syndrome due to acute nicotine withdrawal].

Delirium or acute confusional state among hospitalized patients is a frequent and serious problem. It is characterized by acute onset symptoms, fluctuating course, impaired attention, unorganized thinking, and altered level of consciousness. Delirium, as a manifestation of acute nicotine withdrawal syndrome has been reported in the reviewed literature only in eight cases. We report the case of a heavy smoker admitted because of a reagudization of his chronic obstructive pulmonary disease. At the third day of nicotine abstinence, he developed delirium with a rapid improvement of his symptoms after treatment with a transdermal nicotine patch. This description suggests that in hospitalized heavy smokers who develop delirium with agitation, a simple trial with a nicotine patch can offer a dramatic therapeutic response in a few hours, constituting additionally a confirmatory test. The recognition of delirium as a manifestation of nicotine withdrawal could allow to determine the origin of symptoms and to apply the appropriate therapy, in certain complex cases that now remain undiagnosed.

Acute Disease↗

[Smoking cessation].

We estimate that more than 80% of tobacco-smokers hope that they will stop smoking one day. The major obstacle is the psychologic and pharmacologic dependence generated by the cigarette. Different weaning methods have been tried, but their rate of success remains low. The nicotinic sustitution by transdermic track (patch) will give good results providing it is prescribed within the framework of a medical help to wean away from smoking tobacco.

Administration, Cutaneous↗

What is a significant response in drug studies of attention-deficit/hyperactivity disorder: statistical significance is necessary, but is it sufficient?

The methods used to report data of clinical treatment trials can influence the interpretation of the results. Reporting that a study drug achieves a statistically significant result does not provide the absolute likelihood and magnitude of benefits. Reporting results using an absolute definition of clinical expectation from a pharmacological intervention may be useful, and characterization of placebo response may help to frame such an absolute definition. The objective of this report was to characterize placebo response in patients with attention-deficit/hyperactivity disorder (ADHD). The design was a double-blind, placebo-controlled trial of a study drug that did not produce a statistically significantly different response from placebo in a multi-center trial. Data from placebo and study drug groups at a single site were collapsed into one group to evaluate response to placebo (or ineffective drug) in a double-blind fashion. Sixty-four children aged 6 to 12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of ADHD (combined type), were enrolled; 57 completed the study. Subjects were randomized to receive either transdermal buspirone patches or matching placebo patches. Mean ADHD Rating Scale (ADHD-RS) score was 44.3 (SD 5.4) at baseline, and 37.4 (SD 10.9) after 6 weeks. Mean ratio of week 6 to baseline ADHD-RS was 0.84 (SD 0.22). Less than 5% of the sample had a 60% or greater decrease in ADHD-RS in response to placebo or ineffective medicine. A 60% decrease in the ADHD-RS seems to constitute one clear definition of clinical expectation from a pharmacological intervention, with minimal possibility of such a decrease occurring as a placebo effect.

Attention Deficit Disorder with Hyperactivity↗

Testosterone supplementation: what and how to give.

Several epidemiological studies have demonstrated a gradual decrease of serum testosterone with aging in men. A considerable number of men will experience hypogonadal androgen levels, defined by the normal range for young men. Thus, in addition to the long-standing use of androgen replacement therapy in the classical forms of primary and secondary hypogonadism, age-associated testosterone deficiency has led to considerable developments in application modes for testosterone. Since oral preparations of testosterone are ineffective, due to the first-pass effect of the liver, or, in case of 17 alpha-alkylation, cause hepatotoxicity, intramuscular injection of long-acting esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. However, the large fluctuations of serum testosterone levels cause unsatisfactory shifts of mood and sexual function in some men; combined with the frequent injections, this delivery mode is thus far from being ideal. In contrast, the transdermal testosterone patches are characterized by favorable pharmacokinetic behavior and have proven to be an effective mode of delivery. Safety data over 10 years indicate no negative effect on the prostate. Nevertheless, the scrotal testosterone patch system is hampered by the application site, which is not easily accepted by many subjects; the non-scrotal patch has a high rate of skin irritations. In view of the drawbacks of the currently available preparations, the most recent developments in testosterone supplementation appear to be highly promising agents. Androgen, which has been available in the United States since mid-2000, will be introduced this year in most European markets as Testogel, a hydroalcoholic gel containing 1% testosterone. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and to correct the signs and symptoms of hypogonadism. The gel has shown to be very effective and successful in American patients, who have benefited from its availability for almost 3 years. Furthermore, in phase II and III clinical studies, the intramuscular injection of 1000 mg testosterone undecanoate every 12-15 weeks has led to extremely stable serum testosterone levels for a prolonged period of time and has resulted in excellent efficacy. It is very likely in the future that these products will be the mainstay of testosterone supplementation. Whereas the indication for testosterone substitution for men with classical forms of hypogonadism is unequivocal, the use of testosterone in men with age-associated hypogonadism is less uniformly accepted. Yet, the few studies addressing this question indicate that men with testosterone serum levels below the lower normal limit for young adult men and with lack of energy, libido, depressed mood and osteoporosis may benefit from testosterone supplementation. However, it should be kept in mind that the experience documented in studies is limited. Nevertheless, serious side-effects, especially in regard to the prostate, did not occur, with the longest study extending over 3 years.

Drug Administration Routes↗

Are nicotine replacement strategies to facilitate smoking cessation safe?

Professional obligations to curb the prevalence of cigarette smoking reflect the importance of this preventable risk factor for innumerable diseases. These include chronic obstructive pulmonary disease and oral, lung and other cancers, although the morbidity and mortality rates for cerebrovascular disease (e.g., ischemic strokes) and cardiovascular disease (e.g., ischemic myocardial infarction) tend to be greater. Various alternative nicotine sources (e.g., transdermal nicotine patches, nicotine gum, nicotine nasal sprays) have been incorporated into smoking cessation programs. This review is intended to increase professional awareness of nicotine delivery systems available in Canada, including safety considerations. The pathogenic potential of nicotine, regardless of source, and the contraindications to the use of nicotine replacement therapies are discussed. However, the systemic nicotine load in individuals undergoing replacement therapy is generally lower than during active smoking. Nicotine is only one of many thousands of constituents of tobacco smoke. Furthermore, nicotine replacement is usually delivered over the short term (a matter of weeks). Therefore, nicotine replacement is recognized as a relatively safe and effective aid to smoking cessation.

Animals↗

[A transdermal form of combined hormonal contraceptives (EVRA)].

OBJECTIVE: To present a review of a novel transdermal contraceptive patch containing norelgestromin (150 micrograms/d) and ethinylestradiol (20 micrograms/d). DESIGN: Review article. SETTING: Department of Gynecology and Obstetric, 1st Medical Faculty and General Faculty Hospital, Prague. RESULTS: The contraceptive patch exhibits favourable pharmakokinetic profile, maintaining efficacious serum hormone concentrations under varying conditions and without peaks and through characteristic of oral dosing. Efficacy, cycle control, tolerability and side effect profile were comparable to an established oral contraceptive. Compliance with the weekly administered contraceptive patch was significantly better than with an oral contraceptive. The reliability of adhesion of the patch is very high and consistent even under varying conditions (heat, humidity, exercise).

Administration, Cutaneous↗

Nicotine dependence and psychiatric disorders.

Nicotine addiction is the single largest preventable cause of morbidity and mortality in the Western World. Smoking is not any more just a bad habit, but a substance addiction problem. The pharmacological aspects of nicotine show that this substance has a broad distribution in the different body compartnents, due mainly to its lipophilic characteristic. There are nicotinic receptors as members of cholinergic receptors' family. They are located in neuromuscular junction and in the central nervous system (CNS). Although they are similar, pentameric structure with an ionic channel to sodium, there are some differences in the protein chains characteristics. Repeated administration of nicotine in rats, results in the sensitization phenomenon, which produces increase in the behavioral locomotor activity response. It has been found that most psychostimulants-induced behavioral sensitization through a nicotine receptor activation. Nicotine receptors in CNS are located mainly in presynaptic membrane and in that way they regulated the release of several neurotransmitters, among them acetylcholine, dopamine, serotonin, and norepinephrine. In some activities like sleep-wake cycle, nicotine receptors have a functional significance. Nicotine receptor stimulation promotes wake time, reduces both, total sleep time and rapid eye movement sleep (REMS). About nicotine dependence, this substance full fills all the criteria for dependence and withdrawal syndrome. There are some people that have more vulnerability for to become nicotine dependent, those are psychiatric patients. Among them schizophrenia, major depression, anxiety disorders and attention deficit disorder, represent the best example in this area. Nicotine may have some beneficial effects, among them are some neuroprotective effects in disorders like Parkinson's disease, and Gilles de la Tourette' syndrome. Also there are several evidences that support the role of nicotine in cognitive improvement functions like attention, concentration, and memory. Finally there are several strategies to deal with nicotine dependence, Nicotine Replacement Therapy (NRT), which are nicotine chewing-gum, transdermal nicotine patches, and nicotine inhalators device. Also some antidepressants like bupropion has shown to be effective in smoking cessation treatment. To know more about nicotine phenomenon would be important, because that will allow a more mature perspective about the damage and beneficial effects of that substance.

Aging↗

Acute mediastinitis: a severe complication of transdermal therapy in a patient with ischaemic heart disease. A case report.

Acute mediastinitis is an uncommon and potentially devastating infection. Generally, mediastinitis occurs as a postoperative infection following median sternotomy. We describe a case of acute mediastinitis in a patient with ischaemic heart disease, secondary to the spread of cutaneous infection of the chest wall in the application site of transdermal nitroglycerine patches.

Acute Disease↗

Seasickness in totally-enclosed motor-propelled survival craft: remedial measures.

Totally-enclosed motor-propelled survival craft (TEMPSC) are used to evacuate the crews of mobile offshore drilling units in emergencies. The small size and flat bottom of the TEMPSC predispose most occupants to seasickness, even in relatively calm waters. This paper discusses efforts required to improve the well-being of occupants in terms of reducing seasickness, dehydration, hypothermia, anxiety, and the other factors that contribute to loss of comfort and the will to survive. Specific recommendations include the provision of climatic control to regulate temperature, remove odors and provide fresh air; potable water, electrolytes, and survival rations; and an ample supply of motion sickness bags. Overcrowding should be avoided. Anti-motion-sickness drug therapy to control vomiting should be administered in two ways: initial injection of intramuscular scopolamine for fast action followed by a transdermal ear patch for long-term protection. Leadership and seasickness management should be requisite survival training for all oil rig workers.

Antiemetics↗

[Parenteral opioids in end-of-life care in cancer patients].

The ethical obligation to relieve pain and other distressing symptoms in patients with cancer is now receiving increasing attention and concern in palliative and end-of-life care. The vast majority of patients with cancer pain are prescribed opioids in oral formulation. However, a patient at the end of his or her life often needs parenteral administration of opioids as the medical condition deteriorates, irrespective of using sedatives. Controlled release opioid preparations currently available in Japan are CR morphine sulphate, CR oxycodone and transdermal fentanyl patch. The opioids available in injectable preparations are morphine HCL and fentanyl citrate. Accordingly, not only the guideline for switching opioids, so-called "opioid rotation," but the guideline for changing the opioid administration route is also necessary in end-of-life care. The authors specifically indicate when and how to convert opioid administration from the oral to the parental route.

Analgesia, Patient-Controlled↗

Ovum donation program at Chang Gung Memorial Hospital, Taipei.

The ovum donation program at Chang Gung Memorial Hospital currently confronts the difficulty of limited oocyte resources. The oocytes might be donated from the surplus oocytes of IVF patients. However, after the successful introduction of embryo cryopreservation, patients preferred to have their surplus embryos cryop-reserved and thus, few surplus oocyts were available for donation from IVF program. In addition, official policies discourage use of oocytes donated by consanguineous relatives of either one of the recipient couple or for financial rewards. Among the first three oocytes recipients, with ovarian failure, one chemical pregnancy resulted. Oral premarin and transvaginal and intramuscular progesterone were administered as hormone replacement. The fourth recipient, who had had bilateral oophorectomy, received transdermal estradiol patch (Estraderm) and transvaginal progesterone (Utrogestan) as hormone replacement. The Estraderm/Utrogestan protocol became standard in later cases since the first ongoing pregnancy was achieved in patient 4. We feel this protocol satisfies the required ample levels of hormone replacement for ovum donation.

Adult↗