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Fluphenazine-induced neuroleptic malignant syndrome in a schizophrenic patient.

OBJECTIVE: To report a case of neuroleptic malignant syndrome (NMS) associated with fluphenazine in a schizophrenic patient and review the literature related to this condition. CASE SUMMARY: A 21-year-old African American male with schizophrenia came to our medical intensive care unit from the crisis intervention unit (CIU). He was hyperthermic (oral temperature 40.6 degrees C), diaphoretic, tachycardic (heart rate 140 beats/min), and tachypneic (respiratory rate 22 breaths/min), with severe muscle rigidity and shaking tremors. He had an extensive psychiatric history significant for schizophrenia and multiple past hospital admissions, starting at age 14 years. Two days prior to admission to the CIU, he had been given 25 mg of fluphenazine decanoate injection intramuscularly in addition to his regular psychotropic regimen of thioridazine and haloperidol after reportedly making several verbal threats and displaying aggressive behavior toward the personnel at the group home where he resided. Laboratory studies showed elevated creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels, as well as azotemia, hyperphosphatemia, hypocalcemia, and leukocytosis. DISCUSSION: NMS is a rare but potentially fatal reaction associated with neuroleptic drugs. It occurs in approximately 0.07-2.2% of patients treated with neuroleptics. Risk factors include previous episodes, dehydration, agitation, polypharmacy, and the rate and route of neuroleptic administration. CONCLUSIONS: An objective causality assessment revealed that fluphenazine was the probable cause of NMS in this patient. There was no reaction associated with thioridazine and/or haloperidol. Clinicians need to be aware of this drug-induced condition and the potential increased risk associated with concurrent use of multiple psychotropics.

Adult↗

Atomoxetine ingestions in children: a report from poison centers.

BACKGROUND: Atomoxetine uses a novel non-stimulant approach to the treatment of attention deficit hyperactivity disorder. There is limited information on overdose of atomoxetine in children or adults. OBJECTIVE: To provide information on atomoxetine in overdose. METHODS: Case series were conducted at 3 regional poison centers for atomoxetine ingestion in children (age < or = 17 y). Exclusion criteria were polypharmacy or lack of follow-up. RESULTS: Forty patients were included (25 boys; 63%) in the study. The mean +/- SD age was 6.1 +/- 4.9 years (range 9 mo-17 y). Twenty-five patients were managed at home, 14 in hospital emergency departments (3 children were admitted), and 1 patient was managed in a physician's office. Symptoms reported were tachycardia, drowsiness, nausea, hypertension, and vomiting. A seizure was reported in one child who had recently started atomoxetine therapy. No arrhythmias beyond sinus tachycardia were reported. Mean maximum heart rate in patients with tachycardia was 131 +/- 14 beats/min. The mean dose ingested, categorized by medical outcome, was: no effect (n = 22), 40 +/- 32 mg; minor effect (n = 14), 167 +/- 221 mg; and moderate effect (n = 4), 249 +/- 326 mg. There were no major outcomes or fatalities. The lowest dose ingested that resulted in hypertension was 480 mg, in a 14-year-old girl (BP 136/95 mm Hg). CONCLUSIONS: In this case series, clinically significant cardiovascular effects requiring direct intervention did not occur. Activated charcoal and/or observation appear to be sufficient for accidental ingestion. Further investigation may be needed to indicate whether seizures occur from atomoxetine ingestion.

Adolescent↗

Drug interactions in dentistry: the importance of knowing your CYPs.

BACKGROUND: The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs. Certain medications used in dentistry can act as substrates, inducers or inhibitors of this system. METHODS: The authors conducted a MEDLINE search of articles appearing between 1976 and the present using the keywords "drug interactions" and "cytochrome P450," and reviewed reports involving dental therapeutic agents using PubMed links from an Indiana University CYP450 drug interaction table on the World Wide Web. RESULTS: The antibiotics erythromycin and clarithromycin are potent inhibitors of CYP3A4 and can increase blood levels and toxicity of CYP3A4 substrates. Likewise, quinolone antibiotics such as ciprofloxacin inhibit the metabolism of CYP1A2 substrates. Other dental therapeutic agents are substrates for CYP2C9 (celecoxib, ibuprofen and naproxen), CYP2D6 (codeine and tramadol), CYP3A4 (methylprednisolone) and CYP2E1 (acetaminophen). Because codeine and tramadol are prodrugs, inhibition of their metabolism can lead to a diminution of their analgesic effects. While inducers of acetaminophen metabolism, including alcohol, theoretically can increase the proportion of it that is biotransformed into a potentially hepatotoxic metabolite, recent research suggests that concomitant alcohol intake does not increase the hepatotoxic potential of therapeutic doses of acetaminophen. CONCLUSIONS: A number of clinically significant drug interactions can arise with dental therapeutic agents that act as substrates or inhibitors of the CYP450 system. Clinical Implications. As polypharmacy continues to increase, the likelihood of adverse drug interactions in dentistry will increase as well. Ensuring that patients' medical histories are up to date and acquiring knowledge of the various substrates, inducers and inhibitors of the CYP450 system will help practitioners avoid potentially serious adverse drug interactions.

Cytochrome P-450 Enzyme Inhibitors↗

Recent developments in the pharmacological treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.

Antiparkinson Agents↗

Drug treatment of non-motor symptoms in Parkinson's disease.

Non-motor symptoms may considerably reduce parkinsonian quality of life, particularly in advanced stages of the disease. Autonomic features, such as seborrhoea, hyperhidrosis, orthostatic hypotension, excessive salivation, bladder dysfunction and GI disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis and dementia, appear in the course of Parkinson's disease. Pharmacotherapy of these non-motor symptoms complicates long-term antiparkinsonian combination drug therapy due to possible drug interactions, side effects and changes in metabolism. Moreover, antiparkinsonian compounds themselves contribute to the onset of these non-motor symptoms to a considerable extent. This complicates differentiation between the disease process itself and drug-related effects, thus influencing therapeutic options, which are often limited because of comorbidity and polypharmacy. Therefore, standardised recommendations are questionable, since drug tolerability and response differ between patients. Nevertheless, this review tries to provide a survey of possible therapeutic options for the treatment of the symptoms of Parkinson's disease other the dopamine-sensitive motor features.

Animals↗

Clinical use of nifedipine GITS in the treatment of hypertension: an overview.

Given the major role of elevated blood pressure in the pathogenesis of both stroke and coronary heart disease, one of the biggest challenges facing public health authorities and medical practitioners is the control of hypertension worldwide, both in individual patients and at the population level. The prevalence of hypertension increases with age and is nearly 60% in people aged 65 - 74 years. With increasing age, polymorbidity and polypharmacy usually contribute to an increasingly complex approach to manage the respective clinical conditions, including the treatment of hypertension. All subgroups of calcium channel blockers are effective and well-tolerated in lowering blood pressure. They are of demonstrated benefit for the prevention of stroke in elderly patients with systolic hypertension. Calcium channel blockers are particularly recommended for elderly patients with systolic hypertension and for black patients. The nifedipine gastrointestinal therapeutic system (GITS) formulation provides a once-daily dosing regimen with a continuous and slow release of the drug, resulting in a smooth plasma concentration/time profile. The INSIGHT study established that nifedipine GITS decreased mortality and morbidity at the same level as standard diuretic treatment in hypertensive patients with additional risk factors. A subgroup analysis showed that the long-term protective effects of nifedipine GITS extended to hypertensive patients with diabetes mellitus and with previous myocardial infarction. Two substudies of INSIGHT showed that nifedipine slowed the progression of atherosclerosis in carotid arteries (intima-media thickness) and coronary arteries (coronary calcium) as compared to diuretic.

Delayed-Action Preparations↗

Prepubertal bipolar disorder: available pharmacological treatment options.

Awareness of bipolar spectrum disorders in children is rapidly increasing, with a more precise definition of their clinical subtypes and early signs. Paediatric bipolar disorder can lead to an important impairment in scholastic, familial and social functioning, and to a higher risk for substance abuse and suicide. In the context of a multimodal approach, the core treatment of early-onset bipolar disorder is pharmacological. This review focuses on the empirical evidence for pharmacotherapy in paediatric bipolar disorder. Mood stabilizers, including lithium, and older and newer anticonvulsivants will be considered, in mono- or polypharmacy. Atypical antipsychotics will be considered in more severe and/or treatment-resistant manic or mixed episodes. Finally, the prophylaxis of intercritical phases and the management of specific challenging conditions, such as bipolar depression and attention deficit hyperactivity disorder, with bipolar comorbidity, will be reviewed.

Antidepressive Agents↗

Advances in antiplatelet therapy.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the western world. These disorders share a common pathophysiology -- atherosclerosis, which affects various arterial beds, leading to protean manifestations (coronary artery disease [CAD], stroke, peripheral arterial disease [PAD]). The platelet plays a pivotal role in the perpetuation and clinical expression of these disorders. The platelet, once believed to have a role confined to modulation of thrombosis and haemostasis, also plays an active role in vascular inflammation. Antiplatelet agents have become first-line therapy for CVD, and their unequivocal benefits are demonstrated in various basic and experimental models and supported by overwhelming evidence from clinical trials. Search is underway for more effective and safer antiplatelet therapy. Novel therapies are emerging to target the redundant pathways of platelet adhesion, activation and aggregation. Efforts are also ongoing to enhance implementation of existent therapy, target therapy selectively to high-risk patients and to those likely to respond (pharmacogenomics), and study the incremental benefits and safety of various antiplatelet combinations and their interaction with other medications in patients with CVD treated with polypharmacy.

Adenosine Diphosphate↗

Hepatotoxicity of chemotherapy.

The selection of a chemotherapeutic regimen for the oncology patient is based on a thorough assessment of potential hazards relating to the patient's clinical condition and the toxicities of chemotherapy. Liver function abnormalities are commonly seen in this patient population and deducing their aetiology may be difficult. Immunosuppression, paraneoplastic phenomena, infectious disease, metastases and polypharmacy may all confound the clinical picture. While criteria for standardising liver injury have been established, dose modifications often rely on empirical clinical judgement. Therefore, a comprehensive understanding of hepatotoxic manifestations for the most common chemotherapeutic agents is essential. This article reviews the hepatotoxicity of commonly utilised antineoplastic agents.

Antineoplastic Agents↗

Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era.

Combination lipid-altering regimens represent an emerging clinical paradigm to meet increasingly stringent consensus lipoprotein targets for coronary prevention. This practice, together with escalating prevalences of coronary artery disease in certain ageing (western industrial) populations, polypharmacy in the elderly and the recent voluntary market withdrawal of cerivastatin, warrants a re-examination of the safety profiles of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (i.e., statins). These agents are exceedingly well-tolerated in the vast majority of patients, very infrequently precipitating musculoskeletal symptoms and/or signs. Statins vary in their pharmacological profiles, leading to distinct levels of systemic exposure and capacities to penetrate skeletal myocytes. Pharmacokinetic interactions with certain agents increase the likelihood of statin-induced myopathy and, in exceedingly rare instances, potentially fatal rhabdomyolysis with myoglobinuria and renal failure. As with other medical decisions, the anticipated benefits of long-term statin therapy, with or without other lipid-altering agents, need to be weighed against the prospects of clinically significant drug interactions. In clinical trials and postmarketing surveillance, the two statins that are not metabolised by the cytochrome P450 3A4 system (fluvastatin and pravastatin) have exhibited very low propensities to elicit myopathy when combined with other agents. These agents should be considered initially when contemplating combination lipid-lowering regimens for coronary prevention.

Cytochrome P-450 Enzyme System↗

Drug interactions with angiotensin receptor blockers.

Many patients with high blood pressure receive multiple medications for hypertension and other conditions, placing them at risk for adverse drug interactions. Additionally, as the prevalence of hypertension increases with age, factors like greater frailty, comorbidity of the elderly requiring polypharmacy, and reduced hepatic and renal clearance rates for the elimination of drugs increase the likelihood of drug interactions. Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. Due to a favourable side effect profile, this class of drugs deserves increased attention. This article reviews drug interactions of ARBs and suggests measures for reducing the risk of adverse events when drugs are co-administered. MEDLINE, EMBASE, Cochrane library, and CINAHL were searched. Reported and likely clinical relevant interactions of ARBs with concomitantly given drugs are summarised in Table 2 and 3. Compared to other classes of antihypertensive agents, the ARBs appear to have a low potential for drug interactions; however, interactions with this class occur and variations within the class have been detected, mainly due to different affinities for cytochrome P450 isoenzymes.

Angiotensin II Type 1 Receptor Blockers↗

Obesity and obesity-related illnesses in borderline patients.

The purpose of this study was to examine the prevalence, risk factors, and consequences of obesity in borderline patients 6 years after an index admission for psychiatric reasons. Two hundred and sixty-four borderline patients who met Revised Diagnostic Interview for Borderlines (DIB-R; Zanarini, Gunderson, Frankenburg, & Chauncy, 1989) and Diagnostic and Statistical Manual of Mental Disorders (3rd ed. ref.) (DSM-III-R; APA, 1987) criteria for BPD were interviewed concerning their body mass index (BMI) and related medical problems. Seventy-four of the 264 borderline patients at 6-year follow up were obese, having a BMI > or = 30 kg/m2. They were significantly more likely than the nonobese patients to report suffering from diabetes, hypertension, osteoarthritis, chronic back pain, carpal tunnel syndrome, urinary incontinence, gastroesophageal reflux disorder, gallstones, and asthma. Four significant risk factors were found: chronic PTSD, lack of exercise, a family history of obesity, and a recent history of psychotropic polypharmacy. These results suggest that obesity is common among heavily treated borderline patients and is associated with a number of chronic medical disorders.

Adult↗

Diabetes mellitus associated with recombinant human growth hormone for HIV wasting syndrome.

Recombinant human growth hormone (rhGH) is an important treatment option for patients with human immunodeficiency virus (HIV) wasting syndrome. Side effects of rhGH are minimal when administered at physiologic and moderately high dosages, as seen in growth hormone deficiency and Turner's syndrome, respectively. The dosage of rhGH is significantly higher to treat wasting syndrome and still is being studied to determine its long-term efficacy and safety. Individuals with HIV infection are at increased risk for adverse effects due to polypharmacy, immune system alterations, and treatment with newer agents that lack long-term safety data. In addition, rhGH's potential for side effects becomes greater when given at high dosages for wasting syndrome. Clinically significant hyperglycemia developed in an HIV-positive man who started rhGH for wasting syndrome 38 days before the diagnosis of diabetes mellitus.

Blood Glucose↗

Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature.

The elderly population is at an increased risk for major bleeding, possibly due to increased sensitivity to anticoagulation, multiple comorbidities, and polypharmacy. Elderly patients receiving antiplatelet and anticoagulant therapy have an additional risk for bleeding. Omega-3 fatty acids, also known as fish oil, have been used for hyperlipidemia, coronary heart disease, hypertension, and other conditions. Some studies have demonstrated that consumption of fish oil concentrate, n-3 polyunsaturated fatty acid (n-3 PUFA), results in cardiovascular benefits that include reductions in mortality, sudden death, nonfatal myocardial infarction, and thrombotic stoke, as well as improvement in graft patency. The mechanism of action of n-3 PUFA is not completely understood, but a dual antiplatelet and anticoagulant effect has been proposed. Few data exist on whether or not fish oil can be used safely with other antiplatelet or anticoagulant drugs. We report the case of a patient who after a minor fall developed a subdural hematoma requiring craniotomy that likely was precipitated by concomitant use of high-dose omega-3 fatty acids 6 g/day with both aspirin and warfarin. These findings are important because of the wide availability of omega-3 fatty acids and the propensity for use of complementary and alternative medicine in patients with cardiovascular disease who are already taking antiplatelet and/or anticoagulant agents. Judicious use of these combinations is advised, and pharmacists can play an important role in educating patients and other health care providers about the bleeding risks associated with combination therapy.

Accidental Falls↗

Neuroleptic medication and prescription practices with sheltered-care residents: a 12-year perspective.

OBJECTIVES: Most adult residents of sheltered-care facilities (board and care, family care, psychosocial rehabilitation, and other supported housing arrangements) for the chronically mentally ill receive neuroleptics. These facilities house over 300,000 mentally ill residents, but neuroleptic prescription practices with this population have not been studied. METHODS: A probability sample (n = 393) of all adult former psychiatric patients in sheltered care in California was surveyed in 1973; 94% of the located survivors (n = 243) were reinterviewed 12 years later. RESULTS: In 1973, 79% received neuroleptics; in 1985, 76%. Polypharmacy decreased, and the elderly remained less medicated than adults. Yet, mean daily neuroleptic doses doubled, more persons received higher doses, and 62% reported adverse effects. Furthermore, high dosing was attributed to psychiatrists rather than other physicians, even when controlling for residents clinical and sociodemographic characteristics. CONCLUSIONS: Neuroleptic drugs became the staple pharmacological treatment for mentally ill sheltered-care residents. While physicians more cautiously medicated the elderly, they had not reduced doses by 1985, even after a decade of treatment. The specialty of the prescriber was an important factor in preference for high-dose treatment.

Adolescent↗

Drug-induced delirium. Incidence, management and prevention.

Drugs may be the most frequent single cause of delirium, and very often they are a critical element in a multifactorial aetiology. While delirium may be precipitated by virtually any drug, certain classes of drugs are more commonly implicated. Effective management of drug-induced delirium involves recognition, cessation or dosage reduction of the causative drug(s), and initiation of reorientation strategies and supportive medical care. Specific "antidotes' are appropriate in only a few limited cases. Drug treatment aimed at sedation should be introduced for specific indications, such as aggression, risk of harm to self or others, hallucinations, patient distress, and where compliance with therapy or procedures is essential. Certain benzodiazepines (diazepam, lorazepam, midazolam) and/or haloperidol may be the most appropriate choices in these circumstances. Primary prevention requires the prescription of alternative lower risk medications and the minimisation of polypharmacy. Secondary prevention may be achieved through improved recognition of the condition.

Anti-Infective Agents↗

Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome.

Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I(Kr)) of the delayed rectifier potassium current (I(K)). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of I(Kr) current may precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women's health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block I(Kr), both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks I(Kr) and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac 'repolarisation reserve'. This is an important aspect of I(Kr) blockade to be aware of during the development of new drugs.

Electrocardiography↗

Clinical-pharmacological strategies to assess drug interaction potential during drug development.

Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.

Drug Approval↗