First-choice Agent Research Articles

18FDG-PET at 1-Month Intervals Is a Better Predictive Marker for GISTs That Are Difficult to Be Diagnosed Histopathologically: A Case Report

Imatinib mesylate is a tyrosine kinase inhibitor of c-KIT and PDGFRA. Imatinib mesylate is an effective drug that can be used as a first-choice agent for treatment of GISTs. Prior to treatment, molecular diagnosis of c-KIT or PDGFRA is necessary; however, in some types of GISTs, it is impossible to obtain a sufficient amount of specimen for diagnosis. An inoperable or marginally resectable GIST in a 79-year-old female was difficult to be diagnosed at a molecular pathological level, and hence, exploratory treatment was initiated using imatinib combined with 18FDG-PET evaluation at 1-month intervals. PET imaging indicated a positive response, and so we continued imatinib treatment in an NAC setting for 4 months. As a result, curative resection of the entire tumor was successfully performed with organ preservation and minimally invasive surgery. 18FDG-PET evaluation at 1-month intervals is beneficial for GISTs that are difficult to be diagnosed histopathologically.

The Cost Effectiveness of Statin Therapies in Spain in 2010, after the Introduction of Generics and Reference Prices

HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness. The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives. The following treatments were evaluated: rosuvastatin 5-20 mg/day; atorvastatin, simvastatin, and pravastatin 10-40 mg/day; lovastatin and fluvastatin 20-80 mg/day; and combination therapy with a statin plus either cholestyramine 12-24 g/day or ezetimibe 10 mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels. The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10 mg/day to 55% for atorvastatin 80 mg/day. Annual treatment costs ranged from Euro 189.7 for simvastatin 10 mg/day to Euro 759.3 for atorvastatin 80 mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: Euro 6 for simvastatin, Euro 10-12 for rosuvastatin, Euro 10 for lovastatin, Euro 13-16 for atorvastatin, Euro 13-14 for fluvastatin, and Euro 14-20 for pravastatin. Rosuvastatin + ezetimibe, simvastatin + ezetimibe, and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels. Rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of Euro 516. Simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of Euro 217 and Euro 190, respectively. Rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.

Efficacy of carbon dioxide for diagnosis and intervention in patients with failing hemodialysis access

Carbon dioxide (CO₂) is the only proven safe intravascular contrast agent in renal failure and contrast allergy. The use of CO₂ as a contrast agent for the evaluation of failing dialysis fistulas has the potential to preserve residual renal function by eliminating the use of contrast material or decreasing the amount used for fistulograms. To evaluate the feasibility of fistulography using CO₂ for diagnosis and intervention in patients with failing hemodialysis access. Dialysis access failure occurred in 94 patients (54 men, 40 women; mean age, 65 years; range, 32–89 years) on 146 occasions. CO₂ was used as the first-choice contrast agent for fistulography and PTA. Fistulography was performed with the injection of CO₂ in the brachial artery using a power injector. Interventional treatment was indicated in 141 accesses. In 115 of these 141 cases, intervention was performed using CO₂ fistulography alone. When the access flow stopped or decreased very much due to an occlusion and severe stenosis, we could not visualize the access by CO₂ fistulography, or could not perform CO₂ fistulography. For those cases, iodinated contrast fistulography was performed. When the vascular rupture, dissection, or clot formation occurred during intervention, iodinated contrast fistulography was performed. In three patients with arteriovenous fistula, manual injection of CO₂ into the brachial artery resulted in reflux of the gas into the thoracic aorta causing transient loss of consciousness. CO₂ is a useful contrast agent in the diagnosis and intervention of failing hemodialysis access, eliminating or limiting the use of iodinated contrast material. Caution should be exercised to prevent CO₂ reflux into the aorta when injecting the gas into the brachial artery.

Therapie der Dyslipidämie bei entzündlich-rheumatischen Erkrankungen

Cardiovascular diseases are the main cause of death worldwide and dyslipidemia constitutes a substantial risk factor. Patients with rheumatic diseases, especially active inflammatory arthritis and systemic lupus erythematosus, show unfavorable lipid profiles, which, however, do not account for the total excess cardiovascular morbidity. Effective disease management, life-style changes and cholesterol-lowering agents can ameliorate the lipid profile and lower cardiovascular mortality. Due to their anti-inflammatory and potent cholesterol-lowering properties, statins are the pharmacological agents of first choice. National and international guidelines on cardiovascular risk prevention differ concerning appraisal of the individual risk and lipid targets. The EULAR recently released recommendations for cardiovascular risk management in patients with inflammatory arthritis.

Digest

AbstractDepressionSSRIs and suicide rateSSRI antidepressants have replaced tricyclic antidepressants (TCAs) as the agents of first choice and now account for the majority of antidepressants prescribed. This relatively rapid change has been linked to a decline in the rate of suicide but researchers from Norway have found no evidence to support this (BMC Psychiatry 2010;10:62).They found that suicide rates for all four Nordic countries (Denmark, Finland, Norway and Sweden) were already declining when the SSRIs were introduced in the early 1990s. Sales of antidepressants had increased by about half between 1975 and 1989, and increased fivefold between 1990 and 2006. At that time, SSRIs accounted for about two‐thirds of antidepressant sales. There was no statistical evidence that the increase in SSRI sales or the decrease in TCA sales was associated with a decline in suicide rates and there was no evidence of a lagged response.Recurrence and rate of discontinuationRecurrence of depression or panic occurs sooner after rapid discontinuation of antidepressant therapy than slow discontinuation, say US investigators (Am J Psychiatry 2010;167:934‐41).They compared the effects of clinically‐determined rapid (over one to seven days, 47 per cent) and slow (over 14 days or longer, 53 per cent) discontinuation of antidepressant in 398 patients with depression, panic disorder or bipolar disorder. All patients were attending a tertiary clinic; they had responded well to treatment and were not depressed at the time of discontinuation.Compared with gradual discontinuation, rapid discontinuation was associated with a shorter time to the first new episode of depression or panic (3.6 vs 8.4 months). After rapid discontinuation, the time to a new episode was approximately one quarter of the interval between episodes while taking an antidepressant. Also, after rapid discontinuation, the difference in time to a new episode between tricyclic antidepressants (TCAs) and newer antidepressants was less than one week; after gradual discontinuation, the time to a new episode was five months longer with TCAs than with newer antidepressants.Looking at baseline factors, rapid discontinuation was associated with younger age (by four to five years) and shorter treatment duration (by three months). There was no difference according to diagnosis or type of antidepressant. Rapid discontinuation was 16 times more likely to have been the patient's choice than slow discontinuation.Augmenting antidepressant therapyTwo US trials have evaluated the efficacy of new strategies to augment unsuccessful antidepressant therapy.S‐adenosyl methionine (SAMe) is a methyl donor that occurs naturally in the body; it is available in Europe and marketed in the US as a dietary supplement. Meta‐analysis of several small trials suggests that it may be effective as monotherapy for depression.In 73 patients with depression despite at least six weeks' treatment with an adequate dose of an SSRI, the addition of SAMe 400mg twice daily significantly increased response rate (36 vs 18 per cent with placebo) and remission rate (26 vs 12 per cent), according to Hamilton Depression Rating Scale (HAM‐D) score after six weeks (Am J Psychiatry 2010;167:942‐8). This was supported by Clinical Global Impression (CGI) ratings.• With a slightly different aim in mind, a crossover trial tested whether the NMDA antagonist ketamine could induce a rapid improvement in 18 patients with treatment‐resistant bipolar depression during stable treatment with lithium or valproate (Arch Gen Psychiatry 2010;67:793‐802).Compared with placebo, IV infusion of ketamine 0.5mg per kg improved depression symptom scores within 40 minutes, reaching a peak effect on day 2 (about 10 points on the Montgomery Åsberg Depression Rating Scale (MADRS) score) and persisting through to day 3. The response rate according to the MADRS score was 71 per cent with ketamine and 6 per cent with placebo. The main adverse effect of ketamine was dissociation, though this was recorded only at 40 minutes after administration; one patient in each group developed manic symptoms.The authors say their findings prove the value of targeting the NMDA receptor complex and say further studies are needed to develop a long‐term treatment. Copyright © 2010 Wiley Interface Ltd

Digoxin

Digoxin

Treatment for osteoporosis in Australian residential aged care facilities: consensus recommendations for fracture prevention

Older people living in residential aged care facilities (RACFs) are at considerably higher risk of suffering fractures than older people living in the community. When admitted to RACFs, patients should be assessed for fracture risk to ensure early implementation of effective fracture prevention measures. Routine or regular determination of calcium and phosphate serum levels in institutionalised older people is not indicated. Opinion is divided about the value of routine measurements of serum concentrations of 25-hydroxyvitamin D, parathyroid hormone and bone turnover markers. The non-pharmacological approach to fracture prevention includes multifactorial programs of falls prevention and the use of hip protectors. Vitamin D supplementation is recommended for all patients in RACFs. Dietary calcium intake should be optimised (1200-1500 mg per day is recommended) and supplementation offered to those with inadequate intake. The decision to prescribe calcium supplements should be guided by patients' tolerance, whether or not they have a history of kidney stones, and emerging data about its cardiovascular safety. Bisphosphonates are the first-choice pharmacological agents for fracture prevention in older persons at high risk. Intravenous administration is as efficient as oral and has the significant advantage of better adherence. Use of strontium ranelate has not been tested on people in RACFs, but evidence in the "old-old" (those aged 75 years and older) suggests it could be a therapeutic option for fracture prevention in this setting. In general, teriparatide should not be considered as a first-line treatment for fracture prevention, particularly for people in RACFs.

Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

BackgroundChloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells.MethodsHT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed.Results5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU.ConclusionOur findings suggest that the combination therapy with CQ should be a novel therapeutic modality to improve efficacy of 5-FU-based chemotherapy, possibly by inhibiting autophagy-dependent resistance to chemotherapy.

Mitochondrial Disorders Therapy: The Utility of Melatonin~!2009-11-18~!2010-01-21~!2010-06-23~!

Mitochondria play a central role in the cell physiology. It is now recognized that, besides their classic function of energy metabolism, mitochondria are enrolled in multiple cell functions including energy distribution through the cell, energy/heat modulation, reactive oxygen species (ROS) regulation, calcium homeostasis, and apoptosis control. Recently, evidence is accumulating for a direct participation of mitochondria in stem cell proliferation and/or differentiation. All these functions suggest that mutations in either nuclear or mitochondrial DNA may induce serious cell impairments, and there is now evidence of more than 200 mtDNA mutations responsible for human pathologies. Moreover, mitochondria are, simultaneously, the main producer and target of ROS and, thus, multiple mitochondrial diseases are related to ROSinduced mitochondrial injuries. Among these, neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), inflammatory diseases such as sepsis, and aging itself, are caused or accompanied by ROS-induced mitochondrial dysfunctions. With regard to its action spectrum as an antioxidant, melatonin may be regarded as a firstchoice agent for preventing and/or reducing the excess of ROS, thereby maintaining mitochondrial homeostasis. Multiple in vitro and in vivo experiments have shown the protective role of melatonin on mitochondrial physiology, yielding a significant improvement in those diseases in which energy supply to the cell had been compromised. New lines of evidence suggest the participation of mitochondria in stem cell proliferation and differentiation, and preliminary data support the role of melatonin in these processes. This review accounts for the multiple functions of mitochondria and the mechanisms involved in the numerous beneficial effects of melatonin to maintain mitochondrial homeostasis.

Mitochondrial Disorders Therapy: The Utility of Melatonin

Mitochondria play a central role in the cell physiology. It is now recognized that, besides their classic function of energy metabolism, mitochondria are enrolled in multiple cell functions including energy distribution through the cell, energy/heat modulation, reactive oxygen species (ROS) regulation, calcium homeostasis, and apoptosis control. Recently, evidence is accumulating for a direct participation of mitochondria in stem cell proliferation and/or differentiation. All these functions suggest that mutations in either nuclear or mitochondrial DNA may induce serious cell impairments, and there is now evidence of more than 200 mtDNA mutations responsible for human pathologies. Moreover, mitochondria are, simultaneously, the main producer and target of ROS and, thus, multiple mitochondrial diseases are related to ROSinduced mitochondrial injuries. Among these, neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), inflammatory diseases such as sepsis, and aging itself, are caused or accompanied by ROS-induced mitochondrial dysfunctions. With regard to its action spectrum as an antioxidant, melatonin may be regarded as a firstchoice agent for preventing and/or reducing the excess of ROS, thereby maintaining mitochondrial homeostasis. Multiple in vitro and in vivo experiments have shown the protective role of melatonin on mitochondrial physiology, yielding a significant improvement in those diseases in which energy supply to the cell had been compromised. New lines of evidence suggest the participation of mitochondria in stem cell proliferation and differentiation, and preliminary data support the role of melatonin in these processes. This review accounts for the multiple functions of mitochondria and the mechanisms involved in the numerous beneficial effects of melatonin to maintain mitochondrial homeostasis.

Seizures in low- and high-grade gliomas: current management and future outlook

Major difficulties in patients with epilepsy and brain tumors include refractory seizures, potential interactions between anticonvulsants and chemotherapeutic agents and enhanced risks of toxicity, including cognitive deterioration. For seizure control, levetiracetam, valproic acid, topiramate and lamotrigine can each be considered as agents of first choice. We advocate starting with levetiracetam monotherapy, based on efficacy, good tolerability and the absence of interactions. If levetiracetam alone is not sufficiently effective, we propose adding a second antiepileptic drug, rather than switching to monotherapy with another anticonvulsant. Under these circumstances we advise the use of valproic acid as an add-on over topiramate or lamotrigine, based on its reported clinical activity in brain tumor patients. The combination of levetiracetam and valproic acid seems synergistic, and produces few or no cognitive side effects. Antitumor therapy by neurosurgery, cranial radiation or chemotherapy contribute substantially to reducing seizure activity. Future research on seizure management in brain tumor patients should focus on better insight into the influence of multidrug resistance proteins on anticonvulsant drug transport over the blood–brain barrier, efficacy of new anticonvulsants with no or few interactions with other drugs, synergistic combinations of anticonvulsants in order to limit toxicity and therapeutic drug monitoring of anticonvulsants in current clinical practice and in new drug studies, including the effects of concomitant administration of chemotherapeutic agents.

Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure

To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine. A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h. With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 +/- 19 vs. 15 +/- 9 ng ml(-1); difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration-time curve was almost three times higher [885 +/- 560 vs. 304 +/- 84 ng h ml(-1); difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 +/- 6.2 vs. 12.9 +/- 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 +/- 0.77 vs. 2.25 +/- 0.66 l h(-1) kg(-1); difference (95% CI) -1.13 (-1.80, -0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=-0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects. Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.

Adrenergic Support in Septic Shock: A Critical Review

The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. To restore adequate organ perfusion and cell homeostasis, cardiac output should be restored with volume infusion plus vasopressor agents as indicated. Appropriate arterial pressure for each individual patient and proper arterial oxygen content are key elements to restoring perfusion. Tissue perfusion can be monitored by markers of organ and mitochondrial function, namely urine output, level of consciousness, peripheral skin perfusion, central or mixed venous oxygen saturation, and lactate. The hemodynamic effects of the different vasopressor agents depend on the relative affinity to adrenergic receptors. Those with predominant α-agonist activity produce more vasoconstriction (inoconstrictors) while those with predominant β-agonist stimulation increase cardiac performance (inodilators). The debate about whether one vasopressor agent is superior to another is still ongoing. The Surviving Sepsis Campaign guidelines refer to either norepinephrine or dopamine as the first-choice vasopressor agent to correct hypotension in septic shock. However, recent data from observational and controlled trials have challenged these recommendations concerning different adrenergic agents. As a result, our view on the prescription of vasopressors has changed from a probably oversimplified “one-size-fits-all” approach to a multimodal approach in vasopressor selection.

Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia

Mycoplasma pneumoniae is one of the main pathogens causing community-acquired respiratory tract infections in children and adults. Macrolide (ML) antibiotics are recognized generally as first-choice agents for M. pneumoniae infections, and these antibiotics were thought to have excellent effectiveness against M. pneumoniae for many years. In 2000, however, M. pneumoniae showing resistance to macrolides was isolated from clinical samples obtained from Japanese pediatric patients with community-acquired pneumonia (CAP). Since then, prevalence of ML-resistant M. pneumoniae isolates in pediatric patients has increased rapidly. In 2007, ML-resistant M. pneumoniae isolates were obtained from Japanese adults with CAP; numbers of such isolates also have gradually increased in Japan. Recently, similar antimicrobial resistance in M. pneumoniae has begun to emerge worldwide. In this review, we focus on changes of ML-resistant M. pneumoniae from year to year and consider resistance mechanisms as well as clinical features of patients with resistant M. pneumoniae infection.

Costs of Eprosartan versus Diuretics for Treatment of Hypertension in a Geriatric Population

Diuretics are considered to be agents of first choice when treating hypertension in the elderly because of their clinical efficacy and, in particular, their low cost. Indeed, the latter consideration has been used by health resource managers to promote the use of diuretics. However, when considering the costs of treating hypertension in a population it is also necessary to assess the adverse effects that diuretics produce, particularly in elderly people. To compare the overall expenditure associated with the treatment of hypertension (specifically the angiotensin II type 1 receptor antagonist eprosartan vs diuretics) in an elderly population, taking into consideration not only the drug acquisition costs but also the adverse effects of treatment and the costs associated with such adverse effects. This was a prospective, observational, nonrandomized, open-label, multicentre study based in eight community health centres and the Hypertension Unit of the University Hospital of Salamanca, Spain. The study included 220 hypertensive geriatric outpatients (males and females aged >or=65 years) referred from general practitioners and the Hypertension Unit, with a mean age of 71.8 years and distributed into two groups: one (n = 90) treated with diuretics and the other (n = 130) treated with eprosartan. Following an initial clinical assessment of patients at the beginning of the study, monitoring of treatment continued for 1 year with follow-up consultations scheduled for 3, 6 and 12 months. Both the costs relating to acquisition of the drugs and the costs derived from secondary adverse effects of drug treatment were included in the analysis. The response to the antihypertensive therapy was similar in both groups. In patients taking diuretics, adverse events resulted in increased use of healthcare resources because of urinary incontinence, purchase of adsorbents, hyponatraemia and the need to admit two patients to hospital. The patient/day cost was euro 1.05 for the group treated with diuretics and euro 0.98 for the group treated with eprosartan (year of costing 2006). In the geriatric population, the acquisition cost of the prescribed diuretics is not representative of the actual antihypertensive treatment expenditure. According to the results obtained in our study, the overall costs of eprosartan therapy were no different to those of diuretics, despite the fact that eprosartan had a higher acquisition cost. This is consistent with a more favourable safety profile for eprosartan, which may possibly contribute to improved prescription compliance. This conclusion should be taken into consideration when evaluating economic restrictions on the use of drugs.

Postpartum Psychosis: Detection of Risk and Management

Mrs. A, a 34-year-old married mother who lived with her husband and their 5year-old daughter, strangled her infant son to death 3 weeks after birth. She had a planned, healthy pregnancy with some depression at 28 weeks’ gestation. She had a normal spontaneous vaginal delivery, giving birth to a healthy boy, “B.” She began breastfeeding immediately. From postpartum days 2 through 11, her depression worsened. She was unable to sleep but could not get out of bed or attend to her hygiene. She was suspicious that her husband would harm B. On postpartum day 2, she began having obsessional, ego-dystonic images of throwing B out the window. She believed, despite the pediatrician’s reassurances, that she was harming B with her breast milk and that he was losing weight. She was unable to give him a bath, believing that he had “gas” or “something bad” inside and could not be moved.

Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin

The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.

Medical Management of the Diabetic Patient with Coronary Artery Disease

The prevalence of type 2 diabetes is rising at an alarming rate worldwide. Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the diabetic population. Future CAD risk should be routinely assessed in patients with diabetes as specific subgroups might benefit from information derived from cardiac stress testing and other diagnostic procedures. Risk factor control is of paramount importance in all cases and it usually requires sustained lifestyle modifications, coupled with pharmacological interventions. Statins and angiotensin-converting enzyme (ACE) inhibitors are the first-line agents for the treatment of dyslipidaemia and hypertension, respectively. Microvascular, but not macrovascular, complications of diabetes are effectively prevented by good glycaemic control. Metformin is considered the first-choice agent in overweight diabetic subjects, while the role of thiazolidinediones is currently the focus of medical research. The diagnosis of acute coronary events in patients with diabetes is often challenging because of the high prevalence of silent ischaemia in these subjects. All acute cardiac events need to be promptly treated and myocardial reperfusion attempted without delay. Maintaining glucose levels as close to normal as possible, during and shortly after an acute event, improves prognosis in patients with diabetes. Risk factor control remains the cornerstone of secondary prevention; beta-blockers, ACE-inhibitors and antiplatelet agents confer additional symptomatic and survival benefit. Similar therapeutic principles also apply to patients with type 1 diabetes. This article addresses the complex problem of managing patients with diabetes and coronary artery disease.

Application of selective estrogen receptor modulators for breast cancer treatment according to their intrinsic nature

The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene exert their estrogen agonist and antagonist actions depending on the target organ and individual circumstances. For instance, tamoxifen increases bone mineral density in postmenopausal patients, but decreases it in premenopausal patients when it is used as the adjuvant therapy for breast cancer in both populations. Due to positive results from recent large clinical trials for early breast cancer, the aromatase inhibitors (AIs) are the agent of first choice for postmenopausal patients. However, the veteran SERM tamoxifen is still the primary drug for premenopausal breast cancer patients, patients with ductal carcinoma in situ and subset of postmenopausal women. Recent accumulated data suggest that both raloxifene and tamoxifen could be useful in chemoprevention. Further investigation should be made into the development of a systematic strategy for application to a suitable target population, i.e., one more likely to develop hormone receptor-positive breast cancer. Unlike the AIs, SERMs have a distinct function that does not directly relate to hormone receptors when used in higher pharmacological concentration. The attempt to overcome chemo-drug resistance using high-dose SERMs would be one approach to developing such a strategy. There were several reports showing the antiproliferative effect of SERMs for estrogen receptor-negative cells, such as glioma. There are still numerous possible applications for SERMs when their intrinsic nature is utilized.

Urticaria

The term "urticaria" refers to any of a group of distinct skin conditions that are characterized by itchy, wheal-and-flare skin reactions (hives). In spontaneous urticaria, the most common type, the hives seem to arise without provocation. Selective review of the literature, including current guidelines. Spontaneous urticaria is divided into acute (lasting less than six weeks) and chronic types. The pathognomonic itching, hives, and angioedema arise by the same mechanism--cutaneous mast cell activation and release of histamine and other mediators of inflammation--in both acute and chronic urticaria, but these two disorders have different etiological profiles. The underlying cause of acute urticaria cannot be identified in about half of all cases. Chronic urticaria, which is much rarer, is usually caused by autoreactivity, chronic infection, or intolerance to food additives. If the condition persists after the underlying cause has been treated or eliminated, non-sedating antihistamines are the agents of first choice for symptomatic treatment. Unlike acute urticaria, which is self-limited and should be treated symptomatically, chronic urticaria should be treated by the identification and elimination of underlying causes, which is usually curative.