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Team Trumps The Clumps: Making Biologic Drugs Safer

Scientists at the National Institute of Standards and Technology (NIST) have developed a technique to measure the formation of clumps of proteins in protein-based pharmaceuticals. This first systematic study clarifies the conditions under which scientists can be assured that their instruments are faithfully measuring the formation of protein aggregates, a major concern because of its impact on quality control and safety in biologic drug manufacturing.

Ohio Ranked 4th In Overall Biotechnology Strength

In Business Facilities Magazine's recently released 2008 Biotechnology Strength Report, Ohio is ranked fourth among all states. The report can be viewed at www.businessfacilities.com/bf_08_07_cover.php.

Genentech Confirms Receipt Of Proposal From Roche

Genentech, Inc. (NYSE:DNA) announced today that it has received a proposal from Roche to acquire all of the outstanding shares of Genentech stock not owned by Roche at a price of $89.00 in cash per share. Currently, Roche owns approximately 55.9% of the outstanding shares of Genentech.

Rexahn Pharmaceuticals Receives U.S. Patent For New Cancer Compounds

Rexahn Pharmaceuticals, Inc. (AMEX:RNN), a, leader in innovative therapeutics for life-threatening and life-debilitating diseases, today announced that the U.S. Patent & Trademark Office has issued to the Company U.S. Patent 7,388,014, entitled "Quinazoline Derivatives and Therapeutic Use Thereof.

Royal Pharmaceutical Society Of Great Museum Takes The Public Behind The Scenes

The Museum of the Royal Pharmaceutical Society of Great Britain (RPSGB) is inviting people to get a dose of history with its new Behind the Scenes initiative. These brand new sessions have been designed to encourage people from the local community to get up close to the Museum's collection. Ten sessions will be hosted from August through to December, with the Museum exploring a new theme each month.

Royal Pharmaceutical Society Of Great Britain Submits Views On Darzi Report To Health Select Committee

The Royal Pharmaceutical Society of Great Britain has given its views on the Final Report by Lord Darzi to the House of Commons.

Screening Of Tiny Chemical Fragments May Pay Big Dividends In Drug Discovery

Scientists who develop new drugs are closely following the progress through clinical trials of a cache of drugs developed with counter-intuitive strategy that defies conventional wisdom, according to an article scheduled for the July 21 issue of Chemical & Engineering News.

H.R. 6331 - The RX For Community Pharmacy, Bill Includes Three Provisions That Protect Patient Access To Community Pharmacies, USA

The U.S. Senate and House of Representatives have voted to override President's George W. Bush's veto of H.R. 6331, the Medicare Improvements for Patients and Providers Act of 2008. In response Bruce T. Roberts, RPh, executive vice president and CEO of the National Community Pharmacists Association (NCPA), issued the following statement: "America's 23,000 community pharmacies have just been given the prescription for success in the healthcare marketplace.

USP Chief Science Officer Darrell Abernethy To Receive ACCP Distinguished Service Award

The U.S. Pharmacopeial (USP) Convention is pleased to announce that its chief science officer, Darrell Abernethy, M.D., Ph.D., will be honored with the American College of Clinical Pharmacology's (ACCP) Nathaniel T. Kwit Memorial Distinguished Service Award at the 2008 ACCP Annual Meeting in Philadelphia, Pa., September 14-16. Dr. Abernethy is being recognized for his lasting contributions to cardiovascular clinical pharmacology. As chief science officer of USP, Dr.

By 2012, Legitimate Generics Will Account For 20% Of Brazil's Pharmaceuticals And Healthcare Market

Research and Markets has announced the addition of the "Brazil Pharmaceuticals and Healthcare Report Q2 2008" report to their offering. The "Brazil Pharmaceuticals and Healthcare Report" provides independent forecasts and competitive intelligence on Brazils pharmaceuticals and healthcare industry. Brazil's pharmaceutical market remains one of the bright spots globally, having posted 17.0% growth in 2007 and reaching an estimated value of US$12.9bn in final consumer prices.

Massachusetts House Approves Bill That Aims To Control Health Care Spending

The Massachusetts House on Wednesday approved legislation that aims to rein in health care spending, the AP/Boston Herald reports (AP/Boston Herald, 7/16). Members of the Massachusetts House

Patent System For Drugs 'Morally Unacceptable'

Major drugs companies are using fierce lobbying tactics to protect a pharmaceutical patent system that is "simply morally unacceptable", a world-leading political philosopher told a major meeting of UK and European pharmacologists.

European Biotech Industry Identifies The Real Culprits Causing Food Price Rises

The European Biotech Industry Association (EuropaBio) questions the premises and the methods used by recent reports, including the recently leaked and unofficial World Bank internal note which claims that 75% of the recent price increase of food is due to increasing demand for biofuel.

SEM Thought-Leaders To Gather For Eyeforpharma's Search Engine Marketing Summit 2008

eyeforpharma has announced the launch of the premier pharmaceutical Search Engine Marketing Event on October 22nd in Boston. The conference has been highly anticipated and in a sneak preview of the agenda, Gerard Moore, the Event Producer, has announced that the following Search experts will be speaking at the event.

U.S. Investigating Indian Pharmaceutical Company Ranbaxy Over Generic Drugs, Including Antiretrovirals Used In PEPFAR

U.S. investigators are looking into whether Indian pharmaceutical company Ranbaxy Laboratories manufactured substandard generic drugs, including HIV/AIDS medications provided to thousands of HIV-positive people in Africa, the Wall Street Journal reports. Ranbaxy under a U.S. government contract was paid "millions of dollars" to provide low-cost antiretroviral drugs under the

Pharma Sales Executives Meet At Annual Summit To Exchange Sales Force Effectiveness Best-Practice, Network

The Russian-CIS pharmaceutical market is exploding. PriceWaterhouseCooper records suggest that the Russian Pharmaceutical market is growing by over 1/3 every year. This growth creates new challenges. How do you make your Sales Force more effective and not just larger to ensure long-term success? The Sales Force Effectiveness Summit, October 7-8, Moscow, addresses these issues head-on and presents best practices in meeting these challenges.

Bristol-Myers Squibb Agrees To Pay Over $9M To Massachusetts Medicaid Program To Settle Allegations Of Improper Marketing And Business Practices

Attorney General Martha Coakley's Office has entered into an agreement with international pharmaceutical manufacturer Bristol-Myers Squibb Company (BMS) to settle a variety of allegations of improper sales, marketing and price reporting practices. Under the terms of the settlement, BMS will pay $9,214,659.43 to the Massachusetts Medicaid Program.

44th Annual Meeting Is Largest Event In Drug Information Association History

The Drug Information Association has announced that the 44th Annual Meeting, held from June 22-26 in Boston, Massachusetts, was the largest event in the association's more than 40-year history. "This year we received the largest ever number of abstracts for the Annual Meeting," notes Annual Meeting Program Chair Jeffrey Sherman, MD, FACP.

Roche To Stop Antiretroviral Research, Company Says

Pharmaceutical company Roche in a memo circulated last week announced that it will stop research on antiretroviral drugs because of "disappointing results in clinical trials," the Financial Times reports.

Australian Discovery First Step To New Therapies

In an Australian first, scientists at Sydney's Centenary Institute have mapped the anatomy of a membrane protein. This exciting discovery has the potential to turn the way we discover new drugs on its head and reduce the development time for new treatments. "These membrane proteins are the target for 70% of all therapeutic drugs so an increased understanding of them is vital for future drug discoveries," said Centenary Institute Executive Director, Professor Mathew Vadas.

Company Suspended From ABPI Membership Over Breaches Of Code Of Practice

Roche Pharma in the UK has been suspended from membership of the Association of the British Pharmaceutical Industry (ABPI) for a minimum of six months in connection with serious breaches of the ABPI Code of Practice, it was announced today. The action is as a result of activities between 2003 and 2005 held to be in breach of the Code, including Clause 2 which deals with actions likely to bring discredit on, or reduce confidence in, the pharmaceutical industry.

PhRMA Announces Revised Voluntary Guidelines To Prohibit Gifts To Physicians

Pharmaceutical Research and Manufacturers of America on Thursday released revised voluntary marketing guidelines that ban gifts from pharmaceutical companies to physicians, Bloomberg/Indianapolis Star reports (Bloomberg/Indianapolis Star, 7/11).

NIH Fails To Oversee Grantees' Conflicts Of Interest, Grassley Says

NIH has failed to oversee conflicts of interest relating to almost $24 billion in annual funds the agency distributes to outside organizations for medical research, according to a recent letter by Sen. Chuck Grassley (R-Iowa) to the Senate Appropriations Committee,

Cancer Drug Reformulation Featured In Prestigious Journal

Dr. Yuri Lvov, a professor of chemistry and T. Pipes endowed chair in micro and nanosystems at Louisiana Tech University, and Anshul Agarwal, a Louisiana Tech doctoral candidate in biomedical engineering feature their cancer drug reformulation work in the most recent issue of Pharma Focus Asia, one of the largest and most respected pharmaceutical science journals in the world.

Op Jaipur Nets Estimated Seizure Of 20,000 Sex Drugs In Wokingham

Enforcement officers from the Medicines and Healthcare products Regulatory Agency (MHRA), together with assistance from Thames Valley Police, have seized approximately 20,000 unlicensed medicines, worth an estimated £50,000. The medicines seized consisted of Kamagra tablets and jellies, used for male impotence. The result came following an early morning visit, codenamed Op Jaipur, by MHRA enforcement officers and police to three addresses in the Wokingham and Bracknell area.

Aminoglycoside-Induced Vestibular Injury: Maintaining a Sense of Balance (September)

OBJECTIVE: To describe the mechanism and risk factors for the development of aminoglycoside-induced vestibular injury and discuss their implications for therapeutic monitoring of aminoglycoside antibiotics. DATA SOURCES: A MEDLINE search (1975-January 2008) was performed to identify literature on aminoglycoside-induced vestibular injury and risk factors associated with this outcome and their impact on therapeutic drug monitoring. Additional references were identified through review of bibliographies of identified articles. STUDY SELECTION AND DATA EXTRACTION: Data on the mechanisms of vestibular toxicity and its development in association with aminoglycoside exposure were extracted from identified references. DATA SYNTHESIS: The mechanism leading to the development of irreversible vestibular injury from exposure to aminoglycosides appears to be through the excessive production of oxidative free radicals. This production and subsequent toxicity appears to be a time-dependent process and is unrelated to dose or serum concentration. For similarly designed studies, the pooled incidence of vestibular toxicity is 10.9% for gentamicin, 7.4% for amikacin, 3.5% for tobramycin, and 1.1% for netilmicin. Current evidence suggests that this form of drug toxicity is not restricted to traditionally dosed systemic therapy, since intraperitoneal administration, high-dose once-daily administration, topical inhalation, and eardrop administration have all been associated with the development of this adverse outcome. CONCLUSIONS: Given the lack of association between serum concentrations and vestibulotoxicity, it is imperative for the pharmacist to interview the patient and not focus solely on maintaining target range drug concentrations. Minimizing the duration of exposure to aminoglycosides is recommended to reduce the risk from this form of drug toxicity.

Impact of Health Literacy on Health Outcomes in Ambulatory Care Patients: A Systematic Review (October)

OBJECTIVE: To examine the relationship between low health literacy and disease state control and between low health literacy medication adherence in the primary care setting. DATA SOURCES: The following databases were searched for relevant articles from date of inception to April 2008: The Cochrane Database of Systematic Reviews, Cumulative Index to Nursing & Allied Health Literature, EMBASE, Education Resources Information Center, PsycINFO, International Pharmaceutical Abstracts, and Iowa Drug Information Service. MEDLINE was searched from 1966 to April 2008. Key words included literacy, health literacy, health education, educational status, disease outcomes, health outcomes, adherence, medication adherence, and patient compliance. Additional articles were identified by reviewing reference sections of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: Studies using a validated measure of health literacy and performing statistical analysis to evaluate the relationship between health literacy and disease state control or medication adherence were evaluated. DATA SYNTHESIS: Eleven evaluations, including 10 discrete studies, met eligibility criteria. Six studies evaluated the relationship between health literacy and disease state control, 3 evaluated health literacy and medication adherence, and 1 study evaluated health literacy and both outcomes. A quality rating of poor, fair, or good was assigned to each study based on the study question, population, outcome measures, statistical analysis, and results. Eight studies had good quality, 1 was fair, and 2 were poor. Two high-quality studies demonstrated statistically significant relationships with health literacy, 1 with disease state control and 1 with medication adherence. Limitations of the other studies included inadequate sample size, underrepresentation of patients with low health literacy, use of less objective outcome measures, and insufficient statistical analysis. CONCLUSIONS: There may be a relationship between health literacy and disease state control and health literacy and medication adherence. Future research, with adequate representation of patients with low health literacy, is needed to further define this relationship and explore interventions to overcome the impact that low health literacy may have on patient outcomes.

Cephalosporin-Induced Leukopenia Following Rechallenge with Cefoxitin (September)

OBJECTIVE: To describe a case of cefazolin-induced leukopenia in a critically ill patient who developed this adverse reaction upon rechallenge with cefoxitin. CASE SUMMARY: A 22-year-old male was admitted after a motor vehicle crash. β- Lactam therapy was initiated with vancomycin, cefepime, and metronidazole and, upon identification of methicillin-sensitive Staphylococcus aureus bacteremia 4 days later, therapy was narrowed to cefazolin 1 g every 12 hours. The dose was adjusted to 1 g every 12 hours during continuous venovenous hemodialysis. Imipenem was given for 2 days, resulting in a total of 18 days of β-lactam treatment, at which time he developed significant leukopenia (white blood cell [WBC] count 0.9 x 103/µL). Antimicrobial treatment was changed to tigecycline and continued for suspected pleural space infection. The patient's WBC count recovered within 4 days after the change in therapy. He was taken to surgery 8 days after cefazolin was discontinued and received perioperative prophylaxis with cefoxitin (total dose 3 g). Subsequently, the patient again became severely leukopenic (WBC count 2.4 x 103/µL). Within a week after surgery, the patient developed septic shock secondary to multidrug-resistant Escherichia coli bacteremia and died. DISCUSSION: β-Lactam-induced leukopenia is a rare but well-described adverse drug reaction. It is a cumulative dose-dependent phenomenon reported to occur most often after 2 weeks of therapy. The mechanism of leukopenia is thought to be secondary to either an immune-mediated response or direct bone marrow toxicity. Rechallenge with a different β-lactam antibiotic has not been shown to consistently cause recurrent leukopenia. The case described here suggests an immune-related mechanism for the development of leukopenia. Use of the Naranjo probability scale determined the association between cephalosporin use and leukopenia to be probable. CONCLUSIONS: Cefazolin was a probable cause of this patient's leukopenia. It is important for clinicians to recognize β-lactam-induced leukopenia and maybe recommend use of a drug from a different antibiotic class if continued treatment is indicated.

Trends in Statin Use and Low-Density Lipoprotein Cholesterol Levels Among US Adults: Impact of the 2001 National Cholesterol Education Program Guidelines (September)

BACKGROUND: Few data are available on the use of statins after publication of the National Cholesterol Education Program Third Adult Treatment Panel (ATP-III) guidelines in 2001. OBJECTIVE: To determine changes in statin use and its impact on low-density lipoprotein cholesterol (LDL-C) control among US adults from 1999 to 2004. METHODS: High LDL-C levels and statin use among 1911 participants of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 were determined and compared with 1770 and 2094 participants of NHANES 1999- 2000 and NHANES 2001-2002, respectively. Statin use was obtained from review of participants' drug containers. High LDL-C levels and LDL-C control were defined, using risk-specific cut-points from the ATP-III guidelines. RESULTS: Statins were taken by 24 million Americans in 2003-2004, an increase from 12.5 million in 1999-2000. In 1999-2000, 2001-2002, and 2003-2004, statins were being used by 19.6%, 27.3%, and 35.9% of US adults with high LDL-C levels, respectively (p trend <0.001). Age-standardized mean LDL-C declined from 119.9 to 112.0 to 100.7 mg/dL among statin users between 1999-2000, 2001-2002, and 2003-2004. LDL-C control to ATP-III recommended targets was achieved by 49.7%, 67.4%, and 77.6% of statin users in 1999-2000, 2001-2002, and 2003-2004, respectively (p trend <0.001). Among US adults with high LDL-C, after multivariate adjustment, non-Hispanic blacks were 39% less likely (prevalence ratio = 0.61; 95 CI 0.39 to 0.97) than non- Hispanic whites to be taking statins. CONCLUSIONS: Statin use continues to increase among US adults and this has led to substantial improvements in LDL-C control. Nevertheless, suboptimal statin use, especially among racial/ethnic minorities, continues to prevent the maximal public health benefit from this effective drug class.

Ixabepilone: A New Antimitotic for the Treatment of Metastatic Breast Cancer (CE) (September)

OBJECTIVE: To evaluate the safety and efficacy of ixabepilone as a new antimitotic chemotherapeutic agent for the treatment of breast cancer. DATA SOURCES: Data were identified by searches of MEDLINE, PubMed, and American Society of Clinical Oncology abstracts from 1966 to March 2008, using the primary search terms ixabepilone, epothilones, BMS-247550, and breast cancer. STUDY SELECTION AND DATA EXTRACTION: Phase 1, Phase 2, and Phase 3 clinical trials examining the safety and efficacy of ixabepilone and its place in cancer treatment were reviewed. Preference was given to large Phase 2 and 3 clinical trials in the breast cancer population. Manufacturer product information was used to supplement data lacking in published trials. DATA SYNTHESIS: Ixabepilone belongs to a novel class of drugs, the epothilones, which are nontaxane microtubule-stabilizing agents. Ixabepilone, in combination with capecitabine, has been approved by the Food and Drug Administration for treatment in patients with metastatic or locally advanced breast cancer that progresses after anthracycline and taxane therapy, or in patients with taxaneresistant cancer with contraindication to further anthracycline therapy. Ixabepilone has also been approved as monotherapy in patients with metastatic and locally advanced breast cancer refractory to taxanes, anthracyclines, and capecitabine. The most common adverse reactions reported by 20% or more of the patients receiving ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities seen in more than 40% of the patients include neutropenia, leukopenia, anemia, and thrombocytopenia. Premedication with histamine H1 and H2 antagonists is recommended to prevent hypersensitivity reactions. CONCLUSIONS: Based on the clinical trials reviewed here and the current information available, ixabepilone is a welcome addition to the options available for the treatment of patients with metastatic breast cancer refractory to standard therapy CE THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-08-xxx-H01-P

Amiodarone Use in Patients with Documented Hypersensitivity to Intravenous Contrast Dye (September)

Ramelteon: A Novel Approach in the Treatment of Insomnia (CE) (September)

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of ramelteon in the treatment of primary insomnia in adults, including elderly adults. DATA SOURCES: MEDLINE (1966-July 2008) and PsycINFO (1985-July 2008) literature searches were conducted to identify clinical data involving ramelteon. The manufacturer provided a summary of clinical data and abstracts of unpublished studies. STUDY SELECTION AND DATA EXTRACTION: All primary literature, including abstracts, focusing on the pharmacology and pharmacokinetics of ramelteon and clinical trials evaluating its use was reviewed. Information deemed most relevant was incorporated. Our search revealed 5 controlled trials evaluating the shortterm efficacy and safety of ramelteon in the treatment of primary insomnia: 3 in adults and 2 in geriatric patients. Additionally, 2 studies in abstract form that evaluated the long-term effects of ramelteon were included. DATA SYNTHESIS: Ramelteon is the first selective melatonin receptor agonist approved by the Food and Drug Administration. It has no affinity for the - aminobutyric acid receptor complex or for receptors that bind acetylcholine, cytokines, dopamine, norepinephrine, neuropeptides, opiates, and serotonin. In the only published Phase 3 trial in adults, investigators found that latency to persistent sleep decreased with ramelteon to 31.5 ± 2.91 minutes with 8 mg and 29.5 ± 2.96 minutes with 16 mg compared with 42.5 ± 2.97 minutes with placebo (p = 0.007 and p = 0.002, respectively). Total sleep time was not significantly different from that with placebo. Safety data from short-term studies showed advantages of ramelteon over other sleep agents including no potential for abuse, no rebound insomnia, and lack of effect on motor and cognitive function. The adverse effects seen most frequently in ramelteon clinical trials were headache, somnolence, fatigue, nausea, dizziness, and insomnia. The overall incidence was similar to that of placebo. CONCLUSIONS: Ramelteon offers a novel mechanism of action for the treatment of insomnia. Studies support its short- and long-term use in adults and elderly adults for the treatment of primary insomnia characterized by difficulty with sleep initiation. Efficacy studies comparing ramelteon with other sleep agents are needed to further solidify the role of ramelteon in the treatment of insomnia. (CE) This article is accredited for continuing education credit ACPE UNIVERSAL PROGRAM NUMBER: 407-000-08-xxx-H01-P A For Our Patients summary of this article is available at www.ForOurPatients.info

Racial Differences in Sleep Medication Use: A Cross-Sectional Study of the Johnston County Osteoarthritis Project (September)

BACKGROUND: Little is known about racial differences in the use of sleep medications. OBJECTIVE: To compare sleep medication use among African Americans and whites with self-reported current sleep problems. METHODS: Participants were 1910 individuals (69% female, 34% African American, 66% white) from the Johnston County Osteoarthritis Project. We examined racial differences in self-reported current use of prescription, nonprescription, herbal, and other medications for sleep. Multivariable logistic regression models controlled for age, sex, education, health insurance, symptomatic hip or knee osteoarthritis, depressive symptoms, obesity, fair or poor general health, and self-reported annual days of sleep problems. Models were conducted separately for the whole sample and for men and women. RESULTS: Among participants with current sleep problems, 31% were using one or more types of sleep medication: 17% prescription, 12% nonprescription, 1% herbal, and 3% other products. African Americans were less likely than whites to be using any sleep medication (25% vs 35%; p < 0.001), prescription sleep medication (14% vs 19%; p = 0.003), and nonprescription sleep medication (10% vs 13%; p = 0.048). These racial differences persisted in multivariable models. In sex-stratified analyses, there were significant racial differences in sleep medication use only among women. CONCLUSIONS: African Americans were less likely than whites to report current use of prescription and nonprescription sleep medications; these results appeared to be largely driven by racial differences among women. Additional research should study possible underlying factors and determine whether these racial differences impact clinical outcomes.

Altered Acetaminophen Pharmacokinetics and Hepatotoxicity Associated with Premature Cessation of Intravenous N-Acetylcysteine Therapy (September)

OBJECTIVE: To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous Nacetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose. CASE SUMMARY: A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 µg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 µg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 µg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 µg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely. DISCUSSION: Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy. CONCLUSIONS: In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of therapy intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.

Famciclovir-Induced Leukocytoclastic Vasculitis (September)

OBJECTIVE: To report a case of famciclovir-induced leukocytoclastic vasculitis (LCV). CASE SUMMARY: A 67-year-old white female presented to the hospital for evaluation of large, bilateral palpable purpura; coalescing ulcers with central eschars; and small, red violaceous papules on her legs and groin. Approximately 2 months prior to this hospitalization, the woman was diagnosed with shingles of her left T1-T2 nerve distribution and was treated with famciclovir 500 mg 3 times daily, which was her first exposure to this medication. Her shingles resolved; however, on day 4 of treatment, she began to notice red spots on both of her legs that began to progressively blister and increase in size. She discontinued famciclovir at that time. The rash persisted and spread to her abdomen, groin, legs, feet, and toes. She underwent punch biopsy that revealed LCV. Workup was negative for antinuclear antibody, rheumatoid factor, hepatitis B and C virus, perinuclear-staining antineutrophil cytoplasmic antibodies, cytoplasmic-staining antineutrophil cytoplasmic antibodies, antibodies to extractable nuclear antigens, proteinase 3, and myeloperoxidase. The patient improved with daily oral steroids and local wound care. DISCUSSION: LCV has been reported only once before in the English literature as of January 2008. The most common cause of LCV is medication use, but it is a diagnosis of exclusion. It is hypothesized that drugs act as haptens, which cause an immune response. An objective causality assessment using the Naranjo probability scale suggested that famciclovir was the probable cause of LCV in this patient. CONCLUSIONS: Healthcare professionals should be aware of the possible development of famciclovir-induced LCV.

Concepts in Immunology and Immunotherapeutics, 4th Edition (September)

Association Between Selective Serotonin-Reuptake Inhibitors, Second-Generation Antipsychotics, and Neuroleptic Malignant Syndrome (September)

OBJECTIVE: To review the published reports of neuroleptic malignant syndrome (NMS) associated with the use of selective serotonin-reuptake inhibitors (SSRIs) and second-generation antipsychotics. DATA SOURCES: Information was selected from a MEDLINE search of English language literature (1950-May 2008). Manual search of all published cases indexed in MEDLINE (English language only) of NMS associated with second-generation antipsychotics was also performed. STUDY SELECTION AND DATA EXTRACTION: Pertinent information from all reports obtained was included, with specific emphasis on patient age, sex, second-generation antipsychotic involved, SSRI or other antidepressant involved, time of onset of NMS symptoms in relation to medication changes, treatment administered, and outcome of the reaction. DATA SYNTHESIS: NMS has been reported with every second-generation antipsychotic agent. It is unclear whether concomitant therapy with other agents may increase the risk of NMS development via pharmacodynamic or pharmacokinetic mechanisms or both. The suggested pharmacodynamic mechanism for increased risk of NMS with concomitant use of SSRIs is the effect of serotonin on dopamine release. Serotonin further inhibits dopamine release and thereby may worsen a hypodopaminergic state induced by antipsychotics. Pharmacokinetic factors may also play a role in some NMS cases involving an SSRI by increasing antipsychotic concentrations. An examination of case reports seems to indicate that at least in some cases, a temporal relationship exists with the addition of an SSRI to existing antipsychotic therapy. CONCLUSIONS: The use of SSRIs may be associated with an increased risk of NMS development in those receiving second-generation antipsychotics. Clinicians should closely monitor patients for the potential development of NMS.

Tigecycline for the Treatment of Acinetobacter Infections: A Case Series (September)

BACKGROUND: Acinetobacter infections resistant to multiple classes of antibiotics have become prevalent in many institutions. Tigecycline has in vitro activity against Acinetobacter spp. and has been suggested as a therapeutic option in these infections. OBJECTIVE: To describe the clinical and microbiologic outcomes of patients who received tigecycline for the treatment of infections caused by Acinetobacter spp. at our institution. METHODS: A retrospective review was conducted of the medical records of 29 sequential patients who received tigecycline for treatment of Acinetobacter infections. The outcomes assessed for efficacy were clinical improvement or cure and microbiologic cure in evaluable patients. RESULTS: Patients received tigecycline a median of 30 days into hospitalization for a median of 11 days. Common indications were pneumonia (15 pts.), bacteremia (6), and urinary tract infection (3). Positive clinical outcomes (clinical cure or improvement) were seen in 8 (28%) of 29 patients. Of the 25 microbiologically evaluable patients, 11 (44%) had resolution of their cultures. Eleven patients had susceptibility testing performed, and the median minimum inhibitory concentration was 4 µg/mL (range 3-8). CONCLUSIONS: In this case series, most patients did not have clinically or microbiologically favorable outcomes with tigecycline therapy. No patient had an isolate that was fully susceptible to tigecycline. Data from more studies are needed before tigecycline can be recommended for the treatment of Acinetobacter infections.

AIDS Therapy e-dition, 3rd Edition (September)

Physical and Chemical Stability of Esomeprazole Sodium Solutions (September)

BACKGROUND: Esomeprazole sodium (Nexium IV, AstraZeneca) is the S-isomer of omeprazole and acts as a proton pump inhibitor gastric antisecretory agent indicated for the short-term treatment of gastroesophageal reflux disease in patients with a history of erosive esophagitis. Currently, there is no information on the long-term stability of esomeprazole sodium in infusion solutions beyond 12 hours. OBJECTIVE: To evaluate the stability of esomeprazole sodium in 5% dextrose, 0.9% sodium chloride, and lactated Ringer's injection, at 2 concentrations, at room temperature and when refrigerated. METHODS: Triplicate samples of esomeprazole 0.4 and 0.8 mg/mL as the sodium salt were prepared in the solutions required. Stability evaluations were performed initially, over 2 days stored at 23 °C, and over 5 days stored at 4 °C. Physical stability was assessed using turbidimetric and particulate measurement, as well as visual observation. Chemical stability was evaluated by stability-indicating high-performance liquid chromatography. RESULTS: The samples in all 3 infusion solutions were physically stable throughout the study. None of the samples had evidence of visible haze or particulates. Most samples developed a slight yellow discoloration within 24 hours, but this discoloration was not accompanied by an excessive loss of drug content. The esomeprazole sodium samples in all 3 infusion solutions exhibited less than 7% loss over 2 days at 23 °C and over 5 days at 4 °C. CONCLUSIONS: Esomeprazole 0.4 and 0.8 mg/mL as the sodium salt in the infusion solutions tested is chemically and physically stable for at least 2 days at room temperature and 5 days under refrigeration.

Therapeutic Lipidology (September)

Burden of Deep Vein Thrombosis in the Outpatient Setting Following Major Orthopedic Surgery (September)

BACKGROUND: Venous thromboembolism (VTE) is a known complication of major orthopedic surgery (MOS) with important clinical and economic consequences. Recently published orthopedic guidelines have focused on prevention of pulmonary embolism as a primary outcome, but deep vein thrombosis (DVT) occurrence should not be readily dismissed. OBJECTIVE: To describe the burden of DVT following hospital discharge for MOS by assessing the impact of DVT on costs and resource utilization from the third-party payer perspective. METHODS: Retrospective analysis used outpatient medical and pharmacy data from the PharMetrics Patient-Centric Database (January 1, 2002-March 31, 2006). Patients 18 years of age or older with a record of MOS were eligible for inclusion. Included patients were stratified based on the presence of a DVT during the first month after hospital discharge. Characteristics of the samples were described. The impact of DVT on total 6-month costs and resource utilization (readmissions, outpatient, emergency department visits) was assessed through statistical models. RESULTS: Of the 32,899 patients in the analysis, 1221 (3.71%) had a record of DVT during the first month following discharge for MOS. Compared with patients who did not develop DVT, patients who developed DVT postdischarge were slightly older (56.5 vs 55.8 y; p = 0.0127), had a higher occurrence of prior VTE (26.2% vs 3.4%; p < 0.0001), and had undergone recent surgical procedures other than MOS (73.0% vs 69.6%; p = 0.0116). After controlling for potential confounders, DVT was associated with a 22% and 74% increase in the average number of expected outpatient and emergency department visits, respectively, during the 6-month postdischarge period but did not significantly impact the number of readmissions. Furthermore, total 6-month costs were significantly higher for patients who developed DVT, with an incremental increase of over $2000. CONCLUSIONS: The burden of DVT following hospital discharge for MOS is substantial. Specifically, DVT increases total costs and outpatient and emergency department visits.

In This Issue

In This Issue Clinical Pharmacology & Therapeutics 83, 373 (March 2008). doi:10.1038/sj.clpt.6100521

Pharmacoecology: A New Name for an Old Science

Pharmacoecology: A New Name for an Old Science Clinical Pharmacology & Therapeutics 83, 375 (March 2008). doi:10.1038/sj.clpt.6100499 Author: C Flexner

News and Views

News and Views Clinical Pharmacology & Therapeutics 83, 380 (March 2008). doi:10.1038/sj.clpt.6100522 Author:

News and Views

News and Views Clinical Pharmacology & Therapeutics 83, 382 (March 2008). doi:10.1038/sj.clpt.6100520

Principles of Clinical Pharmacology, 2nd Edition

Principles of Clinical Pharmacology, 2nd Edition Clinical Pharmacology & Therapeutics 83, 384 (March 2008). doi:10.1038/sj.clpt.6100485 Author: SG Carruthers

Special Cells, Special Considerations: The Challenges of Bringing Embryonic Stem Cells From the Laboratory to the Clinic

Special Cells, Special Considerations: The Challenges of Bringing Embryonic Stem Cells From the Laboratory to the Clinic Clinical Pharmacology & Therapeutics 83, 386 (March 2008). doi:10.1038/sj.clpt.6100384 Authors: RC Addis, JWM Bulte & JD Gearhart

Why the United States Still Needs Improved Dietary Supplement Regulation and Oversight

Why the United States Still Needs Improved Dietary Supplement Regulation and Oversight Clinical Pharmacology & Therapeutics 83, 391 (March 2008). doi:10.1038/sj.clpt.6100500 Author: JD Morrow

Should Herbal Medicines Be Regulated as Drugs?

Should Herbal Medicines Be Regulated as Drugs? Clinical Pharmacology & Therapeutics 83, 393 (March 2008). doi:10.1038/sj.clpt.6100480 Author: M McGuffin

Drug–Drug Interaction Programs in Clinical Practice

Drug–Drug Interaction Programs in Clinical Practice Clinical Pharmacology & Therapeutics 83, 396 (March 2008). doi:10.1038/sj.clpt.6100504 Author: PA Pham

The Implications of Population Admixture in Race-based Drug Prescription

The Implications of Population Admixture in Race-based Drug Prescription Clinical Pharmacology & Therapeutics 83, 399 (March 2008). doi:10.1038/sj.clpt.6100308 Author: G Suarez-Kurtz

Response to “The Implications of Population Admixture in Race-based Drug Prescription”

Response to “The Implications of Population Admixture in Race-based Drug Prescription” Clinical Pharmacology & Therapeutics 83, 400 (March 2008). doi:10.1038/sj.clpt.6100372 Author: SS-J Lee

Male Genital Tract Pharmacology: Developments in Quantitative Methods to Better Understand a Complex Peripheral Compartment

Male Genital Tract Pharmacology: Developments in Quantitative Methods to Better Understand a Complex Peripheral Compartment Clinical Pharmacology & Therapeutics 83, 401 (March 2008). doi:10.1038/sj.clpt.6100342 Authors: Y-J Cao & CW Hendrix

Chronopharmacokinetics of Oral Tegafur and Uracil in Colorectal Cancer Patients

Chronopharmacokinetics of Oral Tegafur and Uracil in Colorectal Cancer Patients Clinical Pharmacology & Therapeutics 83, 413 (March 2008). doi:10.1038/sj.clpt.6100297 Authors: M-C Etienne-Grimaldi, J-M Cardot, E François, N Renée, J-Y Douillard, E Gamelin & G Milano

Effects of Genetic Variation in the Novel Organic Cation Transporter, OCTN1, on the Renal Clearance of Gabapentin

Effects of Genetic Variation in the Novel Organic Cation Transporter, OCTN1, on the Renal Clearance of Gabapentin Clinical Pharmacology & Therapeutics 83, 416 (March 2008). doi:10.1038/sj.clpt.6100271 Authors: TJ Urban, C Brown, RA Castro, N Shah, R Mercer, Y Huang, CM Brett, EG Burchard & KM Giacomini

Physical and Cognitive Performance and Burden of Anticholinergics, Sedatives, and ACE Inhibitors in Older Women

Physical and Cognitive Performance and Burden of Anticholinergics, Sedatives, and ACE Inhibitors in Older Women Clinical Pharmacology & Therapeutics 83, 422 (March 2008). doi:10.1038/sj.clpt.6100303 Authors: Y-J Cao, DE Mager, EM Simonsick, SN Hilmer, SM Ling, BG Windham, V Crentsil, S Yasar, LP Fried & DR Abernethy

Intravenous Parecoxib Rapidly Leads to COX-2 Inhibitory Concentration of Valdecoxib in the Central Nervous System

Intravenous Parecoxib Rapidly Leads to COX-2 Inhibitory Concentration of Valdecoxib in the Central Nervous System Clinical Pharmacology & Therapeutics 83, 430 (March 2008). doi:10.1038/sj.clpt.6100304 Authors: V Mehta, A Johnston, R Cheung, A Bello & RM Langford

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis Clinical Pharmacology & Therapeutics 83, 436 (March 2008). doi:10.1038/sj.clpt.6100307 Authors: ME Mooney, VI Reus, J Gorecki, SM Hall, GL Humfleet, RF Muñoz & K Delucchi

Disease Severity Is a Major Determinant for the Pharmacodynamics of Propofol in Critically Ill Patients

Disease Severity Is a Major Determinant for the Pharmacodynamics of Propofol in Critically Ill Patients Clinical Pharmacology & Therapeutics 83, 443 (March 2008). doi:10.1038/sj.clpt.6100309 Authors: MYM Peeters, LJ Bras, J DeJongh, RMJ Wesselink, LPHJ Aarts, M Danhof & CAJ Knibbe

Pharmacokinetics of Meropenem Determined by Microdialysis in the Peritoneal Fluid of Patients With Severe Peritonitis Associated With Septic Shock

Pharmacokinetics of Meropenem Determined by Microdialysis in the Peritoneal Fluid of Patients With Severe Peritonitis Associated With Septic Shock Clinical Pharmacology & Therapeutics 83, 452 (March 2008). doi:10.1038/sj.clpt.6100312 Authors: J Karjagin, S Lefeuvre, K Oselin, K Kipper, S Marchand, A Tikkerberi, J Starkopf, W Couet & RJ Sawchuk

CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation: A Prospective Randomized Controlled Study

CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation: A Prospective Randomized Controlled Study Clinical Pharmacology & Therapeutics 83, 460 (March 2008). doi:10.1038/sj.clpt.6100316 Authors: Y Caraco, S Blotnick & M Muszkat

The Effect of Herbal Medicine Baicalin on Pharmacokinetics of Rosuvastatin, Substrate of Organic Anion-transporting Polypeptide 1B1

The Effect of Herbal Medicine Baicalin on Pharmacokinetics of Rosuvastatin, Substrate of Organic Anion-transporting Polypeptide 1B1 Clinical Pharmacology & Therapeutics 83, 471 (March 2008). doi:10.1038/sj.clpt.6100318 Authors: L Fan, W Zhang, D Guo, Z-R Tan, P Xu, Q Li, Y-Z Liu, L Zhang, T-Y He, D-L Hu, D Wang & H-H Zhou

Germline Polymorphisms in EGFR and Survival in Patients With Lung Cancer Receiving Gefitinib

Germline Polymorphisms in EGFR and Survival in Patients With Lung Cancer Receiving Gefitinib Clinical Pharmacology & Therapeutics 83, 477 (March 2008). doi:10.1038/sj.clpt.6100320 Authors: V Gregorc, M Hidalgo, A Spreafico, G Cusatis, V Ludovini, RG Ingersoll, S Marsh, SM Steinberg, MG Viganò, D Ghio, E Villa, A Sparreboom & SD Baker

Inter-rater Reliability of a Classification System for Hospital Adverse Drug Event Reports

Inter-rater Reliability of a Classification System for Hospital Adverse Drug Event Reports Clinical Pharmacology & Therapeutics 83, 485 (March 2008). doi:10.1038/sj.clpt.6100322 Authors: K Haynes, S Hennessy, KH Morales, GA Gibson, C Barnhart, CK Jaipaul & DR Linkin

Use of ANOVA to Estimate Inter- and Intra-reader Variability for a Group of Readers in Thorough QT/QTc Studies

Use of ANOVA to Estimate Inter- and Intra-reader Variability for a Group of Readers in Thorough QT/QTc Studies Clinical Pharmacology & Therapeutics 83, 489 (March 2008). doi:10.1038/sj.clpt.6100481 Authors: M Natekar, V Mahajan, A Satra, M O'Kelly & DR Karnad

Perspectives From the Clinic: Will the Average Physician Embrace Personalized Medicine?

Perspectives From the Clinic: Will the Average Physician Embrace Personalized Medicine? Clinical Pharmacology & Therapeutics 83, 492 (March 2008). doi:10.1038/sj.clpt.6100486 Authors: H Levy & JH Young

The Effect of Globalization of Drug Manufacturing, Production, and Sourcing and Challenges for American Drug Safety

The Effect of Globalization of Drug Manufacturing, Production, and Sourcing and Challenges for American Drug Safety Clinical Pharmacology & Therapeutics 83, 494 (March 2008). doi:10.1038/sj.clpt.6100493 Authors: J Woo, S Wolfgang & H Batista

Benefit/Risk Ratio of Statins in Primary Prevention

Benefit/Risk Ratio of Statins in Primary Prevention Clinical Pharmacology & Therapeutics 83, 498 (March 2008). doi:10.1038/sj.clpt.6100256 Author: MM Reidenberg