On impact and volcanism across the Cretaceous-Paleogene boundary.

The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism.

Effectiveness of Risk Minimization Measures to Prevent Pregnancy Exposure to Mycophenolate-Containing Medicines in Europe.

INTRODUCTION: In 2015, the European Medicines Agency (EMA) requested additional Risk Minimization Measures (RMM), consisting of a Direct Healthcare Professional Communication (DHPC), a Guide for Healthcare Professionals (HCPs), and a Guide for Patients, to prevent pregnancy exposure to mycophenolate-containing medicines. OBJECTIVES: This study assessed the effectiveness of the additional RMM for any mycophenolate-containing medicine among prescribers of these products in Europe. METHODS: A cross-sectional survey was conducted among prescribers of mycophenolate-containing medicines in five European countries via the administration of 19 questions checking knowledge levels for the key messages included in the additional RMM. RESULTS: Of 79,783 invitations sent to potential prescribers of mycophenolate-containing medicines, 295 HCPs accessed the survey, giving an overall response rate of 0.4% (range 0.1-8.6%). A total of 231 prescribers were included in the primary analysis. Knowledge levels for 15 questions was fair (50 to < 70%) to high (≥ 70%), and for 4 questions was poor (< 50%). Highest knowledge (≥ 75%) was for knowing that mycophenolate is contraindicated in women of childbearing potential not using highly effective contraception (80.3%) and that mycophenolate should not be routinely prescribed during pregnancy (77.5%). Lowest knowledge (≤ 30%) was for knowing that no specific mechanism of teratogenicity and mutagenicity has been identified for mycophenolate (23.4%). Less than half of HCPs reported receipt of the DHPC (42.5%) or were aware of the Guide for HCPs (32.1%) and Guide for Patients (29.7%). The most frequently reported primary source from which HCPs learned about these risks was the Summary of Product Characteristics (SmPC; 33.8%), while only 9.9% indicated the Guide for HCPs. CONCLUSION: Prescribers who participated in this survey appear to be reasonably well informed about the key messages of the RMM put in place in Europe for mycophenolate-containing medicines. The relatively high knowledge levels, in spite of the low proportion of HCPs reporting receipt of the additional RMM, suggest that the SmPC may be sufficiently informing prescribers about the pregnancy risks of mycophenolate-containing medicines and actions recommended to minimize pregnancy risk. Nevertheless, Roche in consultation with EMA will continue to distribute all additional RMM.

Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review.

A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.

Absence of central nervous system and hypothermic effects after single oral administration of high doses of oseltamivir in the rat.

Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr after dosing. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr after dosing. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr after dosing only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.

Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience.

Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of oseltamivir with other agents. This is followed by a summary of data on the effectiveness of oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies.

Safety profile of oseltamivir during the 2009 influenza pandemic.

PURPOSE: This study evaluated the safety of oseltamivir during the 2009 influenza pandemic. METHODS: Case reports were obtained from the Roche safety database. The incidence of adverse events (AEs) during the pandemic (1 May 2009 to 31 December 2009) was compared with that beforehand (during previous influenza seasons) for USA and Japan only, as exposure data in other countries were collected inconsistently. Events with significantly higher reporting during the pandemic (lower bound of 95%CI for crude rate ratio >1) were analyzed further. RESULTS: Global exposure in the pandemic and prepandemic periods was 18.3 and 64.7 million patients, respectively. In USA and Japan, exposure was 15.5 (1382 cases, 2225 events) and 62.0 million (8387 cases, 12,749 events), respectively. AEs with significantly higher reporting during the pandemic were generally consistent with influenza and its complications and/or with the circulation of a novel virus strain. As might be expected in a pandemic, mortality increased (crude rate ratio, 2.83; 95%CI, 2.23-3.59) versus the prepandemic period. Medical review of serious AEs (fatal or non-fatal outcome) found that most were consistent with pre-existing risk factors, underlying disease, and/or progression of influenza or its complications. Analysis of the remainder did not suggest a causal link with oseltamivir. A review of AEs in previously underexposed subpopulations did not support an association with oseltamivir. CONCLUSIONS: During the first 8 months of the 2009 influenza pandemic, AEs reported in patients exposed to oseltamivir were consistent with the drug's labeled safety profile, underlying medical conditions, or infection with the pandemic virus.

Safety of oseltamivir in pregnancy: a review of preclinical and clinical data.

Pregnant women with influenza are at increased risk of morbidity, particularly due to respiratory complications. A high excess mortality rate among pregnant women has been observed in previous influenza pandemics and healthcare agencies have provided recommendations on the use of oseltamivir to treat pregnant women who are infected with the pandemic (H1N1) 2009 virus. This article reviews pre-clinical and clinical data to assess the safety of oseltamivir administered during pregnancy, in the context of the effects of influenza on adverse pregnancy outcomes and fetal malformations. The effects of influenza during pregnancy, whether mediated directly by the virus or by fever or other events secondary to the underlying infection, are not yet well understood, but some data indicate an increased risk of birth defects in women infected with influenza during the first trimester. Animal and toxicology studies do not suggest that clinically effective dosages of oseltamivir have the potential to produce adverse effects on fetal development. Additionally, transplacental transfer of the drug and its active metabolite was very limited and not detectable at normal therapeutic doses in an ex vivo human placenta model. To investigate the safety of oseltamivir in pregnancy, the Roche oseltamivir safety database was searched for all exposures to oseltamivir during pregnancy in the 9 years up to 14 December 2008. In addition, a search of the literature was carried out. Of 232 maternal exposures to oseltamivir in the Roche database, pregnancy outcomes were known for 115 of these exposures. The incidence of adverse pregnancy outcomes was as follows: spontaneous abortions 6.1% (7/115), therapeutic abortions 11.3% (13/115) and pre-term deliveries 2.1% (2/94 live births), values that are not higher than background incidence rates. Fetal outcomes were known in 100 of the 232 exposures. For the nine cases of birth defect that were reported, the timing of oseltamivir exposure in relation to the sensitive period for inducing the birth defect was analysed. Two cases of ventricular septal defect, a more common birth defect, and one case of anophthalmos, an uncommon birth defect, were consistent with exposure to oseltamivir during the sensitive period for these birth defects. For other birth defects, there was either no exposure to oseltamivir during the sensitive period for the defect or insufficient information for assessment. These findings were consistent with other reports in the published literature, including a series of 79 Japanese women exposed to oseltamivir during the first trimester. Together with the other evidence reviewed herein, review of the company safety database suggests that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but available data are limited. Clinicians who use oseltamivir in pregnant women should consider the available safety information, the pathogenicity of the circulating influenza virus strain, the woman's general health and the guidance provided by health authorities. Roche will continue to monitor all reports of oseltamivir use during pregnancy.

Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review.

After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged < or =16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged < or =16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n = 159,386) was no higher than those not receiving antivirals (n = 159,386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment; events were also similar to those occurring after the initiation of oseltamivir therapy. No clinically relevant differences in plasma pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both oseltamivir and oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting oseltamivir to oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain : plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to > or =100 times the clinical dose. Oseltamivir or oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving oseltamivir is higher than in those who do not, and no mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen such events could be identified.

Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain.

Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a 'stable and low level of cancer pain' receiving a constant dosage of sustained release morphine during a pre-study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrome beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.