Evidence-based anti-seizure monotherapy in newly diagnosed epilepsy: A new approach.

OBJECTIVES: To describe the process and results of the updated Swedish practice guidelines for monotherapy in epilepsy. MATERIALS AND METHODS: The Swedish Medical Products Agency led the process together with medical experts. Evidence rating in accordance with the International League Against Epilepsy (ILAE) template was linked to the Cochrane group's GRADE system. Evidence from recently published trials and meta-analyses was added. A national expert panel participated in the project and contributed their clinical experience. RESULTS: In seizures with focal onset, carbamazepine, lamotrigine, or levetiracetam is recommended for children and adults (ILAE level A-C for adults/Cochrane level strong for children and adults). Oxcarbazepine is an alternative for children, although its level A evidence, in a single class I trial, could relate to poor phenytoin tolerability. Eslicarbazepine acetate, lacosamide, and zonisamide are alternatives for adults and gabapentin for the elderly (ILAE level A). Carbamazepine is not a first choice for the elderly due to its high potential for interactions. In generalized epilepsy with tonic-clonic seizures (GTC), lamotrigine, levetiracetam, and sodium valproate are recommended for children and adults (ILAE level C-D/Cochrane level moderate-strong) although sodium valproate is contraindicated in girls and women of childbearing age unless special considerations are met. Ethosuximide is the first choice in absence epilepsy without GTC (ILAE level A). CONCLUSIONS: Lamotrigine and levetiracetam can be used as first choice for focal seizures and generalized epilepsy with GTC, suitable in all age-groups and for both men and women. Recommendations for GTC seizures have lower evidence than those for focal seizures.

Statin Use Is Associated With Improved Outcomes of Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: There is increasing evidence that statins can benefit patients with chronic liver diseases, but their effects have not been studied in patients with primary sclerosing cholangitis (PSC). We performed a nationwide study in Sweden to determine the effects of exposure to drugs, including statins, in patients with PSC. METHODS: We studied a population-based cohort of patients in Sweden with PSC and concomitant ulcerative colitis or Crohn's disease from 2005 through 2014 (n = 2914), followed through 2016. We collected analyzed data from the patient register, the prescribed drug register, the death certificate register and the cancer register. We calculated risk or death, liver transplantation, bleeding of esophageal varices, and cancer in relation to drug exposure. RESULTS: The mean age of patients at the time of diagnosis with PSC was 41.4 years (inter-quartile range [IQR], 25.6-56.1 years). The total follow-up time was 11769 person-years, during which 3.4% of patients received liver transplants and 19.9% died. Proportions of patients exposed to drugs were: ursodeoxycholic acid, 60.2%; 5-aminosalicylic acid, 74.4%; azathioprine or mercaptopurins, 33.7%; and statins, 13.9%. Statin use was associated with a reduced risk of all-cause mortality (hazard ratio [HR], 0.68; 95% CI, 0.54-0.88) and death or liver transplantation (HR, 0.50; 95% CI, 0.28-0.66). Use of azathioprine was also associated with reduced mortality (HR, 0.66; 95% CI, 0.52-0.84) and risk of death or liver transplantation (HR, 0.65; 95% CI, 0.50-0.83). Exposure to ursodeoxycholic acid did not affect mortality (HR, 1.04; 95% CI, 0.87-1.25). CONCLUSION: In a population-based cohort of patients in Sweden with PSC, we associated use of statins and azathioprine with decreased risks of death and death or liver transplantation. Exposure to ursodeoxycholic acid was not associated with reduced mortality.

Treatment With Bupropion and Varenicline for Smoking Cessation and the Risk of Acute Cardiovascular Events and Injuries: a Swedish Case-Crossover Study.

Introduction: Bupropion and varenicline are non-nicotine medications used for smoking cessation that mitigate craving and withdrawal symptoms. We aim to investigate whether these drugs increase the risk of selected acute adverse outcomes when used in medical practice. Methods: Population-based case-crossover design using data from Swedish health and administrative registers. Adult individuals diagnosed with acute myocardial infarction, stroke, suicide, suicide attempt, fall injury, or that suffered a road traffic crash from 01.10.2006 for bupropion, or from 01.03.2008 for varenicline, until 31.12.2013 were included. Different lengths of exposure periods were analyzed within the 12-week hazard period prior to the adverse outcome (1-14, 15-28, and 29-84 days). The control period was matched using the interval preceding the hazard period (85-168 days), and breaking it up into equivalent periods (85-98, 99-112, and 113-168 days). Conditional logistic regression with each case considered as one stratum was used to estimate adjusted odds ratios (OR) and confidence intervals (CI). Results: Neither medication was associated with consistent higher risks for any of the adverse outcomes. For bupropion and varenicline, respectively, in the 1-14 days hazard period, OR (95% CI) were: myocardial infarction 1.14 (0.55 to 2.34) and 1.06 (0.70 to 1.62); stroke 1.16 (0.39 to 3.47) and 1.26 (0.72 to 2.17), and traffic crashes 0.85 (0.39 to 1.85) and 1.48 (0.90 to 2.41). In the other periods, ORs were similar or even lower. For falls and suicidal events ORs were generally below one for both drugs. Conclusion: The available evidence suggests that if prescription guidelines are properly followed regarding potential contraindications both of these medications could be considered relatively safe. Implications: The reliable exposure and diagnosis assessment used in this nationwide register-based study, along with the number of cases gathered makes this sample one of the largest of its type to assess potential side effects associated with the use of these drugs. Neither medication was associated with consistent higher risks for any of the adverse outcomes studied.

Ecological Effect of Solithromycin on Normal Human Oropharyngeal and Intestinal Microbiota.

Solithromycin is a new fluoroketolide. The purpose of the present study was to investigate the effect of orally administered solithromycin on the human oropharyngeal and intestinal microbiota. Thirteen healthy volunteers (median age, 27.3 years) received oral solithromycin at 800 mg on day 1 followed by 400 mg daily on days 2 to 7. Fecal and saliva samples were collected at baseline and on days 2, 5, 7, 9, 14, and 21 for pharmacokinetic and microbiological analyses. Plasma samples were collected predose on days 2, 5, and 7 as proof of exposure, and solithromycin concentration ranges were 21.9 to 258 ng/ml, 18.0 to 386 ng/ml, and 16.9 to 417 ng/ml, respectively. The solithromycin concentrations in feces were 15.8 to 65.4 mg/kg, 24.5 to 82.7 mg/kg, 21.4 to 82.7 mg/kg, 12.1 to 72.4 mg/kg, 0.2 to 25.6 mg/kg, and 0 to 0.5 mg/kg on days 2, 5, 7, 9, 14, and 21, respectively. The numbers of enterobacteria and enterococci decreased and were normalized on day 14. The numbers of lactobacilli and bifidobacteria decreased from day 2 to day 14 and were normalized on day 21. The clostridia decreased on days 2, 7, and 14 and were normalized on day 21. No Clostridium difficile strains or toxins were detected during the study period. The number of Bacteroides strains was not significantly changed. The solithromycin concentrations in saliva were 0 to 1.2 mg/liter, 0 to 0.5 mg/liter, 0 to 0.5 mg/liter, and 0 to 0.1 mg/liter on days 2, 5, 7, and 9, respectively. The numbers of streptococci decreased on day 2 and were normalized on day 5. The numbers of lactobacilli, prevotellae, fusobacteria, and leptotrichiae decreased from day 2 and were normalized on day 21.

Ecological Effect of Ceftaroline-Avibactam on the Normal Human Intestinal Microbiota.

Ceftaroline-avibactam is a new combination of the antibiotic ceftaroline with a novel non-ß-lactam ß-lactamase inhibitor, avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota. Fourteen healthy volunteers received ceftaroline-avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) intravenously over 2 h every 8 h on days 1 to 6 and as a single dose on day 7. Fecal samples were collected on day -1 (within 24 h of the first infusion on day 1) and on days 2, 5, 7, 9, 14, and 21. Escherichia coli numbers decreased during the study and normalized on day 21. An increased number of Klebsiella bacteria appeared on day 14 and normalized on day 21. The number of other enterobacteria decreased during the study, and the number of enterococci decreased from days 2 to 7 and normalized on day 9. Candida numbers increased from days 5 to 9 and normalized after day 14. The number of lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The number of Bacteroides bacteria was unchanged. Clostridium difficile numbers decreased on days 7 and 9 and increased on days 14 and 21. A toxigenic C. difficile strain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days -1, 2, 5, and 7. Ceftaroline and avibactam concentrations were 0 to 34.5 mg/liter and 0 to 61.6 mg/liter, respectively, in plasma and 0 to 35.4 mg/kg and 0 to 98.5 mg/kg, respectively, in feces. (This study is registered in the European Clinical Trials Database [https://eudract.ema.europa.eu/] under number EudraCT 2012 004921-25.).

Incidence of herpes zoster and associated events including stroke--a population-based cohort study.

BACKGROUND: More detailed understanding of herpes zoster (HZ) is called for in the context of an increasing observed frequency of disease, and ongoing discussions regarding potential consequences of the disease. Thus, population-based data on incidence and complications of HZ are needed. METHODS: We conducted a register-based cohort study in Västra Götaland County (population 1.5 million) in Sweden. We collected data on all patients diagnosed with HZ during the years 2008 to 2010 from population-based registers. Incidence rates (IR) of HZ and related complications were calculated and stratified by age and sex. RESULTS: There were 13 269 new HZ cases during the study period. Overall, the IR of herpes zoster in both genders was 3.25 (95% CI: 3.16-3.34) per 1000 person years in 2010. The incidence was consistently higher in women than in men and in older than in young. A history of immunosuppression was more common than in the general population. The incidence was highest in individuals over 80 years of age (IR 9.2 per 1000 person years, 95% CI: 8.8-9.6) during 2008-2010. The most common complications to HZ were ocular engagement and postherpetic neuralgia; risks for stroke and sepsis were significantly elevated during the one year following diagnosis, especially in the youngest age group of patients 0-39 years. CONCLUSIONS: Herpes zoster is more common in women, the elderly and immunosuppressed individuals. We verify a population-based association between herpes zoster and risk for stroke and sepsis, which may merit concern.

Statin treatment reduces the risk of hepatocellular carcinoma but not colon cancer-results from a nationwide case-control study in Sweden.

BACKGROUND: Several studies have indicated that statins may have anticarcinogenic effects. The aim of the present study was to investigate if statin treatment was associated with a reduced risk of hepatocellular carcinoma (HCC) or colon cancer. METHODS: A nationwide case-control study was carried out in which all cases of HCC and colon cancer in the Swedish population above 40 years of age between 1 July 2006 and 31 December 2010 were identified in the Swedish Cancer Register. For every case, five controls were selected and matched on age and sex. Data on statin use was extracted from the Swedish Prescribed Drug Register. We estimated risks using conditional logistic regression and adjusted for educational level, concomitant medications and comorbidity. RESULTS: Identified were 3994 cases of HCC and matched with 19.970 controls, and 21.143 cases of colon cancer were identified and matched with 105.715 controls. In the adjusted analysis, the odds ratio (OR) for HCC among statin users was 0.88 (95% confidence interval (CI) 0.81-0.96), and the OR for colon cancer was 1.04 (95%CI 1.00-1.08) compared with non-users. CONCLUSION: Statin use was associated with a modest decreased risk of HCC but did not influence the risk of colon cancer. Future randomized placebo-controlled trials in HCC high-risk patients are warranted to further investigate the possible prophylactic effect of statins in HCC.

CYP2D6-inhibiting drugs and risk of fall injuries after newly initiated antidepressant and antipsychotic therapy in a Swedish, register-based case-crossover study.

Drug-drug interactions have been shown to affect the risk of fall injuries when opioids are used concomitantly with drugs inhibiting the cytochrome P450 2D6 (CYP2D6) enzyme in a previous pharmacoepidemiological study. The aim of this study was to determine whether CYP2D6-inhibiting drugs reinforce the risk of fall injuries when used concomitantly with antidepressants or antipsychotics. We identified all 252,704 adults with a first fall injury leading to hospitalisation from the National Patient Register in Sweden 2006-2013. Data on dispensed drugs was linked from the Swedish Prescribed Drug Register. We applied a case-crossover design to analyse newly dispensed (28 days preceding the fall injury, preceded by a 12-week washout period) antidepressants and antipsychotics, respectively, in relation to risk of a fall injury and according to concomitant use of CYP2D6-inhibiting drugs. Newly dispensed drugs were assessed correspondingly in a control period of equal length, 28 days prior to the 12-week washout period. Overall, the risk of fall injury was increased after newly initiated antidepressant and antipsychotic treatment. For antidepressants, concomitant CYP2D6 inhibitor use further elevated the risk estimates compared to non-use, most pronounced for the groups selective serotonin reuptake inhibitors (sertraline excluded) [OR = 1.47 (95% CI 1.19-1.80) vs. OR = 1.19 (95% CI 1.13-1.26)], and tricyclic antidepressants [OR = 1.71 (95% CI 1.17-2.51) vs. 1.27 (95% CI 1.11-1.47)] as well as for sertraline [OR = 1.61 (95% CI 1.05-2.38) vs. 1.12 (95% CI 1.00-1.26)]. For antipsychotics, the risk of fall injury was not altered by concomitant use of CYP2D6-inhibiting drugs. In conclusion, concomitant use of CYP2D6 inhibiting drugs tends to further increase the risk of fall injury in newly initiated antidepressant treatment, but not in antipsychotic treatment.

[New recommendations for antiepileptic drug therapy: the last piece in the review of epilepsy care]. / Sista pusselbiten på plats i översynen av epilepsivården - Nu finns nya rekommendationer för läkemedelsbehandling.

Antiepileptic drug (AED) therapy is symptomatic. New AED:s have not decreased the proportion of epilepsy patients resistant to pharmacological treatment. Lamotrigine, levetiracetam and carbamazepine are first-line options for focal seizures. Lamotrigine, levetiracetam and valproic acid are first-line options for generalized seizures. However, valproic acid is contraindicated during pregnancy unless there is no other effective treatment available, as well as for fertile girls/women unless the conditions of a specific pregnancy prevention programme are met.

Statins and Angiotensin-Converting Enzyme Inhibitors are Associated with Reduced Mortality and Morbidity in Chronic Liver Disease.

Liver fibrosis is a common response to many chronic liver diseases. The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver-related mortality and liver-related morbidity in patients with chronic liver disease. We performed a register-based cohort study of all patients with a first-time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n = 70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked. We studied whether the use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver-specific mortality and morbidity. We found a reduction in mortality risk for statin users (n = 11,245) with hazard ratios from 0.57 (95% CI: 0.32-0.99) for patients with autoimmune hepatitis to 0.84 (95% CI: 0.75-0.95) for patients with alcoholic liver disease. There was a significantly reduced liver-related mortality for patients with alcoholic liver disease who used angiotensin-converting enzyme inhibitors, 0.85 (95% CI: 0.65-0.96). There were increased overall mortality risks for antibiotic users (n = 44,572), with hazard ratios up to 1.67 (95% CI, 1.55-1.80) for viral hepatitis. Statin use was associated with decreased risks of liver-specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin -converting enzyme inhibitors was associated with reduced liver-related mortality among patients with alcoholic liver disease.

CYP2D6-inhibiting drugs and the increased risk of fall-related injuries due to newly initiated opioid treatment--a Swedish, register-based case-crossover study.

It has been shown that newly initiated opioid therapy increases the risk of fall-related injuries. Yet, it remains to be determined whether drug-drug interactions can affect this negative effect, for instance with drugs inhibiting cytochrome P4502D6 (CYP2D6) that metabolizes codeine and also has a partial effect on tramadol and oxycodone. Our aim was to investigate how CYP2D6-inhibiting drugs contribute to explaining the risk of fall-related injuries for newly initiated opioid treatments with codeine, tramadol or oxycodone. Data from a Swedish national case-cross over study were revisited. This study identified a total of 167,257 fall-related injuries leading to hospitalization that occurred between 1 May 2006 and 31 December 2009 and linked information about dispensed drugs to them. Use of newly dispensed opioids in the 28 days before fall-related injury with and without CYP2D6-inhibiting drugs was compared with an earlier control period. For codeine, there was a two-times increased risk with concomitant CYP2D6-inhibiting drug use (OR, 1.76; 95% CI 1.40-2.20) and a three-times risk increase without (OR, 3.17; 95% CI 2.88-3.50). For tramadol, the risks were doubled when CYP2D6-inhibiting drugs were used (OR, 2.19; 95% CI 1.84-2.60) and tripled without their use (OR, 3.04; 95% CI 2.82-3.27). The risks were about the same for oxycodone, morphine, fentanyl and buprenorphine irrespective of CYP2D6-inhibiting drug use. In newly initiated opioid therapies, drug-drug interactions from concomitant use of CYP2D6-inhibiting drugs are associated with a lower risk of fall-related injury for codeine and tramadol that undergo metabolism via CYP2D6, but not for other opioids.

Cytochrome P450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications.

In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.