Targeting immunoliposomes to EGFR-positive glioblastoma.

BACKGROUND: We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. PATIENTS AND METHODS: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. RESULTS: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. CONCLUSIONS: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study.

OBJECTIVES: Controversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC. MATERIALS AND METHODS: We included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%. RESULTS: From a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95-1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment. CONCLUSION: The present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors.

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug-drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct-acting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug-drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug-drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug-drug interactions when used concomitantly with P2Y12 receptor inhibitors.

[Severe pancytopenia and stomatitis in a patient treated with low-dose methostraxate]. / Schwere Panzytopenie und Stomatitis unter low-dose-Therapie mit Methotrexat.

A 68-year-old female patient presented at the emergency room with episodes of epistaxis, dysphagia and malaise. The patient had acute prerenal renal failure, probably in association with previous infection of the airways and treatment with NSAID's. Laboratory values revealed greatly decreased leukocyte and platelet counts as well as anemia. The patient had a diagnosis of a seronegative arthritis since 9 months and, therefore, was treated with low dose methotrexate (MTX) 10 mg/week. After exclusion of other causes, myelosupression was considered to be associated with low-dose MTX. After stopping MTX and treatment with folic acid leucocyte and platelet counts returned to normal and stomatitis recovered as well within nine days. We discuss the pharmacology of low-dose MTX and in particular the risk factors and prophylaxis of its toxicity. Renal function needs special attention in patients treated with low-dose MTX.

Bile duct injury and use of cholangiography during laparoscopic cholecystectomy.

BACKGROUND: Bile duct injury (BDI) remains the most serious complication of laparoscopic cholecystectomy (LC). A Swiss database was used to identify risk factors for BDI and to assess the effect of intraoperative cholangiography (IOC). METHODS: Data for patients from 114 Swiss institutions who underwent LC for acute or chronic cholecystitis between 1995 and 2005 were used in univariable and logistic regression analyses. RESULTS: In total 31 838 patients, mean(s.d.) age 54·4(15·9) years, were analysed. The incidence of BDI was 0·3 per cent (101 patients), which did not change over time (P = 0·560). Univariable analysis revealed that male patients had a higher risk of BDI (0·5 per cent versus 0·2 per cent in female patients; P = 0·001), as did patients whose operation lasted at least 150 min (1·1 per cent versus 0·1 per cent for operating time of less than 150 min; P < 0·001). Logistic regression confirmed male sex (odds ratio (OR) 1·89, 95 per cent confidence interval 1·27 to 2·81) and prolonged surgery (OR 12·60, 10·87 to 23·81) as independent risk factors. Comparison of groups with and without intraoperative cholangiography showed no difference in the incidence of BDI (both 0·3 per cent; P = 0·755) and BDIs missed during surgery (10 versus 8 per cent; P = 0·737). CONCLUSION: Male sex and prolonged laparoscopic surgery are independent risk factors for BDI during LC. Frequent use of IOC does not seem to reduce BDI or the number of injuries missed during surgery.

Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach.

Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.

Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial.

BACKGROUND: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC(HD-MTX)) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUC(HD-MTX) from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling. RESULTS: AUC(HD-MTX), the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC(HD-MTX) did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC(HD-MTX) was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUC(HD-MTX) and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 micromol l(-1) h(-1) increase in AUC(HD-MTX). CONCLUSIONS: Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT.

The aim of this study was to assess the frequency of potential drug-drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.

Endoscopic retroperitoneal neurectomy for chronic pain after groin surgery.

BACKGROUND: Chronic postoperative pain after inguinal surgery remains a difficult problem. The role of minimally invasive surgery in this complex setting is still unexplored. METHODS: Between January 1997 and January 2007, 34 men and five women with a mean(s.d.) age of 47(16) years underwent endoscopic retroperitoneal neurectomy (ERN) for chronic neuropathic groin pain due to genitofemoral nerve with or without ilioinguinal nerve entrapment. Follow-up data were obtained 1 and 12 months after surgery. RESULTS: At both timepoints after ERN, the severity of chronic postoperative groin pain at rest and during daily activities, and the rate of occupational disability, were significantly decreased in 27 of the 39 patients compared with preoperative values (all P < 0.001). CONCLUSION: ERN for chronic postoperative genitofemoral nerve entrapment neuropathy was successful in the majority of patients selected for the procedure. This minimally invasive approach allows simultaneous neurectomy of genitofemoral and ilioinguinal nerves.

Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues.

BACKGROUND AND PURPOSE: Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH(2)CH(2)-N-diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life-threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether-a-go-go-related protein (hERG) channel inhibition but with reduced cytotoxicity. EXPERIMENTAL APPROACH: We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. KEY RESULTS: Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH(2)-CH(2)-OH), the corresponding acid (B2-O-CH(2)-COOH) and, finally, the newly synthesized B2-O-CH(2)-CH(2)-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH(2)-CH(2)-N-diisopropyl and the B2-O-CH(2)-CH(2)-N-piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2-O-CH(2)-CH(2)-N-piperidine and B2-O-CH(2)-CH(2)-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. CONCLUSIONS AND IMPLICATIONS: Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds.

[Drug-induced toxic hepatitis]. / Medikamentös-toxische Hepatitis.

A 55-year-old male patient was hospitalized with severe nausea, vomiting and icterus. Laboratory testing showed hepatocellular damage. After exhaustive testing, the exclusion diagnosis of a toxic hepatitis was reached. There was a strong temporal correlation with the ingestion of Hong Hua 29, a preparation from Traditional Chinese Medicine (TCM). This medication had been started twelve days prior to the first appearance of symptoms. The existing drug regimen included gabapentin (Neurontin), esomeprazole (Nexium) and prednisone (Prednison Streuli) for the therapy of an acute sensory and motor neuropathy of unknown aetiology. After cessation of Hong Hua 29, gabapentin and esomeprazole, transaminase levels started to declined and normalized within three months. According to the Swissmedic criteria of imputability, a causal correlation between the observed symptoms and the administration of Hong Hua 29 is possible.

[Prevalence of potential drug-drug interactions in ambulatory patients with statin therapy]. / Prävalenz potentieller Arznei- mittelinteraktionen bei ambulanten Patienten unter Statin-Therapie.

AIM: To asses the prevalence of potentially critical drug-drug interactions (DDIs) in outpatients treated with a statin. PATIENTS/METHODS: Data of patients (e.g. age, sex, comorbidities, individual statin, number of drugs, number of diagnoses) were collected from 242 Swiss practitioners. The medication was screened electronically for potentially critical DDIs. RESULTS: We included 2742 statin-treated patients (mean age 65.1 +/- 11.2 [SD] years, 3.2 +/- 1.6 diagnoses, 4.9 +/- 2.4 drugs prescribed) from the German (53.3%), French (36%) or Italian speaking (10.7%) part of Switzerland. Of those, 401 (14.6%) had a total of 591 potentially severe DDIs; 190 patients (6.9%) had potential statin DDIs, 288 (10.5%) potential non-statin DDIs, mainly due to pharmacodynamic mechanisms. The prevalence of potential DDIs was similar between regions, except for a trend for a higher prevalence of drug-statin interactions in the French-speaking part. The number of drugs per patient and a diagnosis of arrhythmia or heart failure were identified as risk factors for DDIs. CONCLUSIONS: Drug combinations with potentially severe DDIs are common in patients treated with statins due to pharmacotherapy of their co-morbidities. Special attention in this specific population should be drawn on patients with polypharmacy and those with drug treatments for arrhythmia or heart failure.

Hepatic carbohydrate metabolism in rats after laparotomy and laparoscopy.

BACKGROUND: Portal venous and mesenteric blood flow are reduced by 40-60% in humans and animals during laparoscopic surgery compared to laparotomy. Little is known about whether these intraabdominal micro- and macrocirculatory changes are associated with alterations in the hepatic energy metabolism. METHODS: We operated on male Sprague-Dawley rats, performing either laparoscopy (CO2, 6 mmHg; n = 27) or laparotomy (n = 28), and compared the results with two control groups: intraperitoneal (i.p.) endotoxin administration (n = 28, positive control) and anesthesia only (n = 28, negative control). We investigated the impact of the two different surgical techniques on daily food intake, body weight gain, glycogen content in the liver, levels of blood glucose, and liver function tests (LFTs) on postoperative days 1, 2, 4, and 8. Local (hepatic) and systemic inflammatory responses (interleukin-6 and tumor necrosis factor-alpha) during the postoperative time course were also determined. Data were analyzed using the Kruskal-Wallis test or univariate analysis of variance. RESULTS: Body weight gain, food intake, liver and spleen weights, as well as LFTs [except aspartate aminotransferase (AST)] did not differ among the four groups. The significant increase in the AST level following laparoscopy compared to the anesthesia-only group was found on postoperative days 1 and 2; however, a similar difference was not detected after laparotomy or i.p. endotoxin injection. Laparoscopy showed no alterations in the hepatic glycogen stores compared to anesthesia only, whereas laparotomy and endotoxinemia significantly reduced the hepatic glycogen stores on postoperative days 2 and 4. The systemic postoperative inflammatory response did not differ between laparotomy and laparoscopy, but it was higher in both groups than in anesthesia only. In rats treated with endotoxin, the systemic inflammatory response was even higher than in the two surgical groups. The hepatic inflammatory response did not differ between the four groups. CONCLUSION: This study shows a significant postoperative decrease in the hepatic glycogen content after laparotomy and i.p. endotoxin injection but not after laparoscopy. Food intake and inflammatory response cannot explain this difference between the two surgical groups, which suggests that alterations in the postsurgical hormonal stress response are the most likely explanation for these findings.

[Pharmacokinetics and pharmacodynamices in the elderly]. / Pharmakokinetik und -dynamik im Alter.

Pharmacokinetic and dynamic alterations, the appearance of multiple illnesses which are treated with polypharmacy and, possibly as a consequence of polypharmacy, impaired compliance with drug therapy are associated with a higher incidence of drug-drug interactions and adverse drug reactions in geriatric patients. The most important among these alterations are discussed and possible solutions are presented.

Myocardial function and energy metabolism in carnitine-deficient rats.

Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.

Cholangiopathy after short-term administration of piperacillin and imipenem/cilastatin.

We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.

Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis.

We report the case of a 66-year-old male with ulcerative colitis diagnosed in 1987, who had been treated with azathioprine (AZA) for the past two years (average dose about 1.6 mg/kg/day). In May 1999 he presented with painless jaundice, fatigue and recent weight loss. Cholestatic enzymes were elevated, alpha-fetoprotein was normal and hepatitis B/C serology negative. After diagnosis of veno-occlusive disease (VOD) and hepatocellular carcinoma (HCC) via biopsy, tumour resection was performed. The histology was typical for a well-differentiated HCC with trabecular and pseudoglandular structures. Neighbouring liver tissue was atrophic, with nodular regenerative hyperplasia (NRH), peliosis-like sinusoidal ectasias and intra-sinusoidal accumulation of blood, associated with peri-sinusoidal fibrosis. Although none of the well-established risk factors for HCC such as cirrhosis, hepatitis B/C, metabolic liver disease or toxins were present, this patient developed HCC. This and previous reports suggest that NRH and/or VOD associated with AZA represent a risk factor for HCC. AZA should therefore not only be stopped in patients with NRH/VOD but patients should also be screened for HCC.

[Clinical pharmacology: proteins for the transport of drugs]. / Klinische Pharmakologie: Proteine für den Transport von Arzneistoffen.

Most drugs have to pass cellular barriers in order to reach their site of action. This can be accomplished passively by diffusion, but more often it is an energy-consuming process using specific carrier proteins. Two groups of such proteins which are well characterised, the organic cation transporters and the multidrug resistance proteins, are discussed in detail in the present review. The clinical significance of these proteins is due not only to their role in drug distribution and elimination, but also to possible drug interactions when different drugs and/or endogenous substrates compete with the same carrier protein. Inhibition of multidrug resistance proteins could be of therapeutic value in impairing transport of drugs from their site of action and this could be particularly beneficial in the treatment of malignant diseases.