The CMF-regimen. Toxicity patterns following stepwise combinations of cyclophosphamide, methotrexate and fluorouracil

The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.     

Three-year registry data on biological treatment for psoriasis: the influence of patient characteristics on treatment outcome

Background The course of biological treatment in clinical practice may be highly different from treatment schedules in clinical trials. Treatment modifications and patient characteristics may influence treatment safety and efficacy. So far, long‐term results from the use of biological treatment in clinical practice are lacking. Objectives To report short‐ and long‐term efficacy and safety data on biologics, especially etanercept, used in daily clinical practice. Special attention has been paid to patient characteristics that may have influenced the response to therapy. Methods Prospectively collected registry data of all patients with psoriasis treated with biologics in the Radboud University Nijmegen Medical Centre outpatient clinic were used for analysis. Patient and treatment characteristics were surveyed. Efficacy and safety of etanercept for up to 3 years were analysed. Moreover, the influence of patient characteristics on etanercept treatment response was studied. Results The analysed cohort, consisting of 118 patients, went through 142 treatment episodes in total. Patients treated with biologics had an extensive medical history. Optimization of biological treatment was established in various ways, including treatment switches and introduction of concomitant therapies. Short‐term etanercept efficacy analysis showed a mean Psoriasis Area and Severity Index (PASI) improvement at week 24 of 59·7%. No significant influence of gender, age, baseline PASI, body mass index, number of previous systemic therapies or duration of psoriasis was found on week 24 efficacy results, although trends were discernible. The efficacy of etanercept remained stable for up to 156 weeks. Long‐term daily practice treatment with etanercept was only occasionally accompanied by major safety concerns. Conclusions The current study demonstrates that etanercept is able to improve psoriasis symptoms for a considerable time, and that serious side‐effects are infrequent. The influence of patient characteristics on treatment response is limited.     

Kosten-Nutzen-Analyse klinisch-evaluierter Behandlungsprogramme Erweiterte Entzugstherapie bei Alkoholabh?ngigkeit Erweiterte Entzugstherapie bei Alkoholabh?ngigkeit

Kosten-Nutzen-Analysen neuer Therapieans?tze erg?nzen klinische Evaluationsstudien und erlauben eine bessere Gesamtabsch?tzung der Therapieeffizienz. Das Modell einer bereits klinisch evaluierten erweiterten Entzugsbehandlung Alkoholabh?ngiger (Entzug II) sollte unter Kosten-Nutzen-Gesichtspunkten überprüft werden. Es wurden 57 Patienten nach Entzug II und 37 nach konventioneller Entgiftung (Entzug I) untersucht. In einem retro- und prospektiven Ansatz wurden für 5 Jahre vor und nach Indextherapie Krankenversicherungsdaten zur Hospitalisierungsh?ufigkeit und -dauer, Arbeitsunf?higkeit und Krankengeldbezug erhoben. Entzug-II-Patienten wurden nach Indextherapie durchschnittlich seltener (3,5+4,4 vs. 7,3+11,3) und weniger lange (66+75 vs. 136+167) hospitalisiert und bezogen weniger lange Krankengeld (67+73 vs. 220+187) als Patienten nach Entzug I. Für den station?ren Bereich ergaben sich bei Entzug-II-Patienten um ca. 50% geringere Gesamtbehandlungskosten (Indextherapie und Folgekosten). Insgesamt sprechen bei einer leichten klinischen überlegenheit in den 12 Monaten nach Indextherapie (ca. 14% h?here Abstinenzrate) erheblich geringere Folgehospitalisierungen und Folgekosten für eine ausreichend hohe Effizienz der erweiterten Entzugstherapie Alkoholabh?ngiger.     

Dantrolene plasma and urine concentrations after oral pretreatment for malignant hyperthermia: report of a case

Dantrolene plasma concentrations and renal clearance calculations in a patient undergoing major surgery are reported. The family history was positive for malignant hyperthermia. Following oral pretreatment the plasma concentrations in this patient were not noticeably different from values obtained in a study in awake volunteers and which were thought to be effective. This is the first report of dantrolene measurements made during anaesthesia and in the post-operative period.     

Benzodiazepines and neuromuscular blocking drugs in patients

The interaction between four benzodiazepines (diazepam, lorazepam, lormetazepam and midazolam) and two nondepolarizing neuromuscular blocking drugs (vecuronium and atracurium) was investigated in 113 patients during general anaesthesia. Neuromuscular function was monitored by recording the mechanical twitch tension of the adductor pollicis muscle of the thumb in response to ulnar nerve stimulation with single supramaximal stimuli of 0.2 ms at 0.1 Hz. In the first group of patients a benzodiazepine (diazepam 20 mg, lorazepam 5 mg, lormetazepam 2 mg or midazolam 15 mg), was injected i.v. 15 min before a single bolus of vecuronium 45 micrograms kg-1. In the second group of patients suxamethonium 1 mg kg-1 was given for endotracheal intubation, and 30 min later the patients received atracurium 200 micrograms kg-1. Fifteen min before injection of atracurium one of the same benzodiazepines as in the first group was injected i.v. Comparisons were made with control patients receiving thiopentone. Neither benzodiazepine caused significant potentiation of neuromuscular blocking agents in comparison with control. With midazolam, however, the duration to 25% and to 75% recovery of the twitch height after vecuronium was significantly longer than with diazepam. The time to 25% recovery of the twitch height after atracurium was significantly longer in patients receiving midazolam than in those receiving diazepam. The recovery index was not influenced by the four benzodiazepines.     

Pharmacokinetics of diazepam and four 3-hydroxy-benzodiazepines in the cat

Biotransformation and elimination of diazepam and four 3-hydroxy-benzodiazepines after i.v. injection in anaesthetized cats were investigated. Decay of plasma concentration of 3-hydroxy-benzodiazepines was slow and plasma concentrations of their glucuronides were lower than of unchanged parent compounds. In the urine, very low excretion rates of all investigated benzodiazepines were found during the first eight hours. It is concluded that cats poorly glucuronidate 3-dydroxy-benzodiazepines.     

Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules. Such loading occurs after endosomal degradation of the invariant chain to a approximately 3-kD peptide termed CLIP (class II-associated invariant chain peptide). Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s). Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Recombinant cathepsin Z did not generate CLIP from Ii-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading.