Logical calculi for reasoning with binding

In informal mathematical usage we often reason about languages involving binding of object-variables. We find ourselves writing assertions involving meta-variables and capture-avoidance constraints on where object-variables can and cannot occur free. Formalising such assertions is problematic because the standard logical frameworks cannot express capture-avoidance constraints directly. In this thesis we make the case for extending logical frameworks with metavariables and capture-avoidance constraints. We use nominal techniques that allow for a direct formalisation of meta-level assertions, while remaining close to informal practice. Our focus is on derivability and we show that our derivation rules support the following key features of meta-level reasoning: • instantiation of meta-variables, by means of capturing substitution of terms for meta-variables; • ??-renaming of object-variables and capture-avoiding substitution of terms for object-variables in the presence of meta-variables; • generation of fresh object-variables inside a derivation. We apply our nominal techniques to the following two logical frameworks: • Equational logic. We investigate proof-theoretical properties, give a semantics in nominal sets and compare the notion of ??-renaming to existing notions of ??-equivalence with meta-variables. We also provide an axiomatisation of capture-avoiding substitution, and show that it is sound and complete with respect to the usual notion of capture-avoiding substitution. • First-order logic with equality. We provide a sequent calculus with metavariables and capture-avoidance constraints, and show that it represents schemas of derivations in first-order logic. We also show how we can axiomatise this notion of derivability in the calculus for equational logic

Behavioural analysis of an I2C Linux driver

We present an analysis of the behaviour of an I2C Linuxdriver, by means of model checking with the mCRL2 toolset and static analysis with UNO.We have reverse engineered the source code to obtain the structure and interactions of the driver. Based on these results, we have semi-automatically created an mCRL2 model of the behaviour of the driver, on which we have checked mutual exclusion properties. This revealed non-trivial potential errors, like unprotected usage of shared memory variables due to inconsistent locking and disabling/enabling of interrupts. We also applied UNO on the instrumented source code and were able to find the same errors. These defects were confirmed by the developers

Irinotecan: from clinical pharmacokinetics to pharmacogenetics

Four decades ago, a plant alkaloid was isolated from the Chinese tree Camptotheca acuminata (Nyssaceae family), which showed promising antitumor activity in vitro (1 ). At that moment, a relatively new class of anticancer agents was born. Unfortunately, during clinical trials, this alkaloid, called camptothecin (CPT), showed severe and unpredictable side effects (myelosuppression, diarrhea, and hemorrhagic cystitis), which were unmanageble during this early chemotherapeutic era (2-4). Later on, the drug's relative lack of hydrophility was found to be the main reason for these adverse events. Despite this ''false starf', renewed interest in this compound was found after the elucidation of its mechanism of action during the mid-1980s (i.e the inhibition of topoisomerase I; ref. 5-7). Topoisomerase I is an essential enzyme in DNA replication and RNA transcription and is present in all eukaryotic cells (8). In the physiologic state of the cell nucleus, DNA is double-stranded, super-coiled and fits tightly into a chromosome. To synthesize new DNA, this topological constrained DNA should unwind. To this end, topoisomerase I binds to the DNA, forms a covalent reversible adduct (which is called the cleavable complex), cleaves a phosphodiester bond and a single-strand break occurs (6). Next, the DNA molecule is able to rotate freely around its intact single strand, and relaxation of DNA takes place. After the religation of the cleavage, the enzyme dissociates from DNA. The cleavable complex usually binds for a short period, just to allow the single strand to unwind (9, 1 0). CPT induces the stabilization of the cleavable complexes (11, 12), what will lead to a disruption of the DNA-strand when the replication fork meets the cleavable complex (7). This doublestrand break will lead to the activation of apoptosis pathways and ultimately result in cell-death (7). In subsequent years, various derivatives of CPT with improved water solubility have been developed, of which irinotecan (CPT-11) was considered to be among the most promising ones (13). It is a semisynthetic water-soluble prodrug, with minor intrinsic cy1otoxic activity. After administration, the drug is partially converted into the 1 00- to 1 ,000-times more active metabolite SN-38 by the enzyme carboxyl esterase (14-17). In the liver, SN-38 is de-toxified by undine-diphosphate glucuronosyltransferase 1 A isoforms, whereby SN-38-glucuronide is formed (18). All these compounds can be secreted into the bile by specific transporters (19). In the intestines, several bacteria produce ~-glucuronidase, which enables re-activatation of the glucuronidated form of SN-38 (20). Relatively high concentrations of SN-38 will lead to damage of the bowel mucosa, which results in one of the drug's most prominent side effects: diarrhea (21). In addition, irinotecan can also be oxidated by cy1ochrome P450 isozymes (22, 23), which will lead to the formation of several inactive metabolites, including APC and NPC

Pharmacological and clinical aspects of immediate release fentanyl preparations: Criteria for selection

In palliative care, pain management is often hampered by episodes of breakthrough pain, characterised by a rapid onset and, on average, duration less than 1 h. Until recently, only immediate release morphine and oxycodon preparations were available for the treatment of these episodes but time until effect is too long for both of these drugs. Recently, immediate release fentanyl products have become available for the treatment of breakthrough pain. These products can be classified as oromucosal and nasal products. Both are absorbed rapidly by the mucosa, although the oromucosally delivered products are partly absorbed by the gastrointestinal tract and therefore reach maximum plasma levels somewhat slower (after 30-90 min) than the nasally delivered products (after ~15 min). In clinical placebo controlled studies, all new immediate release fentanyl products were proven to be effective from 15 min after administration in the treatment of breakthrough pain. The first studies comparing immediate release fentanyl with immediate release morphine or oxycodon also found superiority for the new fentanyl products

Quantification of afatinib, alectinib, crizotinib and osimertinib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry; focusing on the stability of osimertinib

The development and full validation of a sensitive and selective ultra-performance liquid chromatography/ tandem mass spectrometry (UPLC–MS/MS) method are described for the simultaneous analysis of afatinib, alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%

Recent Clinical Developments of Nanomediated Drug Delivery Systems of Taxanes for the Treatment of Cancer

Conventional taxanes are used as cornerstone of the chemotherapeutical treatment for a variety of malignancies. Nevertheless, a large proportion of patients do not benefit from their treatment while they do suffer from severe adverse events related to the solvent or to the active compound. Cremophor EL and polysorbate 80 free formulations, conjugates, oral formulations and different types of drug delivery systems are some examples of the several attempts to improve the treatment with taxanes. In this review article, we discuss recent clinical developments of nanomediated drug delivery systems of taxanes for the treatment of cancer. Targeting mechanisms of drug delivery systems and characteristics of the most commonly used taxane-containing drug delivery systems in the clinical setting will be discussed in this review

Effects of St. John's wort on irinotecan metabolism

St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome