Trace-level quantitation of iralukast in human plasma by microbore liquid chromatography/tandem mass spectrometry

Iralukast (CGP 45715A) is a potent peptido-leukotriene antagonist that is active in various in vitro and animal models for the treatment of asthma. An analytical challenge was to develop a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 10 pg/mL for the analysis of iralukast when administered at low doses during clinical trials. Several issues had to be addressed in order to devise a LC/MS/MS assay for the above compound. First, iralukast appeared to be light sensitive and unstable at room temperature under acidic conditions. Second, a LLOQ of 10 pg/mL was needed to support several clinical trials. Third, positive electrospray ionization of iralukast did not yield the necessary sensitivity required for studies in humans. Consequently, LC/MS/MS conditions were optimized for the negative ion mode of detection. Fourth, sample preparation steps proved to be critical to reduce the possibility of microbore HPLC column (50 mm x 1.0 mm i.d.) obstruction, chromatographic deterioration, and matrix-mediated electrospray ion suppression. While our validated method addressed the above challenges, its major drawback was limited sample throughput capability. Nonetheless, plasma concentration-time profiles for patients with moderate asthma after oral administration of 200, 500, 1000, and 5000 microgram/kg/day of iralukast were successfully obtained.     

On constant discrete programming problems

Let H be a subset of the set S_n of all permutations

$\text{1}\text{2}\text{???}\text{n}\text{s(1)}\text{s(2)}\text{???}\text{s(n)}$

C=6c_ij6 a real n?n matrix L_c(s)=c_1s(1)+c_2s(2)+???+c_ns(n) for s ? H. A pair (H, C) is the existencee of reals a₁,b₁,a₂,b₂,…a_n,b_n, for which c_ij=a₁+b_j if (i,j)?D(H), where D(H)={(i,j):(?h?H)(j=h(i))}.For a pair (H,C) the specifity of it is proved in the case, when H is either a special cyclic class of permutations or a special union of cyclic classes. Specific pairs with minimal sets H are in some sense described.     

On the average performance of the adjustable RO and its use as an offline tool for multi-period production planning under uncertainty

Robust optimization (RO) is a distribution-free worst-case solution methodology designed for uncertain maximization problems via a max-min approach considering a bounded uncertainty set. It yields a feasible solution over this set with a guaranteed worst-case value. As opposed to a previous conception that RO is conservative based on optimal value analysis, we argue that in practice the uncertain parameters rarely take simultaneously the values of the worst-case scenario, and thus introduce a new performance measure based on simulated average values. To this end, we apply the adjustable RO (AARC) to a single new product multi-period production planning problem under an uncertain and bounded demand so as to maximize the total profit. The demand for the product is assumed to follow a typical life-cycle pattern, whose length is typically hard to anticipate. We suggest a novel approach to predict the production plan’s profitable cycle length, already at the outset of the planning horizon. The AARC is an offline method that is employed online and adjusted to past realizations of the demand by a linear decision rule (LDR). We compare it to an alternative offline method, aiming at maximum expected profit, applying the same LDR. Although the AARC maximizes the profit against a worst-case demand scenario, our empirical results show that the average performance of both methods is very similar. Further, AARC consistently guarantees a worst profit over the entire uncertainty set, and its model’s size is considerably smaller and thus exhibit superior performance.     

Derivatization of Methylamine and Ethylamine Followed by LC and Fluorescence Detection for Measurement of Urinary Clearance

Monomethylamine (MMA) and ethylamine (EtA) accumulate in uremia. However, the urinary clearances of these compounds in normal humans and those with chronic kidney disease (CKD) have not been studied. In this work, an LC based fluorescence assay for MMA and EtA was developed. In applying the method, we found that some previous assays of urinary levels of MMA and EtA lead to overestimations. Normal subjects with average creatinine clearance of 82 ± 21 mL min^?1 demonstrate clearances for the two aliphatic amines less than the creatinine clearance, and in the range of urinary urea clearance. CKD subjects with an average creatinine clearance of 37 ± 12 mL min^?1 had modestly but significantly elevated serum levels of MMA and EtA above normals. Their fractional clearances were increased markedly compared to normals, mitigating the rise in their plasma levels. These findings imply enhanced secretion and/or reduced reabsorption of the amines with CKD.     

Models and Approximations for Call Center Design

A call center is a facility for delivering telephone service, both incoming and outgoing. This paper addresses optimal staffing of call centers, modeled as M/G/n queues whose offered traffic consists of multiple customer streams, each with an individual priority, arrival rate, service distribution and grade of service (GoS) stated in terms of equilibrium tail waiting time probabilities or mean waiting times. The paper proposes a methodology for deriving the approximate minimal number of servers that suffices to guarantee the prescribed GoS of all customer streams. The methodology is based on an analytic approximation, called the Scaling-Erlang (SE) approximation, which maps the M/G/n queue to an approximating, suitably scaled M/G/1 queue, for which waiting time statistics are available via the Pollaczek-Khintchine formula in terms of Laplace transforms. The SE approximation is then generalized to M/G/n queues with multiple types of customers and non-preemptive priorities, yielding the Priority Scaling-Erlang (PSE) approximation. A simple goal-seeking search, utilizing SE/PSE approximations, is presented for the optimal staffing level, subject to GoS constraints. The efficacy of the methodology is demonstrated by comparing the number of servers estimated via the PSE approximation to their counterparts obtained by simulation. A number of case studies confirm that the SE/PSE approximations yield optimal staffing results in excellent agreement with simulation, but at a fraction of simulation time and space.     

IPA derivatives for a discrete model of make-to-stock production-inventory systems with backorders

We consider a class of single-stage, single-product Make-to-Stock production-inventory system (MTS system) with backorders. The system employs a continuous-review base-stock policy which strives to maintain a prescribed base-stock level of inventory. In a previous paper of Zhao and Melamed (Methodology and Computing in Applied Probability 8:191–222, 2006), the Infinitesimal Perturbation Analysis (IPA) derivatives of inventory and backorders time averages with respect to the base-stock level and a parameter of the production-rate process were computed in Stochastic Fluid Model (SFM) setting, where the demand stream at the inventory facility and its replenishment stream from the production facility are modeled by stochastic rate processes. The advantage of the SFM abstraction is that the aforementioned IPA derivatives can be shown to be unbiased. However, its disadvantages are twofold: (1) on the modeling side, the highly abstracted SFM formulation does not maintain the identity of transactions (individual demands, orders and replenishments) and has no notion of lead times, and (2) on the applications side, the aforementioned IPA derivatives are brittle in that they contain instantaneous rates at certain hitting times which are rarely known, and consequently, need to be estimated. In this paper, we remedy both disadvantages by using a discrete setting, where transaction identity is maintained, and order fulfillment from inventory following demand arrivals and inventory restocking following replenishment arrivals are modeled as discrete jumps in the inventory level. We then compute the aforementioned IPA derivatives with respect to the base-stock level and a parameter of the lead-time process in the discrete setting under any initial system state. The formulas derived are shown to be unbiased and directly computable from sample path observables, and their computation is both simple and computationally robust.     

Characterization of probability laws by the properties of the identical distributions of linear forms with random coefficients

In the paper one considers the conditions under which two linear statistics with random coefficients are identically distributed.Translated from Zapiski Nauchnykh Seminarov Leningradskogo Otdeleniya Matematicheskogo Instituta im. V. A. Steklova AN SSSR, Vol. 136, pp. 58–73, 1984.