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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cor.2006.03.026 Byline: S.S. Chauhan, Alain Martel, Sophie D'Amour Abstract: Fine paper mills produce a variety of paper grades to satisfy demand for a large number of sheeted products. Huge reels of different paper grades are produced on a cyclical basis on paper machines. These reels are then cut into rolls of smaller size which are then either sold as such, or sheeted into finished products in converting plants. A huge number of roll sizes would be required to cut all finished products without trim loss and they cannot all be inventoried. An assortment of rolls is inventoried with the implication that the sheeting operations may yield trim loss. The selection of the assortment of roll sizes to stock and the assignment of these roll sizes to finished products have a significant impact on performances. This paper presents a model to decide the parent roll assortment and assignments to finished products based on these products demand processes, desired service levels, trim loss and inventory holding costs. Risk pooling economies made by assigning several finished products to a given roll size is a fundamental aspect of the problem. The overall model is a binary non-linear program. Two solution methods are developed: a branch and price algorithm based on column generation and a fast pricing heuristic, and a marginal cost heuristic. The two methods are tested on real data and also on randomly generated problem instances. The approach proposed was implemented by a large pulp and paper company. Author Affiliation: FOR@C Research Consortium, Network Organization Technology Research Center (CENTOR), Universite Laval, Sainte-Foy, Que., Canada G1K 7P4

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cor.2005.02.047 Byline: Nafee Rizk, Alain Martel, Sophie D'Amours Abstract: This paper examines a multi-item dynamic production-distribution planning problem between a manufacturing location and a distribution center. Transportation costs between the manufacturing location and the distribution center offer economies of scale and can be represented by general piecewise linear functions. The production system at the manufacturing location is a serial process with a multiple parallel machines bottleneck stage and divergent finishing stages. A predetermined production sequence must be maintained on the bottleneck machines. A tight mixed-integer programming model of the production process is proposed, as well as three different formulations to represent general piecewise linear functions. These formulations are then used to develop three equivalent mathematical programming models of the manufacturer-distributor flow planning problem. Valid inequalities to strengthen these formulations are proposed and the strategy of adding extra 0-1 variables to improve the branching process is examined. Tests are performed to compare the computational efficiency of these models. Finally, it is shown that by adding valid inequalities and extra 0-1 variables, major computational improvements can be achieved. Author Affiliation: Research Consortium on e-Business in the Forest Products Industry (FORAC), Network Organization Technology Research Center (CENTOR), Universite Laval, Quebec, Canada

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ijpe.2005.03.011 Byline: Didier Vila (a)(b), Alain Martel (a), Robert Beauregard (a) Abstract: This paper presents a generic methodology to design the production-distribution network of divergent process industry companies in a multinational context. The methodology uses a mathematical programming model to map the industry manufacturing process onto potential production-distribution facility locations and capacity options. The industrial process is defined by a directed multigraph of production and storage activities. The divergent nature of the process is modeled by associating one-to-many recipes to each of its production activities. Each facility may use different layouts and the plants capacity is specified by selecting appropriate technological options. Seasonal shutdowns of these capacities are possible and finished product substitutions are taken into account. The objective is to maximize global after tax profit in a predetermined currency. The methodology is illustrated by applying it to the case of the softwood lumber industry. Guidelines for the use of the methodology are provided. The resolution of the mathematical model with commercial optimization software is also discussed. Author Affiliation: (a) Universite Laval, FOR@C Research Consortium, Network Organization Technology Research Center (CENTOR), Sainte-Foy, Quebec, Canada, G1K7P4 (b) Ecole Nationale Superieure des Mines de Saint-Etienne, Centre G2I, 158 cours Fauriel, 42023 Saint-Etienne cedex 2, France Article History: Received 16 November 2004; Accepted 28 March 2005

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ijpe.2005.02.015 Byline: Nafee Rizk (a), Alain Martel (a), Amar Ramudhin (b) Keywords: Multi-item lot-sizing; Dynamic demand; Piecewise linear costs; Discounts; Mixed integer programming; Lagrangean relaxation Abstract: In this paper we study a class of multi-item lot-sizing problems with dynamic demands, as well as lower and upper bounds on a shared resource with a piecewise linear cost. The shared resource might be supply, production or transportation capacity. The model is particularly applicable to problems with joint shipping and/or purchasing cost discounts. The problem is formulated as a mixed-integer program. Lagrangean relaxation is used to decompose the problem into a set of simple sub-problems. A heuristic method based on sub-gradient optimization is then proposed to solve a particular case often encountered in the consumer goods wholesaling and retailing industry. Our tests show that the heuristic proposed is very efficient in solving large real-life supply planning problems. Author Affiliation: (a) Centor, Network Enterprise Technology Research Center, Universite Laval, Quebec, Canada (b) Ecole de technologie superieure, Montreal, Canada Article History: Received 5 November 2002; Accepted 28 February 2005 Article Note: (footnote) [star] This research was supported by the Natural Sciences and Engineering Council of Canada, by CAPS LOGISTICS, and by FORAC.

The integration of transportation or purchase price discounts into lot sizing decisions in the context of a multi-echelon distribution system is examined. Price discounts for the transportation and purchase of commodities are often given for firms involved in such operations. The distribution of goods among a network of warehouses given such discounts has rarely been modeled in the case of more than two echelon-systems. A mixed-integer model of this problem is proposed that includes a branch-and-bound procedure that incorporates the properties of Langrangian relaxation. The results suggest that the model is applicable in physical distribution systems wherein the firm may take advantage of the transportation discounts involved.

Herpes simplex virus type 2 (HSV) is the virus that causes genital herpes. This infection can be transmitted through sexual contact and is a major public health concern. Primary infections tend to be the most severe, but recurrent infections are common. At the present time, oral acyclovir is the only medication approved for the treatment of recurrent herpes infections. However, in a recent study, patients with genital herpes showed a favorable response to treatment with interferon-alpha applied directly to the skin. Another drug, called edoxudine, has been shown to kill HSV in laboratory animals. This articles describes the results of a study designed to evaluate the effectiveness of a 3.0 percent topical cream containing edoxudine in treating patients with recurrent genital herpes. During the course of the study 102 patients were treated with edoxudine (six times a day for five days) and 97 were treated with a placebo cream. Treatment with edoxudine reduced viral shedding (the amount of virus) and healed the skin lesions faster than treatment with the placebo cream. In women, treatment with edoxudine reduced the formation of new skin lesions and relieved tenderness. Treatment with edoxudine was well tolerated and produced few side effects; itching and burning sensations were reported by eight subjects. These results demonstrate that edoxudine cream has antiviral activity against HSV; patients with recurrent genital herpes may benefit from this treatment. (Consumer Summary produced by Reliance Medical Information, Inc.)

At least 85 percent of patients with AIDS will develop Pneumocystis carinii pneumonia as a complication of the infection. In 65 percent of AIDS patients, this will be the first presenting infection of the disease. Studies have been conducted to determine the most effective regimen to use as prophylaxis (prevention) of P. carinii pneumonia. Pentamidine is a drug known to be efficacious in treating Pneumocystis, and can be given intravenously or in aerosol form. A group of 162 patients with AIDS who had survived at least one episode of P. carinii pneumonia with preserved lung function were randomly assigned to receive either aerosol pentamidine or a placebo for an average of 15 weeks. A total of 37 patients developed new cases of Pneumocystis during the study period, 27 of these were receiving placebo and the other five were taking pentamidine. This yielded a reduction in the rate of relapse of Pneumocystis of 82 percent over the course of the study. Other studies have demonstrated that the use of aerosol pentamidine is effective in prophylaxis against Pneumocystis, but this is the first in which the drug was administered by patient-held inhalers. The impressive benefit noted in this trial may be enhanced by the fact that the patients enrolled in it were relatively healthy, with good lung function at the start of the study. Patients whose first episode of Pneumocystis carinii pneumonia has left them with impaired lung function might not benefit as much. Few serious side effects were noted in the pentamidine group, other than cough and some wheezing after inhaling the drug. Aerosol pentamidine appears to be a safe and effective means of preventing recurrences of P. carinii pneumonia. (Consumer Summary produced by Reliance Medical Information, Inc.)

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure–activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

This paper presents an optimization methodology to design a network of manufacturing facilities producing several products, with non-trivial bills of material, under deterministic demands. The mathematical programming model developed finds the optimal structure of the manufacturing network, it defines the mission of the selected facilities and it determines the technology and the capacity of each facility. The approach takes economies of scale and scope into account. The model is formulated, a solution method based on Bender's decomposition is derived and computational results are presented.

Two randomized, double-blind, parallel-group clinical trials were conducted in Europe and North America to compare the efficacy and safety of topical 1 percent penciclovir cream with a placebo cream.

Epoxidation of Δ2-1-carbacephems 2followed by base treatment gave the allylic alcohols 4. Oxidation of 4gave the 2-keto-Δ3-carbacephem 9which could be reduced to the isomeric allylic alcohol 7. Conversion of these intermediates to a series of biologically active cephalosporin analogs 13g–land 14is described.

The reaction of acetaldehyde with enolates of N-protected 4-tritylthio-2-azetidinones 4band 4cwas studied. While the lithium enolate of N-methoxymethylazetidinone 4bgave only transS* 3-(1′-hydroxyethyl)azetidinone 8the corresponding tetrabutylammonium enolate gave a mixture of transR* and transS* azetidinones 8and 9. The metal enolate of N-(tert-butyldimethylsilyl)-4-tritylthio-2-azetidinone 4cgave all four possible isomers.

An efficient and stereocontrolled preparation of the key a/etidinone-acid 5ais described.

The synthesis of 7-β-phenoxyacetamido-3-methyl-1-oxo-Δ3-O-2-isocephem-4-carboxylic acid 14is described. Condensation of amine 2followed by β -lactam formation and ozonolysis gave the acid 5. This was converted to its trichloroethyl ester 8and the ketal was hydrolyzed to give 9. Reduction of the azido function followed by amide formation gave 11. The trichloroethyl group was removed and the enol acid 12closed to yield 13. Hydrogenolysis of the benzyl ester gave 14. The structural assignments to the compounds are discussed.

The synthesis of 1-α-methyl and 1-β-methyl isomers of 7-(3-phenoxyacetamido-1,3-dimethyl-Δ3-O-2-isocephem-4-carboxylic acids (14aand 14b) is described. Treatment of amine 2with methacrolein followed by cycloaddition gave 4which was ozonolyzed to yield the methyl ketones 6. Upon reduction of 6there was obtained a mixture of isomeric alcohols 8which were resolved by column chromatography, converted to their mesylates 9, and hydrolyzed to yield 10aand 10b. Conversion of each isomer to the corresponding O-2-isocephems 11aand 11bfollowed by azide reduction, coupling of the amines to phenoxyacetic acid, and removal of the ester blocking groups gave 14aand 14b. An attempt to prepare the gem-dimethyl compound failed. The structural assignments to 14aand 14bare discussed.

Methyl β-nitroacrylate (1) reacted with furan to give the corresponding Diels–Alder adduct, which was converted to D,L-3,4-di-O-isopropylidene-2,5-anhydroallose (9) in a five-step sequence in 14% yield, based on 1. The conversion of 9to its oxime, semicarbazone, and thiosemi-carbazone is described, as well as the synthesis of the free aldehyde 15, and of the Wittig reaction product 14.

The general synthetic scheme to nuclear analogs of cephalosporins described in previous papers of this series is reviewed and the synthesis of a series of sidechain derivatives is given. Thus, systems of the following type were formed: carbacephems (A), 2-isocephems (B), N-2-isocephems (C), and O-2-isocephems (D). The invitromicrobiological activity of these compounds (with appropriate side-chains attached) is given, with comparison to analogous cephalosporins. Systems of type A, B, and C were only prepared with a 3-H or CH3substituent and had modest antibacterial activity. The O-2-isocephems (D) were prepared with a wide variety of sidechains at 3 and 7 and were found to have biological activity quite comparable to the cephalosporins. A more detailed biological examination (both invitroand invivo) of the O-2-isocephem analog (19i) of cephalothin was made.

The synthesis of 6-substituted 2-methylpenem-3-carboxylic acids is described. The dianion 6was prepared insitufrom 2-methylpenem-3-carboxylic acid (5) by the addition of two equivalents of n-butyllithium in THF at −78 °C. This dianion reacted with deuterated acetic acid, acetone, acetaldehyde, benzaldehyde, and methyl thiomethylsulfonate to give 6-deuterio-, 6-(2′-hydroxy-2′-propyl)-, 6-(1′-hydroxyethyl)-, 6-(1′-hydroxybenzyl)-, 6-methylthio-2-methylpenem-3-carboxylic acids and their sodium or potassium salts, 7–11, respectively. The stereochemistry of the products is also discussed.

Penems 5were converted to exocyclic analogs 6and 10. These served as substrates for conversion to the sulfone 11and oxopenam 12. None of the products showed any activity as antibiotics or as β-lactamase inhibitors. A single cyrstal X-ray diffraction analysis of compound 6averified the exocyclic penem structure.

This paper presents models for different types of manpower pooling policies. A multi-grade manpower system with mutually exclusive skills is considered. The work load imposed is a random variable characterized by the known joint distribution of the number of jobs to be performed and of the time to do a job. The basic models are developed as a tool for manpower planning in the jobbing workshops of an oil company. The resulting "two-stage programmes under uncertainty" are shown to reduce to mixed-integer linear programmes. The models are then generalized to permit their use in a larger class of manpower planning problems.

In this study, a highly stereoselective preparation of (3S,4S)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxy-ethyl]-azetidin-2-one (2) is reported. It involves a Lewis acid mediated condensation of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (3) with simple O-silylenol ethers of thiopropionates. From all the examples reported in this paper the 2-picolyl thiopropionate or similar arrangements were found to be essential for this stereoselection. Finally, a mechanism involving chelation control seems to be operative.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.

Aldol condensation of the magnesium enolate derived from anhydro-6,6-dibromopenicillin with acetaldehyde allows for the stereospecific introduction of a 1-R-hydroxyethyl substituent at C-6. Protection of the hydroxy group followed by reductive dehalogenation provides anhydro-6(α)-[(1-R)-(tert;-butyldimethylsilyloxy)-ethyl]-penicillin, an intermediate in the synthesis of thienamycin. A high yield conversion of this anhydro derivative to (4-R)-acetoxy-(3-S)-[(1-R)-(tert-butyldimethylsilyloxy-ethyl]-azetidin-2-one (5) is also reported.

Title compound (IIa) is synthesized in 4 steps from acid (Ia) and converted to its chloride (IIb).

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

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When prescribing home intravenous antibiotic therapy (HIVAT), physicians must consider not only the factors normally considered in a hospital setting, but also the limitations and advantages of home therapy. Examples include dosage schedule, short and long term toxicity, stability of the antibiotics at room temperature after dilution, half-life of antibiotics, compatibility with other antibiotics or medications in the same bag and distribution methods from the supplier (pharmacy) to the patient. Consideration of these factors may direct antimicrobial choices, the mode of delivery and treatment schedule. Other prerequisites for antibiotic selection for home therapy include tolerability and low incidence of toxic reactions. Physicians and nurses must be aware of the adverse effects associated with prolonged outpatient intravenous antimicrobial therapy. Additional knowledge must include pharmacokinetics (absorption, distribution and elimination) and the pharmacodynamics (biochemical and physiological effects and mechanisms of action) of the commonly used antibiotics. One simple guideline is the less often a drug has to be administered, the more convenient the therapy will be for the patients, facilitating a higher rate of compliance. The less frequent administration schedules will also require less staff time for training and troubleshooting. Many antimicrobial agents can be given once daily and, therefore, readily meet this objective. Classes of antimicrobials that can be used once daily include aminoglycosides, ceftriaxone, vancomycin and the new quinolones. The development of antimicrobials that can be administered less often has been a major factor contributing to the growth of HIVAT. If an antibiotic has to be used more frequently than three times a day, the use of a computerized ambulatory infusion pump is helpful; however, pumps are expensive and not readily available. Other considerations for HIVAT include renal impairment, liver failure and hematological toxicities. These factors have led the author and colleagues to develop specific monitoring recommendations and techniques.

The current medical climate has forced all health care providers to search for alternative methods for the delivery of health care. This search has led to the use of sites outside the conventional hospital walls for peritoneal dialysis, parenteral hyperalimentation, blood or blood product transfusions, etc. Home intravenous self-injection of antibiotics is such an alternative to prolonged and/or repeated hospitalization for patients requiring intravenous antibiotics administration only. This alternative was started as a pilot study and soon became a usual service in the Centre hospitalier de l’Université Laval following receipt of a grant from the National Health Research and Development Program. After careful development of inclusion/exclusion criteria and a teaching manual for patient and health care providers. and the standardization of medical. pharmaceutical and nursing approach, a clinical, psychosocial and economical analysis of patients who agreed to participate in a clinical study comparing the two methods of health care delivery (hospital versus home) was started. Patients who met inclusion/exclusion criteria, agreeing to finish their treatment at home instead of staying hospitalized to receive intravenous antibiotics only, were taught the various techniques of intravenous self-injection. Once they were judged to be able to self-administer the antibiotics, they were sent home with the material needed to carry on their treatment, To date, more than 100 patients have participated in the home-treatment, of which 50 were analyzed. The duration of home treatment varied from two days to several months. Most patients had osteomyelitis, septic arthritis, septic bursitis, bacterial cellulitis or lung infections. The therapy allowed some newly defined patients with complicated infections (AIDS patients with cytomegalovirus retinitis) to continue their treatment at home. The clinical outcome of patients treated at home was identical to the outcomes of those treated in the hospital. Side effects were comparable with the hospital treatment and were mainly catheter-related. Compared with hospitalization. home treatment was preferred by the majority of patients. Psychological analysis of the patients showed that those who choose home therapy had a higher internal “locus of control” than those who preferred to stay in the hospital for the entire length of therapy. The economical analysis showed a potential reduction of cost varying between $941.00 and $3325.00 per treatment. Home intravenous self-injection of antibiotics allowed health self-monitoring by the patients or/and their friends or family and increased health care efficiency.