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Montelukast (l-706,631, MK-0476, SINGULAIR), a potent and selective leukotriene D4(CysLT1) receptor antagonist, is currently under development for the treatment of asthma.In vitrostudies were conducted using human liver microsomes to evaluate: 1) the difference in the metabolic kinetics of montelukast between adult and pediatric subjects;2) the relative contribution of flavin-containing monooxygenase and cytochrome P450 (P450) to the sulfoxidation; and 3) the P450 isoforms responsible for montelukast oxidation. No statistically significant difference was observed in the in vitrokinetics for acyl glucuronidation and oxidative metabolism between the two age groups. Results from studies on heat inactivation of flavin-containing monooxygenase and immunochemical inhibition by an anti-rat NADPH P450 reductase antibody on montelukast oxidation indicated that all oxidative metabolism of montelukast—including diastereomeric sulfoxidations, as well as 21- and methyl-hydroxylations—are catalyzed exclusively by P450. Five in vitroapproaches have been used to identify the P450 isoforms responsible for the human liver microsomal oxidation of montelukast. The experimental results consistently indicated that CYP3A4 catalyzes sulfoxidation and 21-hydroxylation, whereas CYP2C9 selectively mediates methyl-hydroxylation.

L-735,524, N-[2(R)-hydroxy-1(S)-indanyl]-5-(2(S)-(1,1- dimethylethylaminocarbonyl)-4-[(pyridin-3-yl)methyl]piperazin++ +-1-yl)-4(S)- hydroxy-2(R)-phenylmethylpentanamide, is a potent and specific inhibitor of the human immunodeficiency virus type 1 protease and is undergoing clinical evaluation. In an initial clinical study, noninfected male volunteers were administered single, 1000 mg oral doses of nonlabeled compound. Urine samples were collected over a period of 48 hr. Metabolic profile of the urine was determined by HPLC-UV comparison with that from a human liver slice incubation of radiolabeled L-735,524. Seven significant metabolites were isolated from pooled human urine, and were characterized by NMR, MS, and/or chromatographic comparisons with authentic standards. The major metabolic pathways were identified as: a) glucuronidation at the pyridine nitrogen to yield a quaternized ammonium conjugate, b) pyridine N-oxidation, c) para-hydroxylation of the phenylmethyl group, d) 3'-hydroxylation of the indan, and e) N-depyridomethylation. A minor product was identified as 2',3'-trans-dihydroxyindan analog. Urinary excretion of L-735,524 and its metabolites represented a minor pathway of elimination. The intact parent compound seemed to be the major component in the urine, whereas the level of each metabolite was relatively low.

L-689,502, N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxy- carbonyl-amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-[2(R)-(4-morpholinyl) ethoxy]phenyl)methylhexamide, is a potent and specific inhibitor of human immunodeficiency virus-type 1 (HIV-1) protease in vitro. Metabolism of this compound in rat liver slices produced four major and several minor metabolites. The major metabolites were identified as morpholin-2-one, 3'(S)-hydroxyindan and 4'-hydroxyindan analogs, and a 4-O-glucuronic acid conjugate of the parent compound. The metabolites were characterized by Heteronuclear Multiple Quantum Coherence and Nuclear Overhauser Effect techniques in NMR spectroscopy, by MS, and/or comparison with authentic standards. Two of the minor metabolites were similarly characterized as a 2(R)-[4-(2-carboxymethoxy)phenyl]methyl analog and a product with a degraded morpholino ring. The hydroxyindan metabolites were lower in activity than L-689,502, whereas the morpholin-2-one and carboxymethoxyphenyl analogs were approximately 6- and 11-fold more potent as inhibitors of HIV-1 protease, respectively.

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vdss, and T1/2were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLpwas reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLpdeclined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higher Tmaxvalues, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmaxwas more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.

Montelukast sodium [1-{[(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl}cyclopropylacetic acid sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene (Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was recovered in feces, with ≤0.2% appearing in urine. Based on these results and the reported modestly high oral bioavailability of montelukast, it could be concluded that a major part of the radioactivity was excreted viabile. A second clinical study was conducted to identify biliary metabolites of montelukast. The bile was aspirated using a modified procedure involving a nasogastric tube placed fluoroscopically near the ampulla of Vater, after an oral dose of 54.8 mg of [14C]montelukast. This technique appears to be a new application for drug metabolism studies. The study was conducted with fasted and nonfasted subjects, with the bile being aspirated continuously under suction over periods of 2–8 hr and 8–12 hr after the dose, respectively. Two hours before the end of the collection procedure, cholecystokinin carboxyl-terminal octapeptide was administered iv to stimulate gallbladder contraction. Plasma samples also were collected periodically over 10 hr. Due to the nature of the collection procedure and the limited sampling time, recovery of radioactivity in bile was incomplete and varied from 3 to 20% of the dose. Radiochromatographic and LC-MS/MS analyses of bile showed the presence of one major and several minor metabolites, along with small amounts of unchanged parent drug. The minor metabolites were identified, by LC-MS/MS comparison with synthetic standards or by NMR, as acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydroxy (diastereomers of a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) analogs of montelukast. The major metabolite was characterized as a dicarboxylic acid (M4), a product of further oxidation of the hydroxymethyl metabolite M6. Chiral LC-MS/MS analyses of M4 revealed that this diacid, like M5 and M6, was formed in both diastereomeric forms. The levels of metabolites in the systemic circulation were low in the fed as well as fasted subjects, with <2% of the circulating radioactivity being due to metabolites M5a, M5b, M6a, and M6b. Overall, this bile aspiration technique, which is less invasive than either T-tube drainage or fine-needle percutaneous puncture, provided a convenient and expedient means of identifying the biliary metabolites of montelukast, relatively free of contributions from colonic microflora.

A solid chelating compound phenanthrenequinone monoxime PQM) supported on naphthalene provides a rapid and economical means of preconcentration and separation of copper from the aqueous samples. Copper forms a complex with PC:: supported on naphthalene in the column at pH 6.1–8.4 with a flow rate of 1 ml/min. The metal complex and naphthalene are dissolved out from the column with 5 ml of DMF and the absorbance is measured at 470 nm against reacent blank. Beer's law is obeyed in the concentration range 0.6 9.6 g of copper in 5 ml of DMF. The molar absorptivity and sensitivity are 6.3×104 L mol-1 cm-1 and 0.001 g cm-2 respectively.

L-754,394, a furanopyridine derivative, is an experimental anti-HIV agent which has been shown to be an unusually potent and selective inhibitor of cytochrome P450 3A enzymes in a number of mammalian species. In the present studies, L-754,394 was demonstrated to undergo NADPH-dependent metabolic activation in hepatic microsomal preparations from rats, dogs, rhesus monkeys, and humans to electrophilic intermediates which became bound covalently to cellular proteins. The extent of binding was species-dependent, the highest levels being observed with liver microsomes from rhesus monkeys. Inclusion in incubation media of the nucleophilic trapping agents glutathione, cysteine, or methoxyamine led to a modest (15−25%) decrease in the covalent binding, while trichloropropylene oxide, an inhibitor of epoxide hydrolase, had no effect. When L-754,394 was incubated with monkey liver microsomes, the corresponding dihydrofurandiol was identified as a metabolite by liquid chromatography−tandem mass spectrometry. In contrast, when incubations were carried out in the presence of methoxyamine, the O-methyloxime derivative of the ring-opened dihydrodiol tautomer was formed, while inclusion of glutathione or N-acetylcysteine led to the formation of S-linked conjugates of a putative furan epoxide. Collectively, these results are taken to indicate that L-754,394 undergoes cytochrome P450-dependent oxidation of the fused furan ring system, leading to the formation of chemically-reactive intermediates. One or more of these electrophilic species may be responsible for the autocatalytic destruction of cytochrome P450 enzymes which accompanies L-754,394 metabolism in vitro and in vivo.

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higher Tmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.

Montelukast sodium [1-([(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl)cyclopropylacetic acid sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene (Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was recovered in feces, with

Montelukast (L-706,631, MK-0476, SINGULAIR), a potent and selective leukotriene D4 (CysLT1) receptor antagonist, is currently under development for the treatment of asthma. In vitro studies were conducted using human liver microsomes to evaluate: 1) the difference in the metabolic kinetics of montelukast between adult and pediatric subjects; 2) the relative contribution of flavin-containing monooxygenase and cytochrome P450 (P450) to the sulfoxidation; and 3) the P450 isoforms responsible for montelukast oxidation. No statistically significant difference was observed in the in vitro kinetics for acyl glucuronidation and oxidative metabolism between the two age groups. Results from studies on heat inactivation of flavin-containing monooxygenase and immunochemical inhibition by an anti-rat NADPH P450 reductase antibody on montelukast oxidation indicated that all oxidative metabolism of montelukast-including diastereomeric sulfoxidations, as well as 21- and methyl-hydroxylations-are catalyzed exclusively by P450. Five in vitro approaches have been used to identify the P450 isoforms responsible for the human liver microsomal oxidation of montelukast. The experimental results consistently indicated that CYP3A4 catalyzes sulfoxidation and 21-hydroxylation, whereas CYP2C9 selectively mediates methyl-hydroxylation.

A 9-year-old female presented to neurology outpatient department of our hospital with complaints of recurrent generalized tonic–clonic seizures since birth and was being treated with anticonvulsants for the same. Patient also had complaints of giddiness and episodes of momentary loss of consciousness. There was history of twitching of left hemiface and eyelid during infancy, often associated with deviation of eyes to the left and groaning. The birth history was unremarkable. Family history revealed no known consanguinity. General examination revealed no dysmorphic features. Neurological examination revealed no cognitive deficits/signs to suggest cerebellar pathology. An electroencephalogram was done in view of her recurrent seizures, which was normal. Initial laboratory work-up was normal. The patient then underwent magnetic resonance imaging (MRI) brain, acquired with a 1.5-T unit (Siemens, Erlangen, Germany). MRI brain revealed hemihypertrophy of left cerebellar hemisphere with disorganized architecture, fissural malorientation with individual folia running vertically rather than horizontally with disorganized foliation, abnormal arborization of white matter predominantly involving mid and dorsal surface of left cerebellar hemisphere and a few suspicious areas of abnormal T2-hyperintense signal in subcortical white matter. Right cerebellar hemisphere and cerebellar vermis were normal. Corpus callosum was normal. Cerebral parenchyma was normal in signal intensity pattern with normal gray–white matter differentiation. Ventricular system was normal (Figures 1 and 2). Cerebellar malformations are uncommon and are usually associated with Dandy–Walker continuum, Joubert syndrome, rhombencephalosynapsis, lissencephaly, Fukuyama congenital muscular dystrophy, Walker–Warburg syndrome, muscle–eye–brain disease, congenital cytomegalovirus infection to name a few.1,2Isolated unilateral cerebellar hemispheric dysplasia is exceedingly rare with only a few cases previously described in English literature. Cerebellar malformations are less adequately understood entity partly because of the complex cerebellar embryology and limited histologic studies of these disorders. Genes expressed in migration and maintenance of the Purkinje cells and/or in the generation and migration of granular cells when mutated will disrupt cerebellar migration and foliation and thus cause cerebellar malformation.3–5Cerebellum is known to be a centre for motor learning, coordination, and higher cognitive functions. Clinical presentation of cerebellar malformations is highly variable and depends on the degree of cerebellar involvement, presence of associated cerebral involvement and the underlying disorders such as muscular dystrophy if any. Patel and Barkovich suggested an imaging-based classification of cerebellar malformations and classified the malformations broadly into two types, malformations with cerebellar hypoplasia and the ones with cerebellar dysplasia. Each of these was further classified into focal and diffuse.1Demaerel gave a classification of abnormalities of cerebellar foliation and fissuration.2Our index case with disorganized architecture, fissural malorientation and disorganized foliation of left cerebellar hemisphere associated with normal cerebellar vermis, corpus callosum, and absence of cerebral malformation falls into Type 2 category as per the classification by Demaerel.2Treatment depends upon the severity of symptoms and the underlying disorder in case of syndromic malformations. Generally, treatment is symptomatic and supportive. Understanding of the basics of cerebellar embryology, knowledge of the imaging features, and clinical presentation aids in the precise diagnosis of this disorder and its optimal management.

The coronavirus disease 19 (COVID-19) pandemic continues to impose a significant burden on global health infrastructure. While identification and containment of new cases remains important, laboratories must now pivot and consider an assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity in the setting of the recent availability of multiple COVID-19 vaccines.

Sterilization of ultra-high molecular weight polyethylene (UHMWPE) based composites used for acetabular cup liner via UV or gamma-irradiation before surgery is inevitable. Thus, understanding the alteration of mechanical properties and wear resistance of cup liner via irradiation process requires investigation. This paper aims to understand the effect of UV (0.03 J/cm2) and gamma (25 kGy) irradiation on mechanical properties and scratch resistance of compression molded UHMWPE composites reinforced with alumina (Al2O3), hydroxyapatite (HAp) and carbon nanotubes (CNTs). After irradiation, nearly 100% increased crystallinity of polyethylene due to recrystallization helped in enhancing the hardness and elastic modulus by ∼1.5 times compared to that of as-processed UHMWPE (Hardness: ∼70 MPa and Elastic modulus: ∼1.25 GPa). The recrystallization was not favored by the presence of nano-reinforcements in irradiated UHMWPE based nanocomposites caused deterioration in the mechanical properties. The micro-scratch results revealed the remarkable wear resistance (i.e., 1.5 to 2 times lower wear rate) of irradiated samples than that of as-processed samples. Mouse fibroblast L929 in vitrocell culture test confirmed the cytocompatibility of irradiated samples. This study indicated that the UV and gamma irradiated UHMWPE nanocomposites are the challenging candidates for acetabular cup liner.

The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.

THAT many breeds of cattle exhibit polymorphism involving two haemoglobin types is now well established1. On the other hand, buffalo haemoglobin seems to be monomorphic in that all buffaloes examined possess two major haemoglobin components2,3. Bovine haemoglobins have been fairly thoroughly characterized1and it has been suggested that the two bovine haemoglobins may contain one polypeptide chain in common4.

Nanomechanics has played a vital role in pushing our capability to detect, probe, and manipulate the biological species, such as proteins, cells, and tissues, paving way to a deeper knowledge and superior strategies for healthcare. Nanomechanical characterization techniques, such as atomic force microscopy, nanoindentation, nanotribology, optical tweezers, and other hybrid techniques have been utilized to understand the mechanics and kinetics of biospecies. Investigation of the mechanics of cells and tissues has provided critical information about mechanical characteristics of host body environments. This information has been utilized for developing biomimetic materials and structures for tissue engineering and artificial implants. This review summarizes nanomechanical characterization techniques and their potential applications in healthcare research. The principles and examples of label‐free detection of cancers and myocardial infarction by nanomechanical cantilevers are discussed. The vital importance of nanomechanics in regenerative medicine is highlighted from the perspective of material selection and design for developing biocompatible scaffolds. This review interconnects the advancements made in fundamental materials science research and biomedical technology, and therefore provides scientific insight that is of common interest to the researchers working in different disciplines of healthcare science and technology. Nanomechanicsis playing a vital role in pushing our capability to detect, probe, and manipulate the biological species, such as proteins, cells and tissues, paving way to knowledge and strategies for superior healthcare. Nanomechanics has enabled early diagnosis of life‐threatening diseases, as well as facilitated the development of biomimetic implants for tissue engineering and prosthesis.

The article describes the author's experience of her experiences of working as a foreign worker in the U.S.

Bone clearing and light-sheet microscopy enables visualization and quantification of fluorescent single cells in intact bone.

We report the clinical details, imaging findings and management of a 45-year-old man who presented with recurrent transient ischemic attacks due to carotid free floating thrombus. Free floating thrombus of the carotid artery is a very rare condition with a high risk of distal embolic shower. The optimal treatment options are debatable and include medical management, surgical thrombectomy and endovascular thrombectomy. We describe the use of a stentriever with filter protection in the management of carotid free floating thrombus as a novel treatment option.

At the outset, I would like to thank the present and previous authors for their quality and impactful contributions to Drug metabolism Letters. With the journal being open to a wide variety of areas in Biochemistry, Pharmacology and Pharmaceutical Sciences, the journal has consistently achieved a high Impact Factor in the last area, in the past four years. This is a true testament to the impactful science published and the caliber of scientists the journal attracts for submission of their research. We continue to strive to improve the quality of articles published, based on innovative, thought-provoking science. This has been streamlined, under the leadership of the Editor-in-Chief Chandra Prakash, by eminent Associate Editors, Editorial Board members, and Review Panel members (http://benthamscience.com/journal/editorial-board.php?journalID=dml#top). Behind this world class scientific team, working in the background, is the publisher’s staff, who work tirelessly and with much dedication to keep the manuscripts flowing to reviewers and authors so we can make timely decisions. My special thanks to the editorial office staff! The current special issue contains articles from the Editorial Board Members (EBM) as well as from select scientists, with the following highlights that the readers should find of great interest. Albert P. Li (EBM) and Kari E. Schlicht provide a new, composite Km estimation for the major CYPs using hepatocytes from 16 donors and isoform-selective substrates in a high-throughput fashion. The composite Km was derived for each pathway by normalization of individual activities to their respective Vmax. The composite Km values were similar to those in the literature generated using various hepatic sub-fractions. Using this more complete hepatic system, the authors claim that the composite Km values could be used to assess compounds’ impact on DDIs in humans. In a second article, Dr Li and Qian Yang devised a novel medium to overcome the issue of spontaneous decrease in CYP gene expression during hepatocytes incubation for days. The hepatocytes with the new medium were responsive to the CYP gene expression changes induced by proinflammatory IL6 cytokine, confirming the viability of the medium. Another example of leading science in the area of covalent binding of drugs to therapeutic target is presented by Mehran F. Moghaddam (EBM) et al. There is tremendous interest in the covalent modification of proteins leading to target silencing, as shown by the recent approval of drugs in both oncology as well as non-oncology areas. New criteria are proposed for a meaningful screening paradigm for such class of therapeutics. Mert Ulgen (EBM) and his colleagues have devised a simplified approach to simultaneously measure combo agents fluticasone and salmeterol present in a dry powder Seretide Diskus inhalers for asthma. One approach requires no purification steps. Natalia Penner, Xiaojing Liu, and Chandra Prakash (Editor-in-Chief) have designed a new trapping reagent to identify reactive species formation during metabolism. The reagent provides greater sensitivity and broader selectivity to detect reactive species, compared to commonly used trapping agents. Hiroshi Yamazaki (EBM) and his group carried out elegant docking simulations for CYP3A4 and CYP3A5 catalytic active sites with a series of substrates and showed that compounds with greater specificity for one of the CYP isoforms also docked closely to the heme of that CYP. These simulations partly explained the difference in Km values of the substrates for CYP3A4 and CYP3A5. Massimiliano Fonsi has emphasized the need for caution for in vitro-in vivo correlations (IVIVC) based on largely hepatic assessments. The article covers three cases where the IVIVC broke down, determined later to be due to involvement of extrahepatic metabolism. It also shows thorough mechanistic investigations undertaken to design corrective strategies that were eventually adopted for screening purposes. Demir et al. describe the purification of paraxonase (PON1) from sera of patients with Behcet’s disease and analysis of certain drugs, used in the treatment of this disease, as inhibitors of this enzyme. PON1 is one of the body’s defense mechanisms to prevent atherosclerosis. PON1 from healthy subjects was activated by the tested drugs, while that from patients was inhibited. Ramifications of these results to understanding the disease control process will require further studies.

Pulmonary atresia with ventricular septal defect (PA-VSD) with pulmonary arterial supply arising from the aorta representing large MAPCAs associated with a right sided aortic arch is an uncommon anomaly. Most of the patients succumb to severe respiratory compromise or congestive cardiac failure very early. We report the clinical details and imaging findings of a case of PA-VSD with a right sided aortic arch and a calcified pulmonary arteriovenous malformation (AVM) in a 21-year-old postpartum female with no previous episodes of cyanosis who was diagnosed as having a cardiac anomaly on echocardiography when she presented with breathlessness during the 8th month of the pregnancy.

The reaction of resorcinol with ethylacetoacetate yielded the 7-hydroxy-4-methyl coumarin (1), which on treatment with benzidine gives 1-(4ʹ-amino-biphenyl-4-yl)-7-hydroxy-4-methyl-1H-quinolin-2-one (2). 1-{4ʹ-[(Substituted benzylidene)-amino]-biphenyl-4-yl}-7-hydroxy-4-methyl-1H-quinolin-2-one (3a-j) were obtained by reacting 1-(4ʹ-amino-biphenyl-4-yl)-7-hydroxy-4-methyl-1H-quinolin-2-one (2) with different substituted aromatic aldehydes in presence of glacial acetic acid by microwave irradiation. The compound 1-{4ɴ-[(substituted benzylidene)-amino]-biphenyl-4-yl}-7-hydroxy-4-methyl-1H-quinolin-2-one (3a-j) on cyclization with chloro acetyl chloride in presence of triethylamine as catalyst under microwave irradiation furnished 1-{4ʹ-[3-chloro-2-(substituted phenyl)-4-oxo-azetidin-1-yl]-biphenyl-4-yl}-7-hydroxy-4-methyl-1H-quinolin-2-one (4a-j). Purity of synthesized compounds was checked by TLC and the structures were elucidated by their IR, 1H NMR, Mass and elemental analysis data. The synthesized compounds were screened for anticonvulsant activity.

Several letters to the editor are presented in response to articles in previous issues including "Repair Legislation Is a Solution in Search of a Problem," by Steve Kalafer in the August 24, 2009 issue and "Clearing the Hot Air on Solar, Wind Projects" in the August 10, 2009 issue.

AIMS: We investigated the prevalence and clinical relevance and significance of the various immunoglobulin (Ig) isotypes of the different aPLs and lupus anticoagulant (LAC). METHOD: Our study registry for the year 2003 included 472 patients who had a complete antiphospholipid antibody laboratory work up and clinical evaluation. 137 had the presence of LAC, detected by the dilute Russell’s viper venom time (Dade Behring, Marburg, Germany), PTT-LA (Diagnostica Stago, Asnieres, France), or hexagonal phospholipid neutralization test (Diagnostica Stago, Asnieres, France); 211 had elevated titers of antibodies of IgG, IgM or IgA isotypes against cardiolipin (aCL), phosphatidylserine (aPS), or β2-glycoprotein-I (aβ2GPI), detected by ELISA (Corgenix, Inc, Westminister, CO, USA). 204 had no evidence of either LAC or aPL. RESULTS: Of the patients with aPL, 67 (32%) had elevated titers of IgG, 126 (60%) had IgM, and 118 (56%) had IgA. Thrombotic events occurred in 61% (41 of 67), 52% (65 of 126), and 61% (72 of 118) of the patients with IgG, IgM, and IgA respectively. Patients with IgG and IgA isotypes of aCL, aPS and aβ2GPI had higher rates (58–67%) of thrombotic events (see table 1) than patients with IgM isotypes (46–50%). Stepwise logistic regression analysis identified elevated titer of IgA of any aPL as an independent risk factor for thrombosis (see table 2), even in the absence of LAC. Thrombotic events observed include deep venous thrombosis (25%), pulmonary embolism (12%), cerebrovascular accident (50%), myocardial infarction (8%), and peripheral arterial occlusion (3%); pregnancy complication, retinal vascular thrombosis, and dialysis access thrombosis were also seen. CONCLUSION: Our study demonstrates that aPL of IgA isotype is prevalent and significantly associated with thrombotic events. Proportions of Patients with Thrombosis amongst various aPLs and Ig Isotypes aCL aPS aβ2GPI Total * Two-sided P < 0.05 by McNemar’s test for equality of two dependent proportions IgG 28/43 (65%) 23/36 (64%) 13/21 (62%)* 41/67 (61%) IgM 17/37 (46%)* 28/58 (48%) 45/90 (50%)* 65/126 (52%) IgG 15/26 (58%)* 22/33 (67%) 54/91 (59%)* 72/118 (61%) Total 44/79 (56%) 58/105 (55%) 85/159 (53%) 118/211 (56%) Risk Factors for Thrombosis Antibody Odds Ratio 95% Wald Confidence Limit * p < 0.05 by the Wald chi-square test. Hosmer and Lemeshow goodness-of-fit test was used to assess the model fit. N=472 for the 1st four analyses, N=335 for the last three analyses. LAC 1.627 1.073–2.466* IgG regardless of LAC 1.364 0.781–2.384 IgM regardless of LAC 0.874 0.569–1.344 IgA regardless of LAC 1.587 1.012–2.490* IgG LAC negative 1.790 0.863–3.714 IgM LAC negative 0.878 0.515–1.499 IgA LAC negative 1.812 1.035–3.172*