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Masing/non-Masing behavior of material plays an important role in the strain energy-based methods of fatigue life prediction. Materials under fatigue are found to show three distinct categories of behavior viz. Masing, non-Masing (Type-I: when master curve can be constructed) and non-Masing (Type-II: when master curve cannot be constructed). The master curve method available in the literature for the estimation of cyclic plastic strain energy density (CPSED) can be used only for Type-I non-Masing and Masing behaviors of materials. Moreover, it could be used for estimation only, not for prediction of CPSED. Very recently (in 2021), a new method, as summarized in this article, was proposed for the prediction of CPSED and fatigue life of material irrespective of Masing or non-Masing (Type-I and Type-II) behavior. Although the method was developed, the validation of the proposed method with different Type-II non-Masing behavior materials remained a matter of further investigation. As Type-II non-Masing behavior was not highlighted earlier in the literature, such data is not readily available. In this article, we conducted low cycle fatigue tests on SS 304L material, and after an extensive literature review and analysis, three materials’ data for each of Type-I and Type-II non-Masing behaviors could be collected. The method of prediction of CPSED and fatigue life is summarized and implemented on the six different materials. The CPSED and fatigue life could be predicted within a scatter band of 1.2 and 2, respectively. This article confirms the universal nature of the new method of CPSED and fatigue life prediction.

Evaluation of text-based answers has stayed as a challenge for researchers in recent years and with the growing acceptance of e-learning system, a solution needs to be achieved fast. While assessing the knowledge content, correctness of expression and linguistic patterns are complex issues in themselves, a smaller answer may be evaluated using keyword matching only. The work proposed in this paper is aimed at evaluating smaller text answers, no longer than a single sentence using keyword matching. The proposed method agglomerates keywords from a group of model answers forming clusters of words. The evaluation process thereafter exploits the inherent roughness of the keyword clusters to evaluate a learners' response through comparison and keyword matching. The novelty in the proposed system lies in the usage of fuzzy membership functions along with rough set theory to evaluate the answers. Rigorous tests have been conducted on dataset built for the purpose returned good correlation values with the average of two human evaluators. The proposed system also fares better than latent semantic analysis (LSA) based and link grammar-based evaluation systems.

Scaffolding is an age-old technique of teacher's intervention to augment and quicken the learners' learning process. While a human teacher has the scope to interact with the learner in contact mode and apply his intelligence to assess the need of such effort, an e-learning system does not have this capacity. This paper presents a scaffolding system for an e-learner. It is targeted towards school level children. The system is structured around the concept of finite state machine to model the cognitive state of the learner. Learning experiences are also taken into consideration. The system is tested on a large number of school going children. Experimental results indicate that under this system, the students achieve their learning objectives to a greater extent with better experience.

Background: Both ovarian/breast cancers are the most prevalent hormone-associated gynecological-cancers, where uncontrolled cellular proliferations/genetic-errors are noticed. The cancer-antigen125 (CA125), which we assessed presently is an important biomarker in the early detection/monitoring of this disease-pathogenesis. Methods: Serum/tissue CA125 was measured by solid-phase-Enzyme-linked-immunosorbentassay in women with ovarian/breast tumors of different types (epithelial/non-epithelial; benign/ borderline/ malignant)/stages. Breast-tumor tissues were employed for histoarchitecture/DNAstability (comet) assay. Extensive protein-protein(CA125) interactions were studied by the STRING (Search-Tool-for-the-Retrieval-of-Interacting Genes/Proteins) Bioinformatics-software. Results: Serum CA125 levels were <35 U/ml in 94% of benign epithelial-cases, 35-65 U/ml in 100% of borderline-tumors and >100 U/ml in the 41.17% of patients with malignant-tumors. The malignant epithelial tumor showed significantly higher (>100U/ml) CA125 than the non-epithelial malignant-tumor (<35-65 U/ml). Highly enhanced cellularity/histo-architectural impairment/unstable- DNA-materials/CA125 was found in advanced breast-cancers. The CA125 is highly metabolically interactive, especially with mesothelin impairing cell-cell adhesion and enhancing tissue anti-establishment. Conclusion: CA125 is a predictive-marker in ovarian/breast carcinoma depending on disease nature/stages. CA125, in combination with other tests like mesothelin/estradiol can be of great use in the better diagnosis of this disease. Not only as a detection-marker, has the CA125 played an interactive role in the disease processes. The Bioinformatics study revealed an important role of mesothelin and other mucin like proteins. Early detection and proper diagnosis are important determinants for the greater possibility of the relief from the disease like cancers. Selection of suitable biomarker combinations may increase the better diagnosis of the types and severity of this disease. Our present result has an impact on these aspects.

In the era of evidenced-based medicine, sexually transmitted infections (STIs) are a major international health issue; adolescents and young people are particularly vulnerable. The current study determines the perceptions of sexual health and condom use in sexual encounters among tea plantation workers of North Bengal in India. A population based cross-sectional study was undertaken with 973 adults of both sexes selected by a multi-stage random sampling using an anonymous pre-tested close-ended structured questionnaire. The majority of study participants were working class in the age range of 16 to 30 years. The gender distribution of the participants was almost equal. The majority of males were in the age group of 46-60 years, while the majority of the females were in the age group of 16-30 years. There was no statistical association between age and use of condoms. Significant statistical differences were seen in condom use in relation to marital status, religion, type of family, and number of living children. This study revealed inadequate protective behavior adopted by plantation workers. In this socio-demography with the acceptance of sexual relation outside marriage, non-use of condoms increases vulnerability to HIV/AIDS/ and other sexually-transmitted infections.

This paper addresses the Complex-Triangle Elimination (CTE) problem of rectangular dualization approach in VLSI floor-planning. Rectangular dualization, where each module is realized as a rectangular area, is an important approach in VLSI floor-planning. It is known that if the input adjacency graph contains a complex triangle, i.e., a cycle of three edges that is not a face, then its rectangular dual does not exist. Elimination of complex triangles, therefore, becomes essential before constructing a floor plan. There are two versions of the CTEproblem—that of weighted adjacency graphs, and of unweighted adjacency graphs. The weighted CTEproblem is known to be NP-complete. Recently it has been proved that the unweighted CTEproblem is also NP-complete [1]. In this paper we first present a greedy heuristic algorithm to solve the unweighted CTEproblem. We then show, with the help of an example, that the greedy algorithm fails to produce an optimal solution in certain cases. Since Simulated Annealing (SA) is an effective technique to solve computationally hard minimization problems, we implemented SA based schemes to solve both the unweighted and weighted CTEproblem. We also implemented three valley descending algorithms each for the weighted and the unweighted CTEproblem. Results show that for the unweighted CTEproblem the valley descending schemes converge much faster. A possible explanation is—the state space of the unweighted CTEproblem is monotonous. However, this is yet to be proved (or disproved). In case of weighted CTEproblem the SA based schemes produce better results, whereas the valley descending schemes get stuck at a sub-optimal solution. This is possibly because though the search space of the unweighted CTEproblem is monotonous, that of the weighted CTEproblem is not. All the schemes were tested with 25 randomly generated problem instances of various sizes.

A new knowledge-based scoring function was developed in this work to facilitate the rapid ranking of ligands in databases. The acronym of the method is BHB based on the descriptors it utilizes:  buriedness, hydrogen bonding, and binding energy. Receptor buriedness is a measure of how well molecules occupy the binding pocket in comparison to known high-affinity ligands or, alternatively, whether they have contact with identified residues in the pocket. The possibility of hydrogen bond formation is checked for selected residues that are recognized as being important in the binding of known ligands. The approximate binding energy is calculated from the thermodynamic cycle using the optimized bound and free solvent conformations of the ligand−receptor system. The information necessary for the scoring function can ideally be gleaned from the 3D structure of the receptor−ligand complex. Alternatively, the descriptors can be derived from the 3D structure of the unbound receptor, provided this receptor has a known ligand that binds to the given site with nanomolar activity. We show that the new scoring functions provide up to 12 times improvement in enrichment compared to the popular commercial docking program GOLD.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory and demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). In the present report, a linear analogue and a series of cyclic semi-mimetic peptides were designed and synthesized based on the human myelin basic protein (MBP87–99) epitope (Val87-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro99) and on Copolymer I (a mixture of random polymers of Ala, Gln, Lys and Tyr used to treat MS). These analogues were designed looking for suppressors of EAE induced by guinea pig MBP72–85epitope (Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-Pro-Val) in Lewis rats. The linear analogue [Arg91,Ala96]MBP87–99,in which Arg substitutes Lys91and Ala substitutes Pro96, was found to be a strong inhibitor which when administered to Lewis rats together with the encephalitogenic agonist MBP72–85completely prevented the induction of EAE. In contrast, three N- and C-termini amide-linked cyclic semi-mimetic peptides, [cyclo-Phe-Arg-Asn-Ile-Val-Thr-Ala-Acp (1), cyclo-Phe-Ala-Arg-Gln-Acp (2), cyclo-Tyr-Ala-Lys-Gln-Acp (3)] as well as a Lys side chain and C-terminous cyclic semi mimetic peptide cyclo(Lys, Acp)-Phe-Lys-Asn-Ile-Val-Thr-Ala-Acp (4) which contain segments of MBP87–99or are constituted from immunophoric residues of copolymer I, were ineffective in inducing or inhibiting EAE in Lewis rats. However co-injection of cyclic analogues with MBP72–85delayed the onset of EAE indicating a modulatory effect on the EAE activity of MBP72–85. These findings suggest that molecule length, size of cyclic moiety and backbone conformation are important elements for immunogenic activity. Moreover blockade of MBP72–85induced EAE by the unrelated peptide [Arg91,Ala96]MBP87–99could indicate that the mechanism of inhibition is not due to binding competition but rather due to the delivery of a negative signal by the antagonist which overcomes the agonist response possibly through the activation of antigen specific regulatory T cells.

The application of recombinant DNA technology to restructure metabolic networks can change metabolite and protein products by altering the biosynthetic pathways in an organism. Although some success has been achieved, a more detailed and thorough investigation of this approach is certainly warranted since it is clear that such methods hold great potential based on the encouraging results obtained so far. In last decade, there have been tremendous advances in the field of glycobiology and the stage has been set for the biotechnological production of glycoproteins for therapeutic use. Today glycoproteins are one of the most important groups of pharmaceutical products. In this study the attempt was made to focus on identifying technologies that may have general application for modifying glycosylation pathway of the yeast cells in order to produce glycoproteins of therapeutic use. The carbohydrates of therapeutic recombinant glycoproteins play very important roles in determining their pharmacokinetic properties. A number of biological interactions and biological functions mediated by glycans are also being targeted for therapeutic manipulationin vivo. For a commercially viable production of therapeutic glycoproteins a metabolic engineering of a host cell is yet to be established.

Chitin is an essential cell wall component, synthesis of which is regulated throughout the cell cycle in the yeastSaccharomyces cerevisiae. We cloned an S. cerevisiaegene, YEA4, whose product is homologous to the Kluyveromyces lactisuridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) transporter. An epitope-tagged Yea4p localized mainly in the 10,000 ×gpellet (P2), suggesting endoplasmic reticulum (ER) localization. Membrane vesicles from the P2 fraction showed an 8-fold higher UDP-GlcNAc transport activity in cells harboring a multicopyYEA4plasmid than in cells harboring vector alone. The activity distribution is identical with the protein distribution in P2, whether the gene is overexpressed or not, suggesting its native localization in P2. Immunolocalization of epitope-tagged Yea4p further revealed ER localization. The increase in transport activity due to theYEA4overexpression is specific for UDP-GlcNAc, but not for UDP-galactose and GDP-mannose. Δyea4-disrupted cells showed a reduced rate of UDP-GlcNAc transport, contained less chitin, and were larger and rounder in shape than the wild type cells. Our results indicate that YEA4encodes an ER-localized UDP-GlcNAc transporter that is required for cell wall chitin synthesis in S. cerevisiae.

1The contractile actions of the proteinase‐activated receptor‐2‐activating peptides (PAR2APs), SLIGRL‐NH2(SL‐NH2), SLIGKV‐NH2(KV‐NH2), trans‐cinnamoyl‐LIGRLO‐NH2(tc‐NH2), and the PAR1‐AP, TFLLR‐NH2(TF‐NH2) as well as trypsin and thrombin were studied in endothelium‐denuded and intact human umbilical vein (HUV) ring preparations.2In HUV rings with, but not without an intact endothelium, PAR2APs caused a concentration‐dependent contractile response, whereas LSIGRL‐NH2trypsin and PAR1APs were inactive. The contractile response was not affected by the endothelin ETAreceptor antagonist, BQ123, the cyclooxygenase inhibitor, indomethacin, the leukotriene synthesis inhibitor, MK886, or the epoxygenase/P450 inhibitor, SKF‐525A. Other pharmacological antagonists (prazosin, Losartan®) were similarly inactive.3The order of potencies of the PAR2APs to cause a contraction in the endothelium‐intact preparation was: SL‐NH2>>KV‐NH2tc‐NH2.4Using an endothelium‐free rat aorta ring as a reporter tissue, surrounded with endothelium‐intact HUV as a donor tissue in a ‘sandwich assay,’ we also monitored the ability of SL‐NH2, TF‐NH2, trypsin and thrombin to release either contractile (EDCF) or relaxant (EDRF) factors.5In the ‘sandwich assay’ done in the presence of L‐NAME (0.1 mm), the endothelium‐intact HUV tissue (but not endothelium‐denuded HUV) released a contractile factor (EDCF) in response to SL‐NH2(50 μm) but not to trypsin or LSIGRL‐NH2. The SL‐NH2‐mediated release/action of the EDCF was not affected by BQ123, indomethacin, MK886 or SKF‐525A.6In the ‘sandwich assay’, trypsin (4–10 nm), SL‐NH2, KV‐NH2and tc‐NH2caused the release of a relaxant activity (EDRF) from the endothelium‐intact (but not the denuded) HUV preparation. The release of EDRF was blocked by 0.1 mmωnitro‐L‐arginine‐methylester (L‐NAME). Neither thrombin (10 u ml−1, 100 nm) nor TF‐NH2(50 μm) were active in this EDRF‐release assay.7The relative potencies of the PAR2agonists for causing the release of EDRF in the HUV sandwich assay were: trypsin>>SL‐NH2>>tc‐NH2>KV‐NH2. This order of potencies differed from the one observed for the same agonists in the HUV contraction assay (above) and in an intracellular calcium signalling assay, conducted with cloned human PAR2that was expressed in cultured rat kidney KNRK cells: trypsin>>SL‐NH2=tc‐NH2>KV‐NH2.8We conclude that PAR2APs (but not PAR1APs) viaa receptor distinct from PAR2, can cause a contractile response in endothelium‐intact HUV tissue viathe release of a diffusable EDCF, that is different from previously recognized smooth muscle agonists (e.g. prostanoid metabolites, endothelin, noradrenaline, angiotensin‐II, acetylcholine).

The in vitro skin permeabilities of ketorolac acid (KA), a potent nonsteroidal analgesic, and its two ester analogs as prodrug through human cadaver skin were investigated. The two esters of KA, namely, the ethyl ester (KEE) and [(N,N/‐dimethylamino)carbonyl]methyl ester (KDAE), were selected. The melting temperature of the two esters was significantly lower than that of ketorolac free acid. The partition coefficients (Ko/w) were 600, 3541, and 124 for KA, KEE, and KDAE, respectively. The enzymatic hydrolysis of KEE and KDAE by human pooled serum at 37 °C was investigated. The esters were hydrolyzed to KA by the serum esterases; the metabolic rate constants were 0.0418 and 0.0148 min‐1for KDAE and KEE, respectively. The serum half‐life of KDAE was about 3 times shorter than KEE. When split‐thickness cadaver skin was incubated with ester solution at 32 °C, the enzymatic hydrolysis of these esters was observed. The metabolic rate in the skin, however, was significantly lower than in the human pooled serum. The skin permeations of KA, KEE, and KDAE through heat‐separated epidermis from propylene glycol (PG), PG/glyceryl monocaprylate (GMC) (9:1), and PG/Azone (19: 1) vehicle mixtures were evaluated using modified Franz flow‐through diffusion cells. The skin fluxes of KA, KEE, and KDAE from PG/GMC (9:1) were 50 ± 10, 15 ± 4, and 57 ± 6 μg/cm2/h, respectively. KA was detected in the receiver compartment, albeit to a lesser extent. In conclusion, KDAE appeared to be a better ester prodrug than KEE because it exhibited relatively higher skin flux and faster enzymatic hydrolysis by human serum to liberate the parent drug.

The permeation of fentanyl and sufentanil through cadaver skin membranes was investigated using in vitro diffusion cell techniques. Neither drug influenced the permeation of the other when they were concurrently applied to the skin membrane. With respect to transdermal delivery, short diffusion lag times of less than 0.5 hr were observed for each compound. Their permeation rates through heat-isolated epidermis and dermatomed (200- to 250-µm) skin sections were essentially the same. However, when the stratum corneum was removed by tape stripping, the respective permeability coefficients were increased >30-fold, establishing the stratum corneum as the principal barrier to their skin permeation. Permeation was also studied as a function of pH. From pH 4 to pH 8 the permeability coefficients of both fentanyl and sufentanil, calculated from the total solution concentration regardless of ionization, increased exponentially. The free base is thus responsible for the relatively facile skin permeation of these drugs. Factoring of the independent permeability coefficients of the ionized and free-base forms was possible, with the latter being over two log orders larger than seen for the protonated species. Permeability coefficients of fentanyl and sufentanil through skin sections obtained from different cadavers varied four- to fivefold. Neither gender nor age was a flux-determining variable for either drug. The permeability coefficients of the drugs through skin sites as diverse as the sole of the foot, chest, thigh, and abdomen were remarkably similar. Their fluxes were sufficient for transdermal administration.

In in vitro skin permeation experiments, the pH of viable epidermis is readily conditioned by the receiver fluid. For weakly ionizable compounds, the flux determined experimentally thus depends on the receiver fluid pH. The purpose of the present work is to characterize this pH effect, since nonphysiological conditions have often been used in the receiver fluid to enhance the solubility of the subject compounds. A transport model was developed to analyze the above-mentioned pH effect of the receiver fluid on the steady state flux of weakly ionizable drugs. The results showed that the skin flux had a strong dependence on pH for those compounds with high intrinsic partition coefficients. Experimentally, this pH effect was observed with a model acid and a model base. The skin flux was found to have a profound dependence on the receiver fluid pH. This dependence also correlates with the octanol/water partition coefficient of the molecule. It was concluded that the use of a physiological receiver fluid would be crucial for a realistic estimation of transdermal potential. The results also suggested that, for weakly ionizable compounds with high partition coefficients, the viable epidermis could be a significant transport barrier for systemic absorption.

Transdermal delivery of ketorolac tromethamine, a potent non‐narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure‐sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure‐sensitive adhesive onto a microporous membrane. Three liquid‐reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD‐A (microporous membrane/acrylic adhesive), TD‐B (microporous membrane/silicone adhesive), and TD‐C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 μg/mL for TD‐A, TD‐B, and TD‐C, respectively. The total AUC values for the concentration–time curves were TD‐C > TD‐A > TD‐B, and the terminal half‐life ranged from 6.6 to 9.7 h.

□ The skin permeation of buprénorphine base and HCI salt through cadaver skin was investigated. The octanol-water partition coefficient and solubilities of both buprénorphine free base and HCI salt were determined at 32 °C. As expected, buprénorphine free base was more lipophilic than its HCI salt and was practically insoluble In aqueous buffer at pH 8.7. The drug solubility decreased exponentially as the pH of the solution increased, whereas the permeability coefficient Increased as the donor solution pH decreased. The skin flux of buprenorphlne-HCI was significantly higher than that of the free base from propylene glycol/laurlc acid vehicle mixtures. Buprénorphine base permeation through tape-stripped epidermis suggested that in addition to stratum corneum, viable epidermis presented a significant diffusion barrier because of the very low aqueous solubility of the free base observed. The mean steady-state skin fluxes of buprenorphlne-HCI were 20.3 and 29.7 /μg/cm2/h from propylene glycol:lauryl alcohol: ethanol (80:15:5) and propylene glycol:propylene glycol monolaurate: water (80:15:5) vehicle mixtures, respectively. The skin flux of buprenorphlne-HCI from various monolithic matrix patches was also evaluated. When capric acid, lauric acid, and lauryl alcohol were separately Incorporated into an adhesive matrix, the skin flux of buprenorphlne-HCI was enhanced by a factor of 2 to 3.5. Finally, based on the total body clearance and minimum effective concentration of buprénorphine, a transdermal delivery rate of 2.5 /μg/cm2/h from a 20-cm2patch was estimated. The in vitroskin permeation data clearly suggest that transdermal delivery of buprénorphine Is feasible to achieve a desired systemic analgesic effect.

Transdermal delivery of ketorolac acid, a potent analgesic, through human skin in vitro and in vivo was evaluated. The following three transdermal solutions were selected to study the in vitro skin permeation rate of ketorolac acid: formulation A, isopropyl alcohol:water:isopropyl myristate (IPA/water/IPM; 11:7:1); formulation B, ethanol: propylene glycol:isopropyl myristate (ET/PG/IPM; 11:7:2); and formulation C, IPM/capmul (glyceryl mono‐ and dicaprylate; Monoctanoin). The permeation of ketorolac acid through cadaver skin from a saturated drug solution was evaluated at 32°C with a modified Franz diffusion cell. The in vitro skin fluxes were 180, 177, and 14 μg/cm2/h for fomulations A, B, and C, respectively. The systemic bioavailability of ketorolac acid from three transdermal formulations was evaluated in nine healthy subjects in a randomized three‐way crossover fashion. Hill Top chambers were used as prototype dermal delivery devices to load the drug solution. This procedure was followed by the immediate application of devices to human subjects for 24h. Blood samples were collected at various time intervals up to 48 h, and the samples were assayed by HPLC. The basic pharmacokinetic parameters were derived from the drug plasma concentration versus time plot. The maximum drug plasma concentrations were 1.265, 0.696, and 0.092 μg/mL for formulations A, B, and C, respectively. Formulation A provided the highest in vitro and in vivo transdermal delivery rate among the three formulations studied. An excellent correlation between the in vitro steady‐state skin flux and the area under the curve of in vivo plasma drug concentration versus time was observed for all the three formulations.

Urine and plasma concentrations of methoxyphenamine (MP) and three of its metabolites were determined after a single oral 60.3 mg dose of MP hydrochloride to healthy subjects of known debrisoquin (D) phenotype. Urine was collected from five extensive (EM) and five poor (PM) metabolizers of D for 12 hours and analyzed after treatment with β-glucuronidase/sulfatase. There were marked interphenotype differences in the total urinary excretion of O-demethylmethoxyphenamine (ODMP) and 5-hydroxymethoxyphenamine (5HMP), as well as in MP/ODMP and MP/5HMP ratios. In contrast, the urinary output of N-demethylmethoxyphenamine (NDMP) or MP/NDMP ratios showed no interphenotype differences. Plasma data from two EMs and two PMs showed that the mean values for maximum concentration, t½, and total AUC for MP were two-, three-, and sixfold greater, respectively, in PMs than in EMs. The plasma levels of ODMP and 5HMP were higher in EMs than in PMs, whereas the converse was true for NDMP. Thus, O-demethylation and aromatic 5-hydroxylation of MP are defective in PMs of D, resulting in increased MP and NDMP plasma levels. The form of cytochrome P-450 involved in the N-demethylation of MP is different from that responsible for O-demethylation and aromatic 5-hydroxylation.

The production of amylolytic enzymes by a thermophilic cellulolytic fungus,Myceliophthora thermophila D14 was investigated by batch cultivation in Czapek-Dox medium at 45° C. Among various nitrogenous compounds used, NaNO3 and KNO3 were found to be the best for amylase production. Starch, cellobiose and maltose induced the synthesis of amylase while glucose, fructose, galactose, lactose, arabinose, xylose, sorbitol, mesoinositol and sucrose did not. Calcium ions had the most stimulating effect on enzyme formation amongst many ions investigated. The synthesis of amylolytic enzymes was dependent on growth and occurred predominantly in the mid-stationary phase. The enzyme was active in a broad temperature range (50° C–60° C) and displayed activity optima at 60° C and pH 5.6.

The purpose of this study was to determine the intestinal absorption characteristics of AG337, a mechanism-based inhibitor of thymidylate synthase, using a perfused rat intestinal model. Effects of site, pH, temperature, concentration, Na⁺, and inhibitors on the absorption of AG337 were determined, after the compound was shown to be stable in buffers of various pH, blank perfusate, and intestinal homogenate. The results indicated that absorption of AG337 was temperature-, pH-, Na⁺-, concentration-, and site-dependent. The best site of absorption is duodenum, where the absorption was 3–10 times (p &lt; 0.05) higher than absorption at jejunum, ileum, and colon. Among the four pH's studied, the best was at pH 6.5 (p &lt; 0.05). Absorption was 80% lower in the absence of Na⁺, and 75% lower when the temperature of the perfusate was decreased to 4 °C. Permeability of AG337 also decreased about 75% when the concentration was raised to 100 µM. These results suggest that a nutrient carrier may be involved in the transport of AG337. To determine the carrier responsible for the absorption of AG337, its absorption was determined in the presence of various inhibitors at different concentrations. The results indicated that transport of AG337 was inhibited significantly (p &lt; 0.01) by 100 µM of adenine, hypoxanthine, and xanthine. The transport was also inhibited significantly (p &lt; 0.01) by a mixture of 100 µM each of adenine, hypoxanthine, and xanthine, but not by a mixture of 100 µM each of thymine and uracil. A higher concentration of hypoxanthine resulted in increased inhibition. In contrast, prototypical inhibitors of nucleoside transporter, dipyridamole and nitroben-zylthioinosine (NBMPR), did not significantly decrease the transport of AG337. The results also showed that absorption of AG337 had a significant nonsaturable component, with a nonsaturable Pw of 0.8. In conclusion, absorption of AG337 in the rat intestine has been shown to be mainly via a purine base carrier with a significant nonsaturable component.

The purpose of this study was to determine the intestinal absorption characteristics of AG337, a mechanism-based inhibitor of thymidylate synthase, using a perfused rat intestinal model. Effects of site, pH, temperature, concentration, Na+, and inhibitors on the absorption of AG337 were determined, after the compound was shown to be stable in buffers of various pH, blank perfusate, and intestinal homogenate. The results indicated that absorption of AG337 was temperature-, pH-, Na+-, concentration-, and site-dependent. The best site of absorption is duodenum, where the absorption was 3-10 times (p < 0.05) higher than absorption at jejunum, ileum, and colon. Among the four pH's studied, the best was at pH6.5 (p < 0.05). Absorption was 80% lower in the absence of Na+, and 75% lower when the temperature of the perfusate was decreased to 4°C. Permeability of AG337 also decreased about 75% when the concentration was raised to 100μM. These results suggest that a nutrient carrier may be involved in the transport of AG337. To determine the carrier responsible for the absorption of AG337, its absorption was determined in the presence of various inhibitors at different concentrations. The results indicated that transport of AG337 was inhibited significantly (p< 0.01) by 100μM of adenine, hypoxanthine, and xanthine. The transport was also inhibited significantly (p < 0.01) by a mixture of 100μM each of adenine, hypoxanthine, and xanthine, but not by a mixture of 100μM each of thymine and uracil. A higher concentration of hypoxanthine resulted in increased inhibition. In contrast, prototypical inhibitors of nucleoside transporter, dipyridamole and nitrobenzylthioinosine (NBMPR), did not significantly decrease the transport of AG337. The results also showed that absorption of AG337 had a significant nonsaturable component, with a nonsaturable Pwof 0.8. In conclusion, absorption of AG337 in the rat intestine has been shown to be mainly via a purine base carrier with a significant nonsaturable component.

The permeability of pure enantiomers of ketorolac acid, a potent non-narcotic analgesic, through human cadaver skin was evaluated. The melting temperature of each enantiomer was 20°C higher than that of the racemic compound. As expected, the solubility of the racemic compound in water and isopropyl alcohol/water/isopropyl myristate (IPA/water/IPM, 50:50:1.5) was roughly 2 times higher than that of the enantiomers. The permeability of the enantiomers through poly-(ethylenevinyl acetate) (EVA) synthetic membrane and human cadaver skin was determined with a side-by-side diffusion cell. The skin flux of the racemic compound was about 1.5 times higher than those of the enantiomers. On the other hand, no significant differences in the intrinsic permeability coefficient of the racemic compound and the enantiomers in the EVA membrane and human cadaver skin was observed. An excellent agreement between the predicted and experimental flux ratio of the racemic compound and enantiomer in the EVA membrane and cadaver skin was observed. The IPA/water/IPM (50:50:1.5) provided the highest in vitro skin flux of theSenantiomer among the three vehicle formulations studied. The skin flux of the active pureSenantiomer was ca. 34% higher than that of the impureSenantiomer in the racemic mixture. Furthermore, about 14% intersubject variability in the in vitro skin flux of theSenantiomer was observed. The required skin flux of theSenantiomer as calculated from the pharmacokinetic parameters was about 32 μg/cm2/h from a 25cm2transdermal patch, which was readily achievable from the IPA/water/IPM (50:50:1.5) ternary vehicle system.

The vascular actions of the proteinase‐activated receptor‐2‐activating peptides (PAR2APs), SLIGRL‐NH2(SL‐NH2) and SLIGKV‐NH2(KV‐NH2) as well as the reverse‐sequence peptide, LSIGRL‐NH2(LS‐NH2) and an N‐acylated PAR2AP derivative, trans‐cinnamoyl‐LIGRLO‐NH2(tcLI‐NH2), were studied in rat intact and endothelium‐denuded artery ring preparations, primarily from the pulmonary artery (RPA).In RPA rings with but not without a functional endothelium, SL‐NH2(but not LS‐NH2) caused either an endothelium‐dependent relaxation (at concentrations: <10 μm) or (at higher concentrations: >10 μm), an endothelium‐dependent contraction. No contractile response was observed in endothelium‐denuded preparations, that otherwise contracted in response to the PAR1AP, TFLLR‐NH2.The endothelium‐dependent contractile response to SL‐NH2was not blocked by the α‐adrenoceptor antagonist prazosin, the endothelin antagonist BQ123, the angiotensin II antagonist DuP753, by tetrodotoxin; nor by the enzyme inhibitors, Nω‐nitro‐l‐arginine‐methylester (NO‐synthase), indomethacin (cyclo‐oxygenase), SKF‐525A (epoxygenase) and MK886 (leukotriene synthesis inhibitor).In the relaxation assay, KV‐NH2was 5 fold less potent than SL‐NH2, whereas in the contractile assay KV‐NH2was about equipotent with SL‐NH2. However, the maximal contractile response to KV‐NH2was lower than that of SL‐NH2.The PAR2AP analogue, tcLI‐NH2, was as active as SL‐NH2in the relaxation assay but was inactive as a contractile agonist in the endothelium‐intact RPA.The relaxant responses caused by SL‐NH2and trypsin, as well as the contractile response caused by SL‐NH2, did not desensitize in the course of repeated exposures of the tissue to agonist; whereas the contractile response to trypsin, only observed at concentrations greater than 30 u ml−1, was desensitized by previous exposure of the tissue to either thrombin or trypsin.In a contractile assay, where the tissue was desensitized to a concentration of trypsin that would otherwise cause a relaxant response, the preparation still contracted in response to SL‐NH2. However, the trypsin‐desensitized preparations were no longer contracted by thrombin.From the cross‐desensitization by thrombin of the contractile response to trypsin (and vice versa), we concluded that the contractile effect of trypsin was due to activation of the thrombin receptor and not PAR2.We concluded that the endothelium‐dependent contraction caused by high concentrations of SL‐NH2is due to an as yet unidentified contracting factor; whereas the endothelium‐dependent relaxation response observed at low concentrations of SL‐NH2(10 μm) is mediated by nitric oxide.The distinct structure activity profiles for the contractile response (potency of KV‐NH2SL‐NH2) compared with the relaxant response (potency of KV‐NH2<5SL‐NH2); the contractile responsiveness to SL‐NH2of an endothelium‐intact RPA preparation, that did not contract in response to trypsin; and the lack of contractile activity of the PAR2AP analogue tcLI‐NH2, that was as active as SL‐NH2in the relaxation assay all argue in favour of receptor heterogeneity in the vasculature for the PAR2APs. It remains to be determined if the distinct endothelial receptor responsible for the contractile action of SL‐NH2can be proteolytically activated, like PAR1and PAR2.

The physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm3) $${\frac{1}{2}}$$ for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphine's solubility parameter from its hexane solubility alone and its melting properties gave a corresponding d2 value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm3) $${\frac{1}{2}}$$ . For these compounds, experimental solubility parameters agreed with solubility parameters estimated from molar attraction constants. Because meperidine, fentanyl, and sufentanil exhibit low levels of intracrystalline cohesion, as reflected in low melting points and relatively modest heats of fusion, theoretically projected ideal solubilities and actual solubilities in organic solvents measured for them were considerably higher than determined for morphine and its analogues. Consistent with the solubilities, the octanol–water partition coefficients of the two 4-anilinopiperidine analogues and of meperidine were several orders of magnitude larger than those of the opioids, evidencing the fact that meperidine, fentanyl, and sufentanil are substantially more lipophilic than the opioids.

Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 × 10-3, 5.6 × 10-3, and 1.2 × 10-2 cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 × 10-6, 4.9 × 10-5, and 1.4 × 10-5 cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have Koctanol/water values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.

Transdermal delivery of fentanyl from various adhesive matrix formulations to achieve a steady-state skin flux was investigated. For this purpose, various pressure-sensitive adhesives selected from the three chemical classes of polymers (polyisobutylene (PIB), acrylate, and silicone adhesives) were characterized with respect to fentanyl's solubility, diffusion coefficient, and permeability coefficient. The solubility of fentanyl in various pressure-sensitive adhesives at 32°C was determined by the drug absorption–desorption method. The solubilities of fentanyl in these adhesives were in the following order: acrylate>silicones>PIB. The permeability coefficient and diffusion coefficient of fentanyl in these adhesives were determined by the membrane diffusion method. The diffusion coefficient rank order was silicone-2920>silicone-2675 ≥ acrylate>PIB. The release profiles of fentanyl in the aqueous buffer from these adhesives with 2–4% drug loading was evaluated. The release rate of fentanyl from the acrylate polymer was significantly higher than those of silicone and PIB adhesives. The in vitro flux of fentanyl through cadaver skin from various adhesives with 2% drug loading was determined at 32°C using modified Franz diffusion cells. The skin fluxes of fentanyl from silicone-2920 and PIB adhesives were 6.3±0.7 and 3.1±0.3 μg/cm2/h, respectively. On the other hand, the skin fluxes of fentanyl from acrylate and silicone-2675 adhesive matrices were about 1 μg/cm2/ h. The effect of drug loading on skin flux was investigated using PIB as a model adhesive. The drug released in the phosphate buffer (pH=6.0) increased linearly as the drug loading in the PIB was increased from 1% to 4%; and as the drug loading exceeded 4%, an initial burst effect followed by a zero-order release was observed. The skin flux of fentanyl increased proportionally as the drug loading in the PIB adhesive was increased from 1 to 4%, and a plateau was reached beyond 4% drug loading. These results suggest that fentanyl concentration in the PIB adhesive might have reached saturation above 4% drug loading and that the optimum skin flux was accomplished from such a system because of attainment of maximum thermodynamic activity.

The paper is concerned with the investigation of the disturbances of a finite elastic rod within the framework of relativistic mechanics of continua and of relativistic electrodynamics under specified boundary conditions.

After incubation with 6,7-3H-estradiol, the uptake of radioactivity was measured in rat fallopian tubes and uterus during diestrus, estrus, early and late stages of gestation, and the postpartum period (PP). Uptake patterns during early and late pregnancy reflect the critical endogenous estogenic influence on in vitro hormonal (estrogenic) sensitivity of fallopian tubes and uterus. Very low levels of uptake are observed during the middle and late stages of pregnancy, i.e., day 12 to day 20 postcoitum, followed by a sharp increase during the puerperium (days 1 to 6 PP). However, a close similarity exists between tubal and uterine estrogen uptake patterns during the estrous cycle and critical stages of implantation, followed by pregnancy and the postpartum period.

In vitroincorporation of dl-valine-1-[14C] was measured in oviducts and uterine TCA precipitable protein during diestrus, estrus, early and late pregnancy (PC) and postpartum period (PP) in albino rats. Incorporation of amino acid (valine) into oviduct protein declined between day 1 and 6 PC and a steep fall was observed between day 6 and 7 PC. In uterus, the valine incorporation into protein showed a moderate rise during implantation (day 5 PC). During post implantation stages (days 7–20 PC) a simultaneous stimulation of oviducal and uterine amino acid uptake occurs. However, on day 1 PP a sharp fall in valine incorporation is observed both in oviduct and uterus followed by a rise on day 5 PP.

This paper is intended to provide a potential basis for a numerical prediction of cavitation erosion damage. The proposed method can be divided into two steps. The first step consists in determining the loading conditions due to cavitation bubble collapses. It is shown that individual pits observed on highly polished metallic samples exposed to cavitation for a relatively small time can be considered as the signature of bubble collapse. By combining pitting tests with an inverse finite-element modelling (FEM) of the material response to a representative impact load, loading conditions can be derived for each individual bubble collapse in terms of stress amplitude (in gigapascals) and radial extent (in micrometres). This step requires characterizing as accurately as possible the properties of the material exposed to cavitation. This characterization should include the effect of strain rate, which is known to be high in cavitation erosion (typically of the order of several thousands s−1). Nanoindentation techniques as well as compressive tests at high strain rate using, for example, a split Hopkinson pressure bar test system may be used. The second step consists in developing an FEM approach to simulate the material response to the repetitive impact loads determined in step 1. This includes a detailed analysis of the hardening process (isotropic versus kinematic) in order to properly account for fatigue as well as the development of a suitable model of material damage and failure to account for mass loss. Although the whole method is not yet fully operational, promising results are presented that show that such a numerical method might be, in the long term, an alternative to correlative techniques used so far for cavitation erosion prediction.

Chromosomes from the peripheral blood of 10 patients with gonadal tumors were studied to detect any inherent chromosomal defect. Aneuploidy, breakages and loss of chromosome X were observed. In all cases the karyotype was compatible with the phenotype.

A case of omental prolapse presented to us on the fifteenth postoperative day following an uneventful Cesarean section. A rare complication as such questions the safety of peritoneal nonclosure that has been adopted by obstetricians in recent times.