Distribution of crushing strength of tablets.

The distribution of a given set of data is important since most parametric statistical tests are based on the assumption that the studied data are normal distributed. In analysis of fracture mechanics the Weibull distribution is widely used and the derived Weibull modulus is interpreted as a material constant. However, the estimation of this parameter is laborious and subject to estimation problems.

Glutamate receptor ligands: synthesis, stereochemistry, and enantiopharmacology of methylated 2-aminoadipic acid analogs.

Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA) analogs, and the synthesis, stereochemistry, and enantiopharmacology of 3-methyl-AA (4a-d), 4-methyl-AA (5a-d), 5-methyl-AA (6a-d), and (E)-Delta(4)-5-methyl-AA (7a and 7b) are reported. The compounds were resolved using chiral HPLC and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses, chemical correlation, and CD spectral analyses.

In vitro Plasmodium falciparum drug sensitivity assay: inhibition of parasite growth by incorporation of stomatocytogenic amphiphiles into the erythrocyte membrane.

Lupeol, which shows in vitro inhibitory activity against Plasmodium falciparum 3D7 strain with a 50% inhibitory concentration (IC50) of 27.7 +/- 0.5 microM, was shown to cause a transformation of the human erythrocyte shape toward that of stomatocytes.

Substantial species differences in relation to formation and degradation of N-acyl-ethanolamine phospholipids in heart tissue: an enzyme activity study.

The formation of N-acyl-ethanolamines (NAEs), including the cannabinoid receptor ligand anandamide, and their precursors N-acyl-ethanolamine phospholipids (NAPEs) are catalyzed by NAPE-hydrolyzing phospholipase D (NAPE-PLD) and N-acyl-transferase, respectively. NAPE and NAE are suggested to have beneficial effects on the heart, but in the literature there are indications of species differences in the activity of these enzymes. We have examined heart microsomes from rats, mice, guinea pigs, rabbits, frogs, cows, dogs, cats, mini pigs and human beings for activities of these two enzymes.

Correlation of aqueous solubility of salts of benzylamine with experimentally and theoretically derived parameters. A multivariate data analysis approach.

Twenty two salts of benzylamine and p-substituted benzoic acids were prepared and characterized. The p-substituent was varied with regard to electronic, hydrophobic, and steric effects as well as hydrogen bonding potential. A multivariate data analysis was used to describe the relationship between the aqueous solubility of the salts and experimentally determined physicochemical parameters and theoretically derived molecular descriptors.

The AMPA receptor binding site: focus on agonists and competitive antagonists.

It is generally agreed that (S)-glutamic acid (Glu) receptors are involved in the development of a number of diseases in the central nervous system (CNS), and ligands that interact with these receptors are of significant interest. Selective ligands are indispensable as tools for the elucidation of the physiological role of AMPA receptors and as leads for the development of therapeutic agents. Over the last decade a wide variety of such ligands have been developed and studies on the structure-activity relationships of these compounds have contributed to our understanding of the mechanisms involved in AMPA receptor activation and blockade.

Targeting vaccines to dendritic cells.

Dendritic cells (DC) are specialized antigen presenting cells (APC) with a remarkable ability to take up antigens and stimulate major histocompatibility complex (MHC)-restricted specific immune responses. Recent discoveries have shown that their role in initiating primary immune responses seems to be far superior to that of B-cells and macrophages. DC are localized at strategic places in the body at sites used by pathogens to enter the organism, and are thereby in an optimal position to capture antigens.

Regioselective lithiation and functionalization of 3-(benzyloxy)isothiazole: application to the synthesis of thioibotenic acid.

Direct functionalization of the 3-oxygenated isothiazole heteroaromatic parental system has not yet been reported in the literature. Here, we report the first regioselective lithiation of the 5-position of 3-(benzyloxy)isothiazole (4) using LDA in diethyl ether. The versatility of the methodology was explored by quenching with a variety of electrophiles to give the desired products 7a,b,d-g in 54-68% yield.

The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation.

The aim of this study was to investigate the effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. A 2(4) full factorial experimentally designed study was performed to investigate the influence of the following independent spray drying variables: feed flow rate, nozzle gas flow rate, inlet air temperature and aspirator capacity (drying gas flow rate). Human insulin (biosynthetic and Ph.

A calorimetric study of phosphocholine membranes mixed with desmopressin and its diacylated prodrug derivative (DPP).

The influence of the water-soluble peptide, desmopressin (DDAVP) and its dipalmitoylated prodrug derivative (DPP) on the thermal behaviour of three different saturated phosphatidylcholine lipid membranes was investigated by differential scanning calorimetry. For lipid membranes composed of dimyristoyl, dipalmitoyl and distearoyl phosphatidylcholines the addition of DDAVP at concentrations of up to 10 mol% resulted in an insignificant change in the thermodynamic phase behaviour. In contrast, the dipalmitoylated DPP prodrug caused major changes on the lipid membrane phase behaviour manifested as a drastic decrease in the heat capacity peak height and a concomitant broadening of the main phase transition as well as a decrease in the transition enthalpy.

Physical stability of redispersible dry emulsions containing amorphous sucrose.

The objective of the present study was to estimate the stability of redispersible dry emulsions containing amorphous sucrose. Dry emulsions were prepared by spray drying liquid o/w-emulsions in a laboratory spray dryer. The effect of hydroxypropyl methylcellulose (HPMC) on the glass transition temperature T(g) of spray dried sucrose-HPMC mixtures, relative to the T(g) of amorphous sucrose, was investigated.

Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia.

Background: We have reviewed the analgesic efficacies of rectal and parenteral paracetamol and tested the evidence for a possible additive analgesic effect of the combination of paracetamol with a non-steroidal anti-inflammatory drug (NSAID) in postoperative pain.

Methods: Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia.

Point mutation in the first transmembrane region of the beta 2 subunit of the gamma--aminobutyric acid type A receptor alters desensitization kinetics of gamma--aminobutyric acid- and anesthetic-induced channel gating.

A conserved glycine residue in the first transmembrane (TM1) domain of the beta2 subunit has been identified to be involved with desensitization induced by gamma-aminobutyric acid (GABA) and anesthetics. Recombinant GABA(A) receptors expressed in Sf9 cells were recorded using semi-fast agonist application. Upon direct activation by GABA or anesthetics, the main effect of the TM1 point mutation on the beta2 subunit (G219F) was to slow the time constant (tau) of desensitization.

Loading into and electro-stimulated release of peptides and proteins from chondroitin 4-sulphate hydrogels.

Chondroitin 4-sulphate (CS) hydrogels were examined as potential matrices for the electro-controlled delivery of peptides and proteins. A CS hydrogel, cross-linked with ethylene glycol diglycidyl ether, and with a swelling ratio of 20, was used to study the influence of molecular size and shape of guest molecules on loading and release rates. Three positively charged molecules of different molecular weights (vasopressin MW 1084, aprotinin MW 6512 and lysozyme MW 14,400), and one negatively charged protein (bovine serum albumin MW 67,000) were used as model solutes.

Convergent synthesis of 6-substituted phenanthridines via anionic ring closure.

[reaction: see text] The addition of organometallic derivatives to the cyano group of 2-(2-fluorophenyl)benzonitrile followed by intramolecular nucleophilic substitution produces 6-substituted phenanthridines. Alkyllithiums, aryllithiums, and sterically nondemanding lithium amides reacted at -78 degrees C to produce the 6-substituted phenanthridines in 82-98% yield upon warming to room temperature. The addition of the corresponding Grignard reagents requires an excess of the organometallic reagent and extented reaction times at elevated temperature.

Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids.

Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are both antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents.

Method optimisation with the use of uncertainty budgets.

Uncertainty budgets can be used for a variety of situations, e.g. reporting the total uncertainty, calculating tolerance limits or method optimisation.

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.

Characteristics of drug substances in oily solutions. Drug release rate, partitioning and solubility.

In vitro rate of drug release from oil solutions was investigated in a rotating dialysis cell. A log linear correlation was established between the rate constant (k(obs)) for attainment of equilibrium and apparent partition coefficient (P(app)) between oil vehicle and release media using various weak acids and bases and non-electrolytes. Collander like linear free energy relationships were observed allowing various oil-aqueous buffer partition coefficients to be calculated from known octanol-aqueous buffer partition coefficients.

Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology.

A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including a series of Glu receptor binding assays, uptake studies on native as well as cloned Glu uptake systems, and the electrophysiological rat cortical slice model. Compounds 7a,b, analogues of AMPA bearing a 1-hydroxy-5-pyrazolyl moiety as the distal carboxylic functionality, showed only moderate affinity for [3H]AMPA receptor binding sites (IC(50) = 2.

Design, synthesis, and pharmacological evaluation of thapsigargin analogues for targeting apoptosis to prostatic cancer cells.

A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells.

Direct pelletization in a rotary processor controlled by torque measurements. II: effects of changes in the content of microcrystalline cellulose.

In the present study we investigated the effect of changes in the content of microcrystalline cellulose (MCC) on a direct pelletization process in a rotary processor in which the liquid addition was terminated once a certain increase in torque was produced. Nine different mixtures of MCC and lactose with MCC contents varying from 10% to 100% (w/w) were pelletized using 6 different torque increase levels, and the changes in pellet characteristics were investigated. The pellet characteristics investigated were pellet shape, size, and size distribution as well as the water content of the pellets at the end of liquid addition.

Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers.

Aims: To evaluate the electroencephalographic (EEG) effects, blood concentrations, vehicle irritation and dose-effect relationships for diazepam administered nasally.

Methods: The study had a cross-over design with eight healthy volunteers (one drop out). It consisted of four legs with four different administrations: intranasal (i.

Intranasal bioavailability of diazepam in sheep correlated to rabbit and man.

The purposes of the present study were to estimate the nasal bioavailability of diazepam in sheep and to compare this to earlier results in rabbits and humans. Additional, to compare the absorption during various initial periods in the two animal models and man, due to the importance of early absorption in emergency treatment. In a cross-over design, diazepam was nasally administered (7 mg) and intravenously (3 mg), respectively, to six sheep.