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Biomedical subjects

E J Lien

Publications and source records attributed to E J Lien.

At least 37 records · Page 2Linked to original sources
PubMed1996

QSAR analysis of membrane permeability to organic compounds.

A general mathematical model involving partition coefficient, molecular weight and hydrogen bonding is used to correlate the structures and permeability of various organic compounds through the toad urinary bladder and human red blood cell (RBC) membranes. Log Per (permeability) is correlated with log Po/w (partition coefficient in olive oil/water, or ether/water), log MW (molecular weight) and Hb (hydrogen bonds). Log Po/w is the most important factor among three parameters examined. While increased MW always has a negative effect on the permeability, increased Hb can have either a slightly positive or a slightly negative effect depending on the solvent and membrane systems used. Systematic comparison of the QSAR's (quantitative structure activity relationship) of different biological membranes may serve as a useful guide in drug targeting to different tissues and cell types.

Alcohols↗
PubMed1995

Hydrophobic contribution constants of amino acid residues to the hydrophobicities of oligopeptides.

PURPOSE: The main purpose of this study is to explore the additive-constitutive nature of common amino acids in their contribution to the partition coefficients of small peptides. METHODS: The Log P values and other physico-chemical parameters of the peptides studied are taken from the literature. The frequency of appearance (ni) of each individual amino acid is calculated as the number of the amino acids in a given peptide. RESULTS: The partition coefficients (Log P(oct./buff.) at pH 7) of 87 N-acetyl-peptide-amides have been correlated with the frequency of appearance of amino acids. From the correlation obtained, the de novo hydrophobic contribution constants of 19 amino acid residues are derived for the first time. The contribution constants are extended to 59 unmodified regular peptides with the inclusion of the pka values of both N-terminal and C-terminal amino acids. The models thus obtained have been validated with additional 27 peptides (both N-acetyl-peptide-amides and unmodified). CONCLUSIONS: The Log P of oligopeptides is very well correlated with the de novo hydrophobic contribution constants of amino acids. The models we have derived are reasonably accurate in predicting the hydrophobicities of new oligopeptides (< or = tetrapeptides) at a fixed pH (e.g., 7).

Amino Acid Sequence↗
PubMed1995

QSAR analysis of skin permeability of various drugs in man as compared to in vivo and in vitro studies in rodents.

A general mathematical model involving partition coefficient, molecular weight and hydrogen bonding has been formulated for correlating the structures and skin permeability of a wide range of compounds through human skin and through hairless mouse skin. The correlations obtained are dependent not only on the biological system but also on the vehicle used. Without the use of lipophilic vehicle, the ideal lipophilicity for maximum permeability through human skin as measured by log Po(oct/w) ranges from 2.5 to 6 (extrapolated value). When a lipophilic vehicle was used in hairless mouse skin study, the log Po(oct/w) was lowered to around 0.4 approximately 0.6. While increased M.W. always has a negative effect on the permeability, increased H-bond can have either a slight positive or a slight negative effect, depending on the experiments (absorption vs. permeability constant). Cross validations with previously unanalyzed data as well as other biological systems support the usefulness of the general model developed for passive diffusion.

Animals↗
PubMed1995

Chirality and drug targeting: pros and cons.

The theoretical basis of stereoselectivity in drug targeting in terms of eudismic ratio and quantitative structure-activity relationship has been presented. Specific examples of the advantages of using the correct stereoisomers (eutomers) rather than the distomers or racemic mixtures have been discussed. With the recent development of new methods of chiral synthesis and chiral analysis, it is not longer justifiable to continue to use racemic mixtures as therapeutic agents, unless it can be proven to be safe to do so. In the area of using peptides, proteins, glycoproteins and polysaccharides as therapeutic agents, mother nature has been very selective in choosing the optically active starting materials (Bradley, 1994), it is a necessity to design and test the proper optical isomer when a mimetic or antagonist compound is contemplated as a therapeutic agent.

Computer Simulation↗
PubMed1994

Inhibition of human adenoviruses by 1-(2'-hydroxy-5'-methoxybenzylidene)amino-3-hydroxyguanidine tosylate.

Antiviral activities of four Schiff bases of aminohydroxyguanidine, designated ML1, ML4, ATL14 and LK11, were tested against human adenovirus types 5 and 8 (Ad5 and Ad8) in A549 cells by plaque reduction and virus yield reduction methods. Compound (ML1 1-(2'-hydroxy-5'-methoxybenzylidene)amino-3-hydroxyguanidine tosylate gave the best therapeutic indices (TC50/IC50) of 27.2 and 17.8 for Ad5 and Ad8, respectively. Pretreatment of cells with ML1 did not affect the adsorption nor the penetration of virus. Ultrastructure studies showed that only the drug treated infected cells had unidentified irregular shaped electron dense structures that might be drug altered viral macromolecules that were not assembled into complete infectious virus particles. Since these compounds have metal chelating properties, their antiviral activity may involve the early IA (EIA) gene which encodes a viral protein of 289 amino acid which has a zinc finger moiety that is required for its transactivation activity.

Adenoviruses, Human↗
PubMed1994

Preventing potential drug interactions in community pharmacy.

With ongoing debate on health care reform including improved pharmaceutical care, there is much current concern about drug interactions and their prevention. Many patients visit more than one doctor for their different diseases and receive more than one drug at a time, and often doctors are unaware of all the medications their patients are taking and the risks to which their patients are exposed when treated with multiple drugs. Pharmacists in the community setting or hospital are the most accessible health care providers able to intervene when faced with potential drug interactions that may occur during patients' multiple drug therapy. A few selected examples of potential drug-drug interactions and interventions instituted are presented in this paper. Possible mechanisms for the drug interactions are also discussed. It is hoped that more documentation of pharmacists' involvement in such interventions will demonstrate the true value of pharmaceutical care.

Chelating Agents↗
PubMed1994

Antileukemic activity studies and cellular pharmacology of the analogues of 2-hydroxy-1H-isoindole-1,3-dione (HISD) alone and in combination with cytosine arabinoside (ara-C) against human leukemia cells CEM/0.

The 2-hydroxy-1H-isoindole-1,3-dione (HISD) derivatives are inhibitors of ribonucleotide reductase (RR). Among the seven new compounds of the PL series, three were found to be active in cell lines sensitive (CEM/0) or resistant to ara-C (CEM/ara-C/7A; CEM/dCk[-]. The compounds PL4, PL7 and PL8 exhibited IC50 values in micromolar range against the three CEM cell lines. The 3 compounds showed 100- to 1000-fold higher cytotoxicity compared to HU against all three CEM cell lines. Combination of each of the three active PL compounds with ara-C showed high degree of synergism in comparison to the combinations of HU with ara-C against both CEM/0 and CEM/ara-C/7A cell lines. The DNA synthetic capacity of CEM/0 cells treated with 10 microM PL4 for 24 or 48 h was inhibited > or = 99.8% simultaneously the cellular NTP pools were severely depleted. Treatment of CEM/0 cells with 10 microM PL4 showed steady depletion in all the dNTP pools at 1 or 2 h and complete depletion by 4 h. The enzyme activity did not recover up to 48 h in presence of the drug suggesting irreversible inhibition of RR.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Evidence for the existence of two forms of alpha 2A-adrenoceptors in the rat.

The alpha 2A-adrenoceptors in rat spleen, kidney, spinal cord and cerebral cortex were studied using [3H]-RX821002 radioligand binding. In the spleen, spinal cord and cerebral cortex, the ligand bound to saturable sites with a Kd of about 1 nmol/l and capacities of 134, 240 and 290 fmol/mg protein, respectively. Computer modelling competition curves for 39 drugs, including those for alpha 2A-, alpha 2B- or alpha 2C-adrenoceptor selective drugs, indicated that the sites labelled by [3H]-RX821002 in the spleen consisted of a single population of alpha 2A-adrenoceptors. However, the competition curves for guanoxabenz were definitely biphasic and resolved into two site fits, indicating that guanoxabenz was binding to both high affinity (Kd = 35 nmol/l) and low affinity (Kd = 8900 nmol/l) alpha 2A-adrenoceptor sites in the proportions 57% and 43%, respectively. The KdS for a number of alpha 2-adrenoceptor subtype selective drugs, measured in competition with [3H]-RX821002 in cerebral cortex and spinal cord, were highly correlated with those obtained in the spleen indicating their alpha 2A-adrenoceptor nature. However, by contrast to the results with the spleen, the guanoxabenz competition curves for the spinal cord and cerebral cortex were monophasic and resolved only into one site fits, the Kd of guanoxabenz being about 4000 nmol/l for both tissues. Drug KdS for kidney alpha 2A-adrenoceptors were also determined using [3H]-RX821002. For nearly all drugs tested, the KdS were highly correlated with those found for the alpha 2A-adrenoceptors in the other rat tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1993

Synthesis and testing of new antileukemic Schiff bases of N-hydroxy-N'-aminoguanidine against CCRF-CEM/0 human leukemia cells in vitro and synergism studies with cytarabine (Ara-C).

A series of eight new N-hydroxy-N'-aminoguanidine (HAG) Schiff bases [ArCH = NNHC(= NH)NHOH.tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-1-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-1-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 +/- 0.1 microM) and the 4-methoxy-2-hydroxyphenyl derivative (LK02) to be the least potent (IC50, 121 +/- 16 microM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 +/- 7.1 microM) and was about 32 times more potent than LK10 (IC50, 97.6 +/- 0.9 microM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1993

Further evidence for the existence of two forms of alpha 2B-adrenoceptors in rat.

Analysis of saturation isotherms of the novel alpha 2-adrenoceptor antagonist radioligand [3H]-MK 912 revealed that the ligand labelled a homogenous population of alpha 2B-adrenoceptors in the neonatal rat lung with a Kd of 0.77 nM and a Bmax of 231 fmol/mg protein. In rat kidney, combined saturation and competition experiments, using [3H]-MK 912 and the alpha 2A-adrenoceptor selective drug guanfacine, revealed that approximately 81% of the sites labelled by [3H]-MK 912 were alpha 2B-adrenoceptors and approximately 19% alpha 2A-adrenoceptors; the Kds of [3H]-MK 912 being 1.1 and 2.0 nM and the Bmax 134 and 33 fmol/mg protein, respectively. The kidney alpha 2B-adrenoceptors were studied separately by using approximately 1.5 nM [3H]-MK 912 in the presence of 0.32 microM guanfacine, the latter which blocked ligand binding to alpha 2A-adrenoceptors completely. Analysis of drug competition curves obtained during these conditions revealed that 18 out of 20 different agonists and antagonists yielded steep and uniphasic competition curves which modelled best into one site fits. However, both guanoxabenz and LT 11 appeared to inhibit [3H]-MK 912 binding at two sites; the Kds of guanoxabenz differing approximately 120-fold and that of LT 11 differing approximately 35-fold for the two sites. Moreover, the addition of mutual fixed concentrations of either 20 microM guanoxabenz or 20 microM LT 11 completely prevented the binding of the other compound to its high affinity site, indicating that both compounds labelled the same site with the high affinity. The analysis indicated that 29% of the sites were of high and 71% of low affinity. However, in the neonatal rat lung guanoxabenz and LT 11 (as well as 15 other compounds) yielded competition curves which modelled only into one site fits. The Kds obtained in the lung correlated well with the Kds obtained in the kidney for alpha 2B-adrenoceptors; for guanoxabenz and LT 11 the values from the lung were close to those determined in the kidney for the low affinity site for guanoxabenz and LT 11. Moreover, when the rat RNG alpha 2B-adrenoceptor was expressed in COS-7 cells and its binding properties tested using [3H]-MK 912 binding, guanoxabenz, LT 11 as well as a number of other drugs inhibited the ligand binding at a single alpha 2-adrenoceptor site; the drug Kds being practically the same as those found for the neonatal rat lung. It is suggested that rat alpha 2B-adrenoceptors may exist in two forms: alpha 2B1 and alpha 2B2.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1993

Hydrophobicity of oligopeptides having un-ionizable side chains.

The hydrophobicity of any peptide is a physicochemical property not only of the amino acid sequence, but also of the secondary and tertiary structure. It is also an essential factor to consider in peptide drug delivery, which has become increasingly important in recent years with the discovery of many peptides with potential pharmaceutical uses. The hydrophobicities (log P) of dito pentapeptides reported by Akamatsu and Fujita have been correlated with 12 parameters including 7 indicator variables. We have tried to simply this equation by using more common and simple parameters. Good correlations have been obtained for log P with a five-parameter equation using the sum of the hydrophobicity of component amino acids (log Paa), molecular weight (log MW), the frequency of beta-turn formation (F beta) of peptides, which is an important tertiary structural parameter, the dipole moment (mu) calculated with a computer-assisted program, and the number of amino acids in a peptide (N). This equation should be useful in drug delivery in predicting the relative hydrophobicity of new peptides with no ionizable side chains.

Amino Acid Sequence↗
PubMed1991

Physical factors contributing to the partition coefficient and retention time of 2',3'-dideoxynucleoside analogues.

Acquired immunodeficiency syndrome (AIDS) is an immunosuppressive disease characterized by an immune impairment and a high susceptibility to unusual forms of certain neoplasms. Since the brain is an important site of the infection, it is necessary to explore new classes of drugs that have the ability to penetrate across the blood-brain barrier, and the potency to suppress viral replication within the central nervous system (CNS). Therefore, the ability to predicate the lipophilicity of the potent anti-AIDS drugs may provide useful information about the potential of the drugs to enter CNS. In this paper, the correlations of log P (octanol-buffer partition coefficient) and log tR (retention time in HPLC; Rt was used by Balzarini et al.) with some physical constants like log MW (molecular weight), hydrogen bond forming ability (HB) of the substituents, and the substituent group dipole moments (mu) are analyzed. Good correlations of log P and log tR with log MW, HB, and mu have been obtained.

Antiviral Agents↗
PubMed1991

Analysis of the quantitative structure activity relationship of technetium-99m-labeled diaminedithiol (DADT) and propylene-amine-oxime (PAO) brain blood flow analogues.

In the search for new brain imaging agents for the use with single photon emission computed tomography (SPECT), quantitative structure activity relationship (QSAR) analysis of the correlations between initial brain uptake and physicochemical parameters like lipophilicity, log P, molecular weight, log MW and log U/D (undissociated/dissociated), of the 99mTc-DADT (diaminedithiol) complexes and 99mTc-PAO (propyleneamineoxime) complexes have been analyzed. High correlations are found for both the 99mTc-DADT complexes (r = 0.94) and for the 99mTc-PAO complexes (r = 0.83) which are significant at 99.9 and 99.5 percentile level, respectively. These results will help the further design of better ligands for 99mTc in brain imaging.

Brain↗