bluuebunny/crossref_metadata_2025 huggingface dataset:
Achilles tendinitis induced by pefloxacin and other fluoroquinolone derivatives
Authors: Meyboom R. H. B. , Olsson S. , Knol A. , Dekens‐Konter J. A. M. , De Koning G. H. P.
Published: October 2006

Four cases have been reported to the Netherlands Pharmacovigilance Foundation LAREB of Achilles tendinitis, as a suspected adverse reaction to pefloxacin. More than 20 cases of tendinitis and tendon rupture have previously been described in the literature in association with pefloxacin and various other fluoroquinolone derivatives. The mechanism involved is still unknown. Tendon disorders as an adverse drug reaction are very rarely reported to the WHO Collaborating Centre for International Drug Monitoring. The exception is in association with fluoroquinolone derivatives. More information is needed with regard to the frequency of tendinopathy during the use of pefloxacin and the other drugs in this group. Patients using a fluoroquinolone derivative should be informed on the risk of developing tendinitis and tendon rupture.
Adverse drug reactions: Comparison of two report methods
Authors: Hanesse B. , Legras B. , Royer R. J. , Guillemin F. , Briancon S.
Published: October 2006

Increasing numbers of effective therapeutic agents changed the practice of medical care. One of the costs of the widespread use of new therapies is the occurrence of adverse drug reactions (ADR). We compared a routine procedure of spontaneous reporting to a systematic registration of medical informations including adverse drug reactions in a cluster‐randomized controlled trial. This study was carried out during the first semester of 1993 at the Centre Hospitalier et Universitaire de Nancy, France receiving about 100,000 patients a year. The 10 participating departments were paired‐matched. For the first eight weeks of the study, reporting methods were randomly assigned within each pair. For the second eight weeks of the study, the attribution of methods was reversed. All patients, who left a participating department within one of these two periods were included. Subsequent discharges after further readmissions for the same patient were not considered. Thus, the study was based on 5967 patients. We received 46 ADR reports. After adjustment for age and sex, using a logistic regression model, the probability for reporting ADR for a patient is twice as likely by systematic registration of medical information than by the routine procedure of spontaneous reporting. Generalization of this supplementary method for reporting adverse drug reactions appears interesting.
The VAMP system and the detection of risk, some examples
Authors: Mann Ronald D.
Published: October 2006

This paper gives a short account of the VAMP Research Database which, in the UK, provides information on 4.4 million patients. A number of published and reported examples are given of work conducted on this unique and important pharmacoepidemiological resource.
Drug risk assessment: A case for large trials with lean protocols
Authors: Hasford Joerg
Published: October 2006

The common tools of pharmacoepidemiology are: the spontaneous report registries, the case control study, and the cohort study. Since large sample sizes are usually needed, the classic randomized trial, which collects large amounts of data per patient, seems to be impracticable. Yusuf et al.6 have suggested using large trials with simple protocols and only minimal data collection to allow for recruitment of large sample sizes (> 1000). As the objectives of drug safety studies are not met by the large trial simple protocol design, the large trial, lean protocol design is suggested. Its characteristics are that it is: multicentric, randomized, with no efficacy assessment, recording only baseline, follow‐up and outcome data which are crucial to the primary objective of the trial; there is no ‘by tradition’ collection of data. The indications, the ethics and the biometry of randomized trials with safety variables as major endpoint are discussed.

Large trials with a lean protocol are feasible. To illustrate the possible usefulness, a trial will be reported whose primary objective was to assess the rate of a specified adverse event. In general, randomized trials with safety measures as primary endpoints can play an important role in drug risk assessment and their use should be encouraged.
Evaluation of ACE‐inhibitor (ACE‐I) associated cough using modified prescription sequence analysis (PSA)
Authors: Bowman Lee , Carlstedt Bruce C. , Miller Michael E. , McDonald Clement J.
Published: October 2006

Objective — Identify whether the prescription sequence of cough suppressant within one year following patients' first ACE‐I prescription can be used as an indicator for the occurrence of ACE‐I associated cough.

Design — Observational retrospective controlled cohort design using all patients receiving ACE‐I as study cohort and patients having prescriptions for hydralazine, clonodine and prazosin as the control. Patient demographics and prescribing indications were controlled statistically using multivariate logistic regression.

Setting — A large computerized clinical database encompassing the medical records of 450,000 patients seen over a 20‐year period at a county medical centre ambulatory clinic.

Patients — 5373 patients exposed to any of captopril, enalapril, lisinopril, clonodine, hydralazine or prazosin.

Main results — This study identified an odds ratio (OR) of 1.53 [95% confidence interal (CI) 1.17 to 2.01] for receipt of an antitussive following patients' first ACE‐I prescription. Other significant risk factors included female gender [OR = 1.52, CI 1.13 to 2.07] and diagnosis of congestive heart failure [OR = 1.47, CI 1.10 to 1.94].

Conclusion — The receipt of an antitussive following ACE‐I prescription may be used to monitor for ACE‐I associated cough, although its utility is unknown.
Recall of medication during pregnancy: Validity and accuracy of an adjusted questionnaire
Authors: de Jong Pieternel C. M. Pasker , Berns Mary P. H. , van Duynhoven Yvonne T. H. P. , Nijdam Wies S. , Eskes Tom K. A. B. , Zielhuis Gerhard A.
Published: October 2006

Objective — To study the validity and accuracy of an adjusted questionnaire on medical drug use during pregnancy eight years after the pregnancy.

Methods — The ability of a questionnaire on medication during pregnancy to detect actual use (= sensitivity) was tested against information collected 8 years previously (in 1983–1984) from 473 women with high‐risk pregnancies who delivered at the University Hospital Nijmegen, the Netherlands.

Results — For separate drug groups, the sensitivity varied between 5% and 91%. The timing of use was recalled moderately well. Although specific questions on drug groups did improve the sensitivity as compared to an earlier questionnaire, the improvement was not enough to make the questionnaire valid. High maternal education, low birth weight, low gestational age and a low 5‐min Apgar score were related to better recall. The sensitivity of the questionnaire depended on the behavioural score of the child, implying recall bias.

Conclusion — Questionnaire data on drug use during pregnancy obtained eight years after delivery are not a valid source of information.
Relevance and limits of pharmacogenetics to detect patients at risk of adverse drug reactions
Authors: Bechtel Pierre R.
Published: October 2006

For more than 15 years genetic polymorphism of drug metabolism has been extensively studied. Poor Metabolizer (PM) and Extensive Metabolizer (EM) Slow Acetylators (SA) Rapid Acetylators (RA) phenotype and genotype can be defined for CYP2D6 (Debrisoquine) and N‐AT (acetylation). Lists of drugs whose metabolism is CYP2D6 or N‐AT dependent have been published. So it is theoretically possible to forecast an adverse drug reaction (ADR) for a specific patient who is given a drug affected by a polymorphism. However, not only PM are at risk of ADRs. When an active or reactive metabolite is produced, EM might be at risk whatever the enzyme involved. Drug interactions must also be taken into account. Competitive inhibition of the metabolism of a drug CYP2D6 dependent provokes not only a blurring effect on phenotyping, leading to a misclassification, but also increases the risk of ADRs. New drug metabolic polymorphism is under scrutiny. Determination of phenotypes and genotypes when possible, development of investigations of drug metabolic capacity at large, in patients exhibiting ADR's, might improve the efficiency of pharmacovigilance to forecast at‐risk subjects.
Pattern of treatment and metabolic control in orally treated diabetic patients in France and Sweden
Authors: Vauzelle‐Kervroëdan Françoise , Bergman Ulf , Forhan Anne , Stålhammar Jan , Papoz Laure
Published: October 2006

There are large differences in therapeutic habits in the treatment of diabetes in European countries. A cross‐sectional comparison was made of 654 French and 241 Swedish orally treated diabetic patients, aged 50–74 years. Good diabetic control was based on HbA1c (<7 per cent) and body mass index (<27 kg/m2 for men and <25 kg/m2 for women). The French patients were more often male, and about 3 years younger in both sexes. Duration of diabetes was similar in men but shorter in Swedish women, while obesity was more frequent among French men and similar in women. HbA1c was significantly lower in both sexes in the French sample. This difference was, however, no longer significant, when obesity was taken into account. Good diabetic control was found only in about a quarter of men and in one out of seven women. Differences in treatment were mainly due to prescription of metformin alone, which was very uncommon in Sweden. The average prescribed daily doses were generally lower in France. The differences between the two diabetic groups indicate different characteristics of the patients, in spite of the same inclusion criteria, together with different strategies for the oral treatment of diabetes in the two countries.
Determinants of drug utilization in an elderly population in North and West Belfast
Authors: Passmore A. P. , Crawford V. L. S. , Beringer T. R. O. , Gilmore D. H. , Montgomery A.
Published: October 2006

This study was designed to survey drug prescribing for all patients over 65 years in institutional and hospital care in North and West Belfast, together with a home‐based sample, and to determine the influence of age, sex, mental score, functional score and place of abode on prescribing habits. Multiple regression analysis was used to analyse the effects of the various parameters on number of drugs received. Drugs were categorized into therapeutic classes and for each class a separate logistic regression analysis was performed to identify the variables which independently predicted receipt of that class.

A total of 1094 people were surveyed with an average of 3.26 medications per person. The most common classes of drugs received were diuretics (39.8 per cent), analgesics (31.7 per cent), hypnotics (25.3 per cent), phenothiazines (21.7 per cent) and laxatives (20.9 per cent). Number of drugs received was not predicted by age or sex but by institutional or hospital placement. Placement was also the most significant independent predictor of drug class. Age, sex, mental and functional scores were less significant.

Drug utilization in this representative elderly population seemed appropriate with low prescribing rates for some drug classes considered hazardous or ineffective in this age group.
Disturbance of menstruation as a side‐effect of nonsteroidal anti‐inflammatory drugs (NSAIDs)
Authors: Meyboom R. H. B. , Heymeijer G. W. J. , van den Bemt P. M. L. A. , de Koning G. H. P.
Published: October 2006

Menstrual disturbances are not a generally recognized side‐effect of non‐steroidal antiinflammatory drugs (NSAIDs). Five case reports to the Netherlands Pharmacovigilance Foundation LAREB concern menstrual disturbances in suspected connection with the use of an NSAID. In one patient at several occasions the use of naproxen for dysmenorrhoea was followed by interruption of menstruation. In four other women the use of diclofenac, indomethacin or naproxen was followed by hypo‐ or amenorrhoea of one cycle duration. Prostaglandins play a complex role in the physiology of menstruation. The effects of NSAIDs on cyclo‐oxygenase and prostaglandin metabolism may explain the observed disturbances of menstruation. Female patients of child‐bearing age using an NSAID — either to treat dysmenorrhea or for other reasons — should be aware of the possibility of interruption, delay, decrease or missing of a menstrual period.
Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): Evaluation for drug risk based on sale numbers in defined daily doses (DDD). Example of the H2‐antagonists
Authors: Rzany Berthold , Mockenhaupt Maja , Holländer Norbert , Stocker Ulrich , Mueller Judit , Baur Susan , Schöpf Erwin
Published: October 2006

We report on the results of the registration of SJS, SJS/TEN overlap and TEN with maculae in West‐Germany and Berlin from 01.04.90 to 31.12.92. The results are based on the ‘Dokumentationszentrum schwerer Hautreaktionen’, a registry on severe skin reactions, which regularly contacts more than 1500 hospitals (departments of dermatology, departments of pediatrics, burn units and internal medicine departments with intensive care facilities). With a response rate ranking from 77% to 95% over a period of 33 months 270 cases of SJS, SJS/TEN overlap and TEN have been included into the registry. More than 1690 single drugs had been taken two weeks prior to the skin reaction. Among those drugs ranitidine was found in 25 patients. Other H2‐antagonists were taken in 12 cases (famotidine in 11 cases and cimetidine in one case). Evaluation of drug risk incidences for these drugs were calculated based on prescription data in defined daily doses (DDD), which were obtained from the ‘Wissenschaftliches Institut der Ortskrankenkassen’ (WIDO), Heidelberg, Germany. For ranitidine incidences of 0.19, 0.14, 0.10 could be evaluated, compared to 0.11, 0.29 for famotidine and 0.06 for cimetidine for 1990, 1991 and 1992, respectively. Over the observation period the incidences for ranitidine were stable in contrast to famotidine. As probable confounding factors co‐medication with phenytoin, dexamethasone, heparin and, in addition, concomitant illnesses as brain‐tumours and cerebral metastasis could be found. The example of the H2‐antagonists shows that incidence data should be interpreted cautiously. To avoid misinterpretation incidences should be observed over a period of several years, and in every case confounding factors should be taken into account.
Utilization patterns of subsidized and nonsubsidized reimbursable peptic ulcer medication in Belgium
Authors: Stichele R. H. Vander , Petri H.
Published: October 2006

Study objective — To provide an exploratory description of a dynamic population of Belgian patients treated with reimbursable peptic ulcer medications (ATC Class A20B) and to estimate the annual number (prevalence) of patients treated with reimbursable peptic ulcer medications per 1000 inhabitants in Belgium in 1991.

Setting — Community pharmacies in Belgium, a country with 107 inhabitants, where reimbursement of attack therapy (3 months) and maintenance therapy (9 months) is only possible after endoscopic or radiologic confirmation of ulcer or severe esophagitis.

Design — Cross‐sectional two month registration study of consecutive recipients of reimbursable peptic ulcer medication in a convenience sample of 31 volunteer community pharmacists (a 0.5% sample of Belgian community pharmacies).

Methods — Data from a simple, self‐administered (with assistance from the pharmacist) questionnaire of two pages were used to classify patients in one of four patterns of therapy (attack therapy, relapse therapy, maintenance therapy for 9 months, maintenance therapy longer than 9 months) and to determine the average consumption of medication packages within each pattern. The number of patients using reimbursable peptic ulcer medication over one year was estimated from these observational data and from the annual sales volume with a theoretical model.

Results — The questionnaire was completed by 432 of 481 elegible patients (an 89.9% response rate) in 27 participating pharmacies. Ninety‐two per cent of the patients had requested or had obtained reimbursement; 74% had at least one EDG in the past 12 months (1/3 combined with at least one X‐ray). Only nine patients of the small subgroup of 34 patients without reimbursement had undergone diagnostic examinations.

Discussion — The study of complex utilization patterns with a simplified model provides a rough estimation of the annual number of medication users.

Conclusions — In Belgium, a country with strict reimbursement control, mainly based on EGD performed by medical specialists, the annual prevalence of patients using reimbursable peptic ulcer medication is estimated at 30.5 patients/1000 inhabitants/ year. In this country, there is a high utilization of EGD, a high rate of 9 months maintenance therapy and some evidence for channelling of omeprazole. Further longitudinal follow up and comparison with different reimbursement systems in other countries is needed to evaluate the cost‐effectiveness and the impact of different regulatory approaches to reimbursement regulation on medication utilization.
A study of the utilization of non‐steroidal anti‐inflammatory drugs using a pharmacy‐based approach
Authors: Sift Rosemary , van Staa Tjeerd‐Pieter , Abenhaim Lucien , Ebner Daniel
Published: October 2006

The extent of compliance and drug exposure characteristics among NSAID users has not been extensively studied. We measured drug compliance in patients who obtained a NSAID in one of four German pharmacies, by an interview four weeks later.

The study population consisted of 526 persons with an average age of 57 years, and two‐thirds of the participants were women. We observed that only half of the patients had followed the recommended dosage regimen for the NSAID. Persons with complaints lasting three months or less were more likely to be compliant than chronically ill patients (OR = 5.0, 95 per cent CI: 3.0–8.2).

We concluded that this heterogeneity in drug utilization must be considered in the design of observational studies.
Incidence of symptomatic liver function abnormalities in a cohort of NSAID users
Authors: Lanza Lee L. , Walker Alexander M. , Bortnichak Edward A. , Gause Douglas O. , Dreyer Nancy A.
Published: October 2006

Background — A small number of published reports have provided estimates of incidence rates of symptomatic liver dysfunction in NSAID users, and most information has pertained to cases admitted to the hospital.

Methods — We studied members of a health maintenance organization who were age 20 to 64 years in 1989–1991. Beginning with health insurance claims data for over 68,000 users of NSAIDs, and obtaining abstracts of medical records of potential cases, we ascertained the frequency of liver function abnormalities, including only cases with documented symptoms treated either as outpatients or hospital inpatients.

Results — Overall, symptomatic liver dysfunction was rare, with 25 cases confirmed in the cohort of 68,028 people (0.37 cases per 1000 users of NSAIDs). For people who received a prescription NSAID in the previous six months, the crude incidence rate was 24 cases in 46,636 person‐years, or 0.51 per 1000 person‐years. For people who did not have a prescription NSAID in the previous six months, the crude incidence rate was 1 case in 13,303 person‐years, or 0.075 per 1000 person‐years. Of the 25 confirmed cases, 19 (76%) had alanine aminotransferase and/or aspartate aminotransferase at least 1.5 times the upper limit of normal values; the remaining six had abnormal results but of lesser magnitude. In five cases (20%) physician's notes document that a diagnosis of drug‐induced hepatic dysfunction was considered. Only 3 (12%) of the 25 cases were admitted to the hospital.

Conclusion — Although symptomatic liver dysfunction was relatively more frequent during the six months following NSAID use than at later times, the overall risk was low. Given the limitations of the available data, the apparent association with NSAID use may be confounded by other causes of liver dysfunction that could not be fully evaluated, such as other hepatotoxic medications, viral infections, or other medical conditions.
Absorption of Ionizable Drugs: Nonlinear Dependence on log P, pKa and pH ‐ Quantitative Relationships
Authors: Schaper Klaus‐Jürgen
Published: October 2006

Observed rates of absorption of drugs by passive diffusion through lipid membranes depend on certain physicochemical properties of the drug being absorbed and of the lipid barrier to be penetrated. By combining the pH partition theory, the unstirred layer hypothesis, and LFE considerations several model equations were derived. Within congeneric series of acidic or basic compounds these equations allow one to quantitatively describe the nonlinear dependence of the rate of absorption on lipophilicity and degree of ionization as well as to explain the observation of pH shifts in pH absorption profiles of drugs. Generally an excellent fit of the equations to observed rate constants for several classes of compounds was obtained. Furthermore some indications are presented that absorption rates are influenced by aqueous as well as by lipid stagnant diffusion layers adjacent to the aqueous/lipid interface.
BC(DEF) Coordinates 3. Their Acquisition from Physical Property Data
Authors: Cramer Richard D.
Published: October 2006

Newly derived property equations correlate BC(DEF) coordinates with calculated molar volume and refractivity and partitioning between water and six organic solvents. A new method is described for obtaining the BC(DEF) coordinates of a molecule from available physical property data. Its application to 500 compounds indicates that the BC(DEF) intercorrelation describes the properties of large and polar molecules, such as drugs, almost as well as those of simpler molecules. The effects of an erroneous physical property value on calculated BC(DEF) coordinates are described.
Relationship between Polarographic Adsorption Data and Hydrophobicity
Authors: Kühne Ronald , Franke Rainer , Dittrich Jürgen , Kretschmer Erhard
Published: October 2006

Gibbs free energies of adsorption of hydrophobic solutes at the dropping mercury electrode at zero potential and of partitioning in the system octanol/water are shown to be correlated for a number of compounds. It is suggested that polarographic adsorption data may serve as hydrophobicity parameters in QSAR work.
2n‐Factorial Schemes in Drug Design Extensions Increasing Versatility
Authors: Austel Voikhard
Published: October 2006

Several extensions of 2n‐factorial series design are reported. These extensions comprise rotation of the factorial schemes as well as “axial” schemes. Thereby factorial series design becomes more flexible so that synthetic accessibility can be better accounted for. By combining 2n‐factorial schemes with axial schemes one can satisfy needs for larger numbers of samples which are required e.g. for deriving quantitative structure‐activity‐relationships or for deciding upon further examination of structural fields. The new schemes can be applied manually as well as in connection with pattern recognition techniques.
Some Critical Remarks Concerning the Inductive Parameter σI Part I: Aliphatic Amines
Authors: Bijloo Greetje J. , Rekker Roelof F.
Published: October 2006

Correlation analysis was applied to a series of pKa values of 135 primary, secondary and tertiary aliphatic amines and included 57 alkyl substituted and 78 nonalkyl substituted structures.

It could be established that the σI data set in its latest version as proposed by Charton is very useful in practice, provided the small σI values for alkylgroups are replaced by zero throughout.
Simplified C‐13 NMR Parameters Related to the Carcinogenic Potency of Polycyclic Aromatic Hydrocarbons
Authors: Nordén Bo , Edlund Ulf , Johnels Dan , Wold Svante
Published: October 2006

Eleven polycyclic aromatic hydrocarbons (PAH) with known carcinogenic activity have been analyzed using a partial least squares (PLS) method. The analysis result using reduced C‐13 NMR parameters of protonbearing and non‐protonbearing carbons (chemical shift mean, variance, skewness and kurtosis) against the carcinogenic activity is compared with a similar analysis using 23 theoretical and measured variables. Similar structure‐activity trends were indicated in the two analyses, showing that C‐13 NMR parameters contain useful information.
Prediction of New Leads from a Distance Geometry Binding Site Model
Authors: Crippen Gordon M.
Published: October 2006

In a previous study, we derived a 9 point model of the binding site of S. faecium dihydrofolate reductase, given only the binding data for a set of 68 quinazoline inhibitors. We have now used this model to search for novel chemical classes of inhibitors with comparable predicted activity. The computer algorithm consults a library of ring systems and other molecular fragments of known structure and fits the most likely of these into the site, making chemical modifications where appropriate. The search has located diaminopteridines with calculated activity comparable to that of the best quinazolines for which the site was constructed. In addition, the search algorithm's unfettered imagination proposes much more bizarre candidates, such as a benzoxazoline‐2‐one dimer. Our present purpose is not to claim we have performed an exhaustive search for all possible antifolates, but rather to outline how the calculations are done and to demonstrate that these preliminary results are reasonable.
Rationalisations among Heterocyclic Partition Coefficients Part 2: The Azines
Authors: Lewis Susan J. , Mirrlees Margaret S. , Taylor Peter J.
Published: October 2006

Azine π‐values are discussed in terms of Δπ, which is the difference in π‐value from that expected for benzene. It is shown that Δπ is close to zero for alkyl and most halogen groups, but for polar substituents capable of hydrogen bonding may be as high as ca. 1.6. Except for peri‐positions, these Δπ‐values may be correlated by a set of equations specific for different types of substituent position and containing terms which separately parameterise proton donor and acceptor ability. The rationale behind this treatment is justified in terms of the nature of the octanol‐water partitioning process and the manner in which electronic effects are expected to operate, in this context and that of the individual molecule. These equations will correlate those compounds for which they are expected to be applicable to Δ logP ± 0.12. Other topics discussed include: reasons for deviations among “irregular” substituents; the special problems of peri‐positions; multi‐substitution; and some consequences of this analysis for other types of compound.
Rational Selection of Test Series for QSAR‐Analysis
Authors: Schaper Klaus‐Jürgen
Published: October 2006

A method for the rational selection of test series with low collinearities of molecular descriptors and high data variance is presented (RVS method). This method selects analogs on the basis of a selection criterium which combines multiple correlation coefficients R, relative parameter variances V and the synthetic feasibility S of test series. Special flexibility of the method is provided by weighting factors which are adapted until a satisfactory series is obtained. Examples of the application of the RVS method are given, and the results are compared with results from other selection techniques.
Computer‐Assisted Prediction of Bioactive Compounds Based on the Hansch‐Fujita Analysis
Authors: Takayama Chiyozo , Miyashita Yoshikatsu , Sasaki Shin‐Ichi , Yoshida Mototsugu
Published: October 2006

Computer programs called PREHAC1 and PREHAC2, which aid in the impartial selection of substituents for the synthesis of highly bioactive compounds among congeners based on the Hansch‐Fujita analysis, were developed. The PREHAC1 and 2 programs are for aliphatic and aromatic monosubstituted derivatives and for aromatic disubstituted derivatives, respectively. Thirteen sets of physicochemical parameter values of 408 useful substituents were previously input into a data file as Master Data. PREHAC programs are activated by the input of the coefficients and intercept of the QSAR equation with the corresponding parameter codes, the information on the number of the substituents to be printed out, etc., and then Master Data is searched. Calculated activity values are ranked in descending order and the high‐ranking substituents are printed out according to the specified number. An example is presented to illustrate the programs.
Some Critical Remarks Concerning the Inductive Parameter σI Part II: Aliphatic Carboxylic Acids
Authors: Bijloo Greetje J. , Rekker Roelof F.
Published: October 2006

Correlation analysis was applied to pKa values of a series of 91 aliphatic carboxylic acids in order to obtain substantial evidence for a σI = 0.00 parametrization of alkyl groups. A very good correlation with r = 0.998 could be established. The results confirm our findings with aliphatic amines as discussed in a previous paper in this series. Some apparent anomalies in the pKa values of amino‐substituted carboxylic acids, diamines and dicarboxylic acids will be treated.
Nonadditivity of 1‐Octanol/Water Partition Coefficients of Disubstituted Benzenes: An Explanation and Its Consideration in Log P Estimation
Authors: Dunn W. J. , Johansson E. , Wold S.
Published: October 2006

Partition coefficient data (logP) for 121 benzene derivatives from the 1‐octanol/water system were subjected to principal components analysis (PCA). The statistical analysis shows an interaction between substituents on a benzene nucleus that affects logP values in a measurable way. The interaction can be modelled by Hammet's ϕ, and is probably due to differences in solvent‐solute hydrogen bonding in the two phases, 1‐octanol and water. The significance of these results for the prediction of logP values is discussed.
Estimation of Substituent Group Electronic Influence from Molecular Connectivity Delta Values
Authors: Kier Lemont B. , Hall Lowell H.
Published: October 2006

An estimation of the relative electronegativities of atoms in their valence state is presented, based upon counts of valence and sigma electrons other than those bonding with hydrogen. This Kier/Hall valence state electronegativity is linearly related to the Mulliken‐Jaffe' electronegativity. This estimation is extended to include group electronegativities. Groups, treated as benzene ring substituents, are evaluated in terms of their electronic influence on a benzene ring. This influence is partitioned into electronegativity equalization effects through sigma and pi orbital interactions plus lone pair orbital pressure on the ring pi system. A simple summation of these three influences, calculated very easily from structure, is found to be well correlated with the Hammett values for 25 common substituents for both para and meta position values. The present treatment deals with first row elements.
Correlation and Estimation of Aqueous Solubilities of Polycyclic Aromatic Hydrocarbons
Authors: Baker Ronald J. , Acree William E. , Tsai Chun‐Che
Published: October 2006

Quantitative structure‐activity relationships have been studied for the aqueous solubilities of 25 polycyclic hydrocarbons (PAH) at 25°C. Multiple regression correlations are reported between aqueous solubility (X) and molecular size descriptor (molecular surface area, molecular volume or molecular weight), melting point temperature (MP), and a newly‐defined molecular symmetry and structure descriptor (R · rd). A generalized correlation takes the form of log X = a0 + a1 (Molecular size descriptor) + a2 (MP‐25) + a3 R · rd in which ai refers to the ith regression coefficient, R is a molecular redundancy index and rd is the summation of interatomic distances in a molecule. These correlations enable the aqueous solubility to be estimated from melting point temperatures and structural information. The 3‐parameter expressions best predict the experimental solubilities and are superior to the 2‐parameter expressions (a3 = 0) suggested in the past. For the majority of compounds considered, agreement between observed and estimated solubility is quite good. The correlations may also be useful in screening experimental solubility data for which serious discrepancies exist in the literature.
Correlation Between Affinity Towards β‐Adrenergic Receptors and Electrostatic Potentials of Phenylethylamine Derivatives
Authors: Šolmajer Tomaž , Hodošček Milan , Hadži Dušan , Lukovits Istvan
Published: October 2006

Molecular electrostatic potentials (MEP) were computed from ab‐initio wave functions for twelve 3,4‐substituent combinations which appear in 52 phenylethylamine derivatives active as ligands to β‐adrenergic receptors. The values of MEP (VA) at a defined point were used as independent variables in multiple regression analysis to derive equations connecting affinities and intrinsic activities of the ligands as determined by Bilezikian et al. [2]. The side chain potentials (VN) computed previously [1] were also used as independent variables. The significance of the electrostatic forces in determining both the affinities and the intrinsic activities is demonstrated.
Selective Antimetastatic Triazenes: A Quantitative Approach
Authors: Lassiani Lucia , Nisi Carlo , Giraldi Tullio , Sava Gianni , Cuman Riccardo
Published: October 2006

Quantitative structure‐activity relationships have been formulated examining a series of para substituted phenyldimethyl‐triazenes for their differential effects on the subcutaneous growth of Lewis lung carcinoma and on the formation of its pulmonary metastases in mice. When the data were expressed as log 1/C, the QSAR obtained for toxicity as well as for the effects on primary tumor and metastases showed a similar dependency on the physicochemical constant chosen. Since drug potency expressed as log 1/C is obtained at the expenses of different toxicities for the tumor bearing host, drug activity was also expressed as the effect obtained at maximum tolerated drug dosages (log T/C). The QSAR resulting from the expression of the data as log T/C showed a dissociation between the effects on primary tumor as compared with those on metastases, quantitatively evidencing the observed selective antimetastatic properties of these substances. Aryldimethyltriazenes more active against metastases could be theoretically obtained for values of logP outside the range presently considered.
PCB and Dioxin Binding to Cytosol Receptors: A Theoretical Model Based on Molecular Parameters
Authors: McKinney J. D. , Long G. A. , Pedersen L.
Published: October 2006

A model based on dispersion interactions is developed to interpret the cytosol‐PCB binding data of Bandiera et al. [1]. The essential parameters in the model are the PCB polarizability and the receptor to PCB separation distance. An approximate linear free energy relationship is derived in terms of these parameters. It is suggested that the oxygens in PCDDs may lead to stabilizing hydrogen bonding with the receptor; this reasonably accounts for the unusual binding affinity of certain PCDDs. Finally, a derivation of [EC50] for the PCBs displacement reaction based solely on equilibrium theory is shown to lead to an expression consistent with the experimental correlation if the displaced TCDD aggregates with the solution PCB or any other cytosol component.
Some Critical Remarks Concerning the Inductive Parameter σI Part IV: Parametrization of the Ortho Effect in Anilines and Pyridines
Authors: Bijloo Greetje J. , Rekker Roelof F.
Published: October 2006

Correlation analysis was applied to pKa values of a series of 70 anilines and a series of 44 pyridines in order to obtain more evidence for the correct rules of parametrization of ortho‐substituents as suggested by Fujita and Nishioka in 1976. The results confirm the findings reported in the third article in this series.

For the inductive effect parameter σI ‐ used in this type of equations ‐ again a σI = 0.00 parametrization for alkyl groups is applied. The results are in agreement with the findings for aliphatic amines and aliphatic carboxylic acids as discussed in previous papers in this series.

Good correlations with r = 0.9970 for anilines and r = 0.9926 for pyridines could be found.
Quantitative description of α2‐adrenergic potency in terms of receptor affinity and intrinsic activity
Authors: De Jonge Adriaan , Timmermans Pieter B. M. W. M. , van Zwieten Pieter A.
Published: October 2006

Attempts were made to describe quantitatively peripheral as well as central α2‐adrenergic potency as a linear combination of affinity for and intrinsic activity at α2‐adrenoceptors within a series of 16 α‐adrenergic agonists, of the imidazolidine type. Central α2‐adrenergic potency was quantified as the ability of the compounds to decrease mean arterial pressure of pentobarbitone‐anaesthetized normotensive rats by 20% following intravenous administration. Peripheral α2‐adrenergic potency was measured in pithed normotensive rats as the inhibitory activity on stimulation‐induced tachycardia. Central and peripheral α2‐adrenergic potencies were linearly correlated upon including logP′ (octanol/buffer partition coefficient, pH 7.4, 37°C), showing the different accessibility of the two α2‐adrenoceptor populations. Affinity of the imidazolidines for α2‐adrenoceptors was determined by the displacement of 3H‐clonidine from its specific binding sites in membranes from rat brain. The linear relationships between peripheral and central α2‐adrenergic potency on the one hand and affinity for α2‐adrenoceptors with or without the addition of logP′ on the other hand were significantly improved by incorporation of a term standing for receptor activation, i.e. intrinsic activity at α2‐adrenoceptors. The results support current concepts in receptor theory stating that only when both efficacy and affinity are known, can the activity of the agonist be predicted with reasonable certainty.
The Chemical Shift of the Alpha Carbon in Amino‐Acids as a Parameter for QSAR Studies of Oligopeptides
Authors: Fauchère Jean‐Luc , Lauterwein Jürgen
Published: October 2006

The 13C‐NMR chemical shift δH of the α‐carbon in amino‐acids is proposed as a new parameter for QSAR studies of biologically active oligopeptides. δH which is known for common amino‐acids, is mainly a measure of the electronic shielding of the α‐carbon. In the aliphatic series, it is computable by empirical rules and very sensitive to β‐branching.

In this study, δH is shown to describe accurately as a single continuous parameter the variations of the biological activity of angiotensin II, when the residue in its position 5 is varied.
Quantitative Structure‐Activity Relationships in the Displacement of the Dihydrosafrole Metabolite‐Cytochrome P‐450 Complex
Authors: Murray Michael , Marcus Craig B. , Wilkinson Christopher F.
Published: October 2006

Twenty‐one 2‐substituted benzimidazoles and two naphtho‐[2,3‐d]‐imidazoles were evaluated for their in vitro ability to displace the dihydrosafrole metabolite from its complex with microsomal cytochrome P‐450. Several proved to be extremely effective displacers, the most active being 2‐(2′,3′‐dichloro‐phenoxy)methylbenzimidazole. Quantitative structure‐activity analyses (QSAR) using the descriptors log P (partition coefficient) and MR2 (molar refractivity) established that up to eighty‐eight percent of the variance in the displacement data could be accounted for in terms of the MR2 of the 2‐substituent of the benzimidazole ring. Other QSAR analyses involving molecular connectivity indices (χ) supported the assertion that steric parameters are of primary importance in the displacement process.
Hansch Approach and Kinetics of Drug Activities
Authors: Baláž Štefan , Šturdík Ernest , Tichý Miloň
Published: October 2006

The relations between isotoxic concentration, the disposition function (the latter relating the concentration of a drug in the receptor region to the initial external concentration) as well as equilibrium and rate characteristics of the drug‐receptor interaction are derived using mass action law for three types of the drug‐receptor interactions (noncovalent interaction, covalent bond, noncovalent interaction followed by covalent bond formation). The results are shown to be consistent with the Hansch equation in most cases, exceptions being discussed.
Shape Indexes of Orders One and Three from Molecular Graphs
Authors: Kier Lemont B.
Published: October 2006

The concept of a shape index derived from the molecular graph previously described, has been expanded to include two additional indexes derived from counts of one‐path and three‐path fragments. Algorithms have been derived using the original model of defining two limiting structures and quantitating any intermediate structural shape relative to these two. Counts of one‐path fragments and three‐path fragments lead to shape indexes of 1K and 3K. The information encoded in each has been extracted in terms of shape attributes. The concept that molecular shape can be viewed as a sum of isolated attributes is put forward and a partial series is presented based on the indexes developed to date. Several examples of QSAR applications are presented where two of these shape indexes are revealed to encode enough information to give good correlations.
A Comparison of Some Measures for the Determination of Inter‐Molecular Structural Similarity Measures of Inter‐Molecular Structural Similarity
Authors: Willett Peter , Winterman Vivienne
Published: October 2006

Six weighting schemes and six similarity coefficients have been used in a systematic comparison of measures for the determination of inter‐molecular structural similarity. The effectiveness of the measures for molecular property prediction was tested using sixteen small sets of compounds for which property data was available. The comparison suggests that the weighting of fragments by their frequency of occurrence in molecules is often useful, but that there are only small differences in performance between the similarity coefficients tested.
Comparison Between X‐Ray Crystallographic Data and Physicochemical Parameters with Respect to Their Information about the Calcium Channel Antagonist Activity of 4‐Phenyl‐1,4‐dihydropyridines
Authors: Berntsson Peder , Wold Svante
Published: October 2006

Triggle et al. [1] investigated a number of 4‐phenyl‐1,4‐dihydropyridines with respect to their X‐ray structure and the relation between a selection of six X‐ray variables and the calcium channel antagonist activity. We here extend their structure‐activity relation to include all fourteen X‐ray data given in ref. [1]. In addition, we develop an alternative QSAR based on a conventional physicochemical parametrization of the phenyl ring.

A PLS model based on the physicochemical data separates active from inactive compounds, in contrast to the model based on the X‐ray data. Both PLS models with physicochemical data and with X‐ray data adequately predict the quantitative variation in activity for the active compounds.
QSAR of 1,4‐Naphthoquinones as Inhibitors of Photosystem II Electron Transport
Authors: Oettmeier Walter , Dierig Christoph , Masson Klaus
Published: October 2006

42 1,4‐naphthoquinones with substituents in the 2‐ and 3‐position were examined for their inhibitory activity on photosynthetic electron transport through photosystem II. The best ones were active in concentrations in the μM range or less. A QSAR was established, using the sum of the σ‐Hammett parameters and Taft's steric E parameter for the substituents in the 2‐ and 3‐position. The QSAR could be improved, if instead of the E, the STERIMOL parameters L (for the 2‐position) and B3 and B4 (for the 3‐position) were applied. QSAR for different types of photosystem I1 inhibitors (urea, phenolic, quinoid) were compared. The differences in between them do support the idea of nonidentical though possibly overlapping binding sites at the reaction center complex of photosystem II.
Polychlorinated Dibenzofuran (PCDF) Binding to the Ah Receptor(s) and Associated Enzyme Induction. Theoretical Model Based on Molecular Parameters
Authors: Long G. , McKinney J. , Pedersen L.
Published: October 2006

A model based on dispersion interactions previously developed to interpret cytosol receptor (Ah receptor)‐PCB binding data is applied to PCDFs and extended to interpret associated monooxygenase induction potencies (AHH and EROD activities). The essential parameters in the model are the PCDF polarizability and the PCDF to receptor separation distance. An empirical relationship based on solvent accessible polar surface area is used to estimate the solvation contribution to the binding free energy. Considerations of PCDF solubility and desolvation energy in the assay are suggested as possible refinements of the model which may improve predictive ability. PCDF binding and enzyme induction potencies are seen to increase with increasing polarizability which is controlled to a large extent by the number of chlorine substituents.
Effect of Substituents at Position 2 on the 1H NMR Chemical Shift of Protons of 2‐Methylbenzimidazole Derivatives
Authors: Nasal Antoni , Kaliszan Roman , Kuźmierkiewicz Wojciech
Published: October 2006

For a series of 17 newly synthesized 2‐methylbenzimidazole derivatives a significant correlation was found between the 1H NMR chemical shift (in ppm) of hydrogens at position 2 and the sum of the inductive electronic constants of the substituents attached to this position. The substituent attached to the nitrogen atom of the imidazole moiety has a significantly less pronounced effect on the substituent in 2‐position hydrogen chemical shift.
A Molecular Modeling Based upon an X‐Ray Crystal Structure: The Enzyme‐Ligand Complexes between Porcine Pancreatic Elastase and Acetyl‐Alanine‐Alanine(Glycine)‐Alanine
Authors: Fujita Tadao
Published: October 2006

Molecular models of the complexes between porcine pancreatic elastase (PPE, EC 3.4.4.7), and acetyl‐alanine‐alanine‐alanine (AAA) and acetyl‐alanine‐glycine‐alanine (AGA) are constructed by means of molecular mechanics (MM) calculation, based upon the previously reported X‐ray structure between PPE and acetyl‐alanine‐proline‐alanine (APA). The MM calculations have been carried out in a 12 Å scoop region from the alpha carbon atom of the second residue of the ligand. During the energy minimization, bond distance, bond angles, improper dihedral angles and dihedral angles are relaxed without a constrain. The resulting structures suggested that the ligands, AAA and AGA could be bound to the active site of PPE in the similar binding arrangements which had been shown in the X‐ray structure between PPE and APA. The stronger inhibition of APA in vivo may be caused by the structural stability to enzymatic hydrolysis.
A Quantitative Stereo‐Structure Activity Relationship Analysis of the Binding of Promiscuous Chiral Ligands to Different Receptors
Authors: Lehmann Pedro A. F.
Published: October 2006

Many important compounds of pharmacological interest bind with high affinities to more than one receptor (promiscuous ligands). If in addition they are chiral, the stereoselectivity each receptor displays towards pairs of such stereoisomeric ligands is of theoretical and practical importance.

The recent literature was culled for data sets in which affinity values were provided for both isomers of a stereoisomeric ligand at three or more receptors or receptor subtypes. Their multiple eudismic‐affinity analysis showed that in general stereoisomeric potency ratios increase as a function of affinity, thus validating an extension of Pfeiffer's Rule.

The increase in stereoselectivity per unit increase in eutomer affinity (M.E.A.Q) tends towards 0.5 with most values lying between 0.3 and 0.7. A simple explanation is offered for this at the molecular level in which the M.E.A.Q. of 0.5 is interpreted in terms of the transfer of a methylene group from a lipidic to an aqueous environment.

The implications for rational drug design and receptor speciation of this generalization are analyzed and it is suggested that quantitative stereo‐structure activity relationships (QSSAR) must be made an integral part of QSAR.