Biomedical subjects

H Kohn

Publications and source records attributed to H Kohn.

At least 37 records · Page 2Linked to original sources

PubMed1996

The antibiotic bicyclomycin affects the secondary RNA binding site of Escherichia coli transcription termination factor Rho.

The interaction of Rho and the antibiotic bicyclomycin was probed using in vitro transcription termination reactions, poly(C) binding assays, limited tryptic digestions, and the bicyclomycin inhibition kinetics of ATPase activity in the presence of poly(dC) and ribo(C)10. The approximate I50 value for the bicyclomycin inhibition of transcription termination at Rho-dependent sites within a modified trp operon template was 5 microM. At antibiotic concentrations near the I50 value, bicyclomycin inhibition of Rho-dependent transcripts was accompanied by the appearance of a new set of transcripts whose size was midway between the Rho-dependent transcripts and the readthrough transcripts. Bicyclomycin did not inhibit poly(C) binding to Rho. In the presence of poly(dC), bicyclomycin showed a reversible mixed inhibition of the ribo(C)10-stimulated ATPase activity. The extrapolated Ki for bicyclomycin was 2.8 microM without ribo(C)10 and increased to 26 microM in the presence of ribo(C)10. Correspondingly, the Km(app) for ribo(C)10 without bicyclomycin was 0.8 microM and with bicyclomycin was 5 microM at infinite inhibitor concentration. The data suggested that the antibiotic binds to Rho, influencing the secondary RNA binding (tracking) site on Rho and slows the tracking of Rho toward the bound RNA polymerase.

Adenosine Triphosphatases↗

PubMed1996

Synthesis and anticonvulsant activities of N-Benzyl-2-acetamidopropionamide derivatives.

Studies have demonstrated that 2-substituted N-benzyl-2-acetamidoacetamides (2) are potent anticonvulsants. A recent investigation has led to the hypothesis that an important structural feature in 2 for maximal anticonvulsant activity is the placement of a small, substituted heteroatom moiety one atom from the C(2) site. This paper validates this hypothesis. Twelve derivatives of N-benzyl-2-acetamidopropionamide have been prepared in which six different heteroatom substituents (chloro, bromo, iodo, oxygen, nitrogen, and sulfur) were incorporated at the C(3) site. Highly potent activities were observed for the two oxygen-substituted derivatives, N-benzyl-2-acetamido-3-methoxypropionamide (18) and N-benzyl-2-acetamido-3-ethoxypropionamide (19). The ED50 values in mice following intraperitoneal (i.p.) dosing for the maximal electroshock-induced seizure test for 18 and 19 were 8.3 and 17.3 mg/kg, respectively. These values compared favorably to the ED50 value found for phenytoin (ED50 = 6.5 mg/kg). Comparable activities were observed for 18 and 19 upon oral (p.o.) administration to rats (18, ED50 = 3.9 mg/kg; 19, ED50 = 19 mg/kg; phenytoin, ED50 = 23 mg/kg). Evaluation of the individual stereoisomers for 18 demonstrated that the principal anticonvulsant activity resided in the (R)-stereoisomer. The ED50 value for (R)-18 was 4.5 mg/kg, and the ED50 for (S)-18 exceeded 100 mg/kg. This difference in activity for the two stereochemical isomers surpassed comparable values for other members within this class of compounds. The protective indices (PI = TD50/ED50) (where TD50 represents a neurotoxic dose impairing rotorod performance) for (R)-18 in mice (i.p.) and in rats (p.o.) were 6.0 and > 130, respectively.

Acetamides↗

PubMed1996

The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent.

Recent studies have demonstrated that substituted N-benzyl 2-acetamidoacetamides provide significant protection against maximal electroshock (MES)-induced seizures in mice and rats. In this study, we investigated whether the 2-acetamido moiety was necessary for anticonvulsant activity. Ten derivatives of the known anticonvulsant, N-benzyl 2-acetamido-2-phenyl-acetamide were prepared in which the 2-acetamido group was replaced by hydrogen, methyl, oxygen, and halogen substituents. Evaluation of these compounds in the MES-induced seizure test demonstrated that both the hydroxy and the methexy compounds provided full protection against MES-induced seizures in mice given ip at 100 mg/kg. Moreover, evaluation of the individual stereoisomers for the hydroxy compound showed that the principal activity resided in the (R)-isomer. These findings demonstrated that the 2-acetamido substituent is important but not obligatory for the prevention of MES-induced seizures. Further supporting evidence was provided by comparing the pharmacological activities of N-benzyl 2,3-dimethoxypropionamide with N-benzyl 2-acetamido-3-methoxypropionamide. The ED50 value for the former in the MES test was 30 mg/kg (i.p.), which compared favorably with phenobarbital (ED50 = 22 mg/kg), but the ED50 value for N-benzyl 2-acetamido-3-methoxypropionamide was 8.3 mg/kg.

Acetamides↗

PubMed1996

Prevalence of oral leukoplakia in 1000 Berliners.

OBJECTIVE: The aim of this study was to determine the prevalence of oral leukoplakia and other oral white lesions in an urban population of non-referred patients to a department of oral surgery in the city of Berlin. DESIGN: A total of 1000 patients over the age of 16 were evaluated for oral leukoplakia and other oral white lesions. Age, sex, and smoking as well as alcohol habits were recorded. RESULTS: Of 506 men (50.6%) and 494 women (49.4%), 0.9% showed oral leukoplakia. Men were more frequently affected (1.6%) than women (0.2%). Patients of older age groups were more frequently affected than younger patients. Other white oral lesions were recorded such as leukoedema (8.3%), smoker's palate (0.1%), frictional white lesions (2.6%) and lichen planus (0.6%) with equal distribution between men and women. CONCLUSION: The prevalence of oral leukoplakia in this limited group of urban patients was low, however comparable to that of other neighbouring west European countries. Association with tobacco and alcohol consumption was demonstrated as in most other studies.

Adolescent↗

PubMed1995

Bicyclomycin and dihydrobicyclomycin inhibition kinetics of Escherichia coli rho-dependent transcription termination factor ATPase activity.

The primary site of action for the novel antibiotic, bicyclomycin, in Escherichia coli has been identified to be the rho transcription termination factor. The inhibition of rho poly(C)-stimulated hydrolysis of ATP by bicyclomycin has been found to proceed by a non-competitive, reversible pathway with respect to ATP (Ki = 20 microM). Inhibition by dihydrobicyclomycin was similar (Ki = 75 microM). No change in the inhibitory properties of the antibiotic was observed under the assay conditions with the two rho mutants, Cys202Gly and Cys202Ser, indicating that Cys-202 does not affect drug binding to rho. Prolonged incubation (32 degrees C, 12 h) of wild-type rho with bicyclomycin (20 mM) led to protein degradation and a slow, permanent loss of rho ATPase activity after dialysis. Evidence was obtained that trace amounts of proteases present with bicyclomycin were responsible for the observed protein degradation. Treatment of wild-type and mutant rho proteins with purified bicyclomycin (25 mM) led to approximately 80% loss of ATPase activity after dialysis with no apparent loss of protein. However, a reduction of the electrophoretic mobility of the bicyclomycin-treated rho versus wild-type rho was seen. Addition of either ATP or poly(C) to wild-type rho led to partial protection against bicyclomycin inactivation, while inclusion of both ligands provided near complete protection against inactivation. The observed loss of ATPase activity upon prolonged incubation of rho with excess purified bicyclomycin is attributed to the covalent modification of the protein by the antibiotic at multiple sites.

Adenosine Triphosphatases↗

PubMed1995

Structural requirements for mitomycin C DNA bonding.

Information of the specific structure of the activated mitomycin species leading to selective DNA bonding has been secured by determining the bonding sequence selectivities of modified mitomycins in which the identity, spatial orientation, and state of unsaturation of the C-9 and C-9a substituents in the mitomycin were varied. Both mitomycin-9a-sulfonate (8) and mitomycin D (9) gave DNA bonding profiles comparable to those obtained for mitomycin C (1) under reductive conditions, indicating that neither the stereochemistry of the C-9 and C-9a substituents nor the identity of the leaving group at C-9a influenced the site(s) of DNA bonding. These results indicated that aromatization of the dihydropyrrole ring in mitomycin C precedes DNA binding and mitomycin C-1 bonding.

Base Sequence↗

PubMed1994

Synthesis and anticonvulsant activities of alpha-acetamido-N-benzylacetamide derivatives containing an electron-deficient alpha-heteroaromatic substituent.

Recent studies have demonstrated that C(alpha)-substituted alpha-acetamido-N-benzylacetamides displayed excellent anticonvulsant activities in mice. Analysis of the structure-activity relationship for this series of compounds has shown that placement of small, electron-rich aromatic and heteroaromatic groups at the C(alpha) site led to pronounced protection against MES-induced seizures. In this note, synthetic protocols are reported for the preparation of three novel nonnaturally occurring electron-deficient C(alpha)-aza aromatic alpha-acetamido-N-benzylacetamides (i.e., pyrid-2-yl (11), pyrazin-2-yl (12), pyrimid-2-yl (13)). Expedient syntheses for 12 and 13 were developed using a phase-transfer, nucleophilic aromatic substitution process. All three adducts exhibited potencies comparable to or greater than phenytoin in the MES test (mice, ip). These findings required us to modify in part the previously proposed structure-activity relationship for this class of anticonvulsants.

Acetamides↗

PubMed1994

Anticonvulsant properties of N-substituted alpha,alpha-diamino acid derivatives.

Recent studies have demonstrated that functionalized alpha,alpha-diamino acids (1) display excellent activity when evaluated in the maximal electroshock seizure (MES) test in mice. The synthesis and pharmacological evaluation of 14 select analogues within this series of compounds are detailed. Included in this survey were 10 N-acyl derivatives in which the basic C(alpha) N-group in 1 was replaced by a neutral N-substituent and four dipeptides where the amino acid fusion point was the alpha-carbon site. N-Acylation of 1 led to decreased anticonvulsant activity. The importance of these findings in relation to the requirements of the C(alpha) substituent for anticonvulsant activity in 1 are briefly discussed.

Amino Acids, Diamino↗

PubMed1993

Synthesis and anticonvulsant activities of alpha-heterocyclic alpha-acetamido-N-benzylacetamide derivatives.

Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides (2) containing a five- and six-membered aromatic or heteroaromatic group appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded set of C(alpha)-heteroaromatic analogues of 2 have been prepared and evaluated. The observed findings extended the structure-activity relationships previously discerned for this novel class of anticonvulsants and have validated previous trends. The alpha-furan-2-yl (4), alpha-oxazol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylacetamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-depth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic requirements existed for maximal activity and revealed the outstanding activity of (R)-(-)-alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)aceta mide [(R)-30].

Acetamides↗

PubMed1993

Transcription termination factor rho: the site of bicyclomycin inhibition in Escherichia coli.

Bicyclomycin is a novel, commercially important antibiotic. Information concerning the site of bicyclomycin inhibition in Escherichia coli has been obtained by the production of bicyclomycin resistant mutants by UV irradiation. Selection by growth in the presence of bicyclomycin of a plasmid clone library generated from a highly resistant mutant in recipient antibiotic-sensitive host cells (E. coli strain W3350) has led to the characterization of three different plasmids that confer drug resistance, which contained the gene encoding the transcription termination factor, rho. These mutant rho genes contained single base changes at nucleotide positions 656, 796, and 1009. Preliminary mechanistic information has been obtained by monitoring the polyC-dependent ATPase activity of rho in the absence and presence of bicyclomycin and dihydrobicyclomycin. Addition of bicyclomycin to aqueous solutions containing rho and ATP led to a decrease in the release of inorganic phosphate with an I50 value of 60-70 microM bicyclomycin. This inhibition is comparable to the drug concentration needed to inhibit bacterial growth on plates. No loss of activity was observed when a similar concentration of dihydrobicyclomycin was used in place of bicyclomycin, while use of 10-fold higher concentrations of this derivative led to partial rho inhibition. PolyC-dependent ATPase activity from partially purified rho isolated from the mutant BCMr108 was not inhibited by bicyclomycin at concentrations (200 microM) found to completely inhibit wild-type rho. These cumulative findings are consistent with the notion that bicyclomycin expresses its activity by interfering with the polyC-dependent ATPase activity of rho.

Adenosine Triphosphatases↗

PubMed1992

A double blind, multicentre, placebo controlled trial of lornoxicam in patients with osteoarthritis of the hip and knee.

Lornoxicam is a new non-steroidal anti-inflammatory agent (NSAID) with a similar pharmacological profile to other oxicams and a potency 10 times greater than piroxicam. A multicentre, randomised, double blind, parallel group study was undertaken to compare the efficacy and tolerance of four weeks' treatment with lornoxicam (6 mg once daily, 4 mg twice daily, and 6 mg twice daily) and placebo in patients with osteoarthritis of the hip or knee. A dose related efficacy of lornoxicam was shown by the numbers of patients in each treatment group who withdrew from the trial owing to inadequate symptom relief (12/40 (30%) receiving placebo, 6/40 (15) receiving lornoxicam 6 mg daily, 4/40 (10%) receiving lornoxicam 8 mg daily, and none receiving lornoxicam 12 mg daily). This effect was confirmed by pain relief scores, which were significantly better than placebo during treatment with lornoxicam 8 mg and 12 mg daily, the effect of 12 mg daily being significantly superior to that of 8 mg daily. Similar results were obtained from functional status scores. Mean functional index (Lequesne) scores were significantly greater than placebo only at a daily dose of 12 mg lornoxicam. Lornoxicam was generally well tolerated, though some gastrointestinal side effects were seen as has been reported with other NSAIDs. Laboratory investigations showed no evidence of drug toxicity.

Administration, Oral↗

PubMed1991

Double-blind placebo-controlled comparison of the analgesic effects of single doses of lornoxicam and aspirin in patients with postoperative dental pain.

The pain experienced after third molar surgery was used as a model to evaluate the analgesic efficacy of a new non-steroidal anti-inflammatory drug, lornoxicam, in a Phase II study. One hundred and fifty fit, young adults participated in this randomised, single dose, double-blind, parallel group clinical study. Three doses of lornoxicam (2 mg, 4 mg, and 8 mg) were compared with aspirin 650 mg and placebo. Patients suffering from moderate to severe pain following surgery were monitored for up to 8 hours. All indices of efficacy showed similar results, all active treatments being associated with highly significant (P less than 0.0001) reductions in pain during the study period. Lornoxicam 8 mg demonstrated significant analgesic efficacy as compared with placebo. The two lower doses of lornoxicam and aspirin all showed apparent degrees of efficacy intermediate between that of placebo and lornoxicam 8 mg, although the trial proved to have inadequate power to show significant differences between these three treatments. Lornoxicam was very well tolerated at all three doses studied, with no adverse events definitely attributable to its administration.

Adolescent↗

PubMed1991

Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids.

Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).

Acetamides↗

PubMed1990

Anticonvulsant properties of 3-oxo- and 3-imino-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides.

Selectively substituted 3-oxo-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides (2, four examples), and 3-imino-4-substituted 1,2,5-thiadiazolidine 1,1-dioxides (3, eight examples) have been evaluated in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole seizure threshold (scMet), and rotorod (Tox) tests. These compounds can be considered as sulfonyl analogues of hydantoins (1). In those cases where comparison between 1 and 2 (or 1 and 3) was possible, replacement of the central carbonyl group in 1 by a sulfonyl moiety led to a significant reduction or abolition of the anticonvulsant activity.

Animals↗

PubMed1990

Preparation and anticonvulsant activity of a series of functionalized alpha-aromatic and alpha-heteroaromatic amino acids.

We recently reported the potent anticonvulsant activity of (R,S)-alpha-acetamido-N-benzyl-alpha-phenylacetamide (2b). Selectively substituted derivatives of this compound have now been prepared (23 examples) and evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. In several key cases, replacement of the alpha-phenyl substituent in 2b by a relatively small, electron-rich, heteroaromatic moiety led to a substantial improvement in the anticonvulsant potency of the drug candidate. The most active compounds were (R,S)-alpha-acetamido-N-benzyl-2-furanacetamide (2g) and (R,S)-alpha-acetamido-N-benzyl-2-pyrroleacetamide (2i). After ip administration, the MES ED50 values for 2g (10.3 mg/kg) and 2i (16.1 mg/kg) compared well with phenytoin (9.50 mg/kg). Evaluation of the two individual enantiomers of 2g demonstrated that the anticonvulsant activity resided in the R stereoisomer. The low ED50 value (3.3 mg/kg) for (R)-2g contributed to the large protective index (TD50/ED50) observed for this drug candidate, which approached that of phenytoin.

Amino Acids↗

PubMed1990

A risk-reduction nutrition course for adults.

This article details the development, delivery, and evaluation of a six-session nutrition course entitled "Eating Today for a Healthier Tomorrow." The course addressed nutrition practices associated with the reduction of risk for coronary heart disease, cancer, osteoporosis, and obesity. Teaching teams, consisting of an extension agent and a registered dietitian, were used in course delivery. A wide variety of printed and audiovisual teaching aids helped participants learn through discussion, goal setting, games, and food tasting. Evaluation components of the course included demographic and pre- and post-course food frequency information as well as an overall evaluation by each participant. Post-course evaluation data were collected at a reunion session held 2 months after course completion. One hundred forty-two of 195 participants (73%) completed the course and the evaluation. Three-fourths of the participants had a family history of at least one of the life-style diseases addressed by the course. The food frequency results indicated that participants made some significant changes in their food practices. They decreased the number of times they selected high-fat cheese, regular red meats, foods from the saturated fatty acid group, desserts, sodium-rich products, and tea/coffee (p less than .05), and they increased selection of low-fat dairy products (p less than .05). Further study is recommended to determine whether individuals maintain the dietary changes and how those changes affect others in the person's immediate environment.

Adult↗

PubMed1989

Mitomycin C analogues with a substituted hydrazine at position 7. Synthesis, spectral properties, and biological activity.

A select number of mitomycin C derivatives with a substituted hydrazine group at position 7 were synthesized and tested for antineoplastic activity by using an in vivo test with murine P388 leukemia. Several of the adducts displayed activity comparable to that of mitomycin C. The X-ray-determined crystal structure of one of the derivatives (3f) is reported.

Animals↗

PubMed1988

Marked stereospecificity in a new class of anticonvulsants.

N-Acetyl-D,L-alanine-N-benzylamide and N-acetyl-D,L-phenylglycine-N-benzylamide are two novel anticonvulsants that selectively blocked maximal electric shock-induced tonic extensor seizures in mice. For both compounds, the anticonvulsant activity is due to the D-stereoisomer, and the L-stereoisomer is virtually inactive as an anticonvulsant. The marked stereoselectivity of these anticonvulsants may make them very useful pharmacological tools for the study of the mechanism(s) of anticonvulsants that selectively inhibit maximal electric shock-induced seizures.

Animals↗