Biomedical subjects
Publications and source records attributed to M Högberg.
Bioisosteric substitution of the thiourea (3, 5, 7, 9) and urea (10) moiety of PETT compounds with sulfamide (1), cyanoguanidine (2, 4) and guanidine (6, 8) functionalities, and replacement of the phenethyl group with benzoylethyl group (compounds 11-20) have been studied. Synthesis and antiviral activities are described.
The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179.
A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.
OBJECTIVES: The questionnaire 16 (Q16) is commonly used to study prevalences of neurotoxic symptoms among workers exposed to organic solvents. It has also been recommended that exposed workers reporting more than six symptoms should be referred for further examination of possible chronic toxic encephalopathy. It would be useful to know whether symptoms reported in the questionnaire also reflect impairment of similar functions measured with objective or semiobjective methods in a formerly highly exposed group. METHODS: 135 painters and 71 carpenters answered the Q16, were interviewed about symptoms compatible with an organic brain damage, and took a battery of psychometric tests. A subsample of 52 painters and 45 carpenters were interviewed for psychiatric diagnosis according to Diagnostic and Statistical Manual for Mental Disorders, 3rd version (DSM III) and their vibration thresholds in hands and feet were measured. The entire group was followed up in the register of diagnoses at early retirement 1971-93. The lifetime exposure to organic solvents was assessed. Current exposure to organic solvents was found to be low or none. RESULTS: The prevalence of people with more than six symptoms in the Q16 rose with increasing cumulative exposure to solvents. The sensitivity of the questionnaire (more than six symptoms) to detect people who were assessed to exhibit symptoms compatible with an organic brain damage was only 38%. One of seven people who had retired early with a diagnosis compatible with a chronic toxic encephalopathy, and two of five people with a psychiatric diagnosis compatible with this condition, had more than six symptoms in the Q16. The agreement between Q16 replies and psychometric test results, as well as other examinations, was low. CONCLUSIONS: The notable exposure-response relation indicates that the questionnaire is useful for comparison of groups with different exposures to organic solvents. There was low agreement between the number of symptoms on the questionnaire and the assessment of symptoms compatible with organic brain damage, as well as psychiatric, or early retirement diagnoses compatible with chronic toxic encephalopathy. The questionnaire does not seem useful for screening of patients with chronic toxic encephalopathy in groups without ongoing exposure to organic solvents.
Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.
A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
Neuropsychiatric effects were examined among 206 men, of whom 135 had been house painters and 71 had been house carpenters, affiliated with their respective trade unions for at least 10 years before 1970. Their lifetime organic solvent exposure was evaluated through the aid of an interview. Relevant potential confounding factors were accounted for in the statistical analysis. Neuropsychiatric symptoms compatible with chronic toxic encephalopathy were more common among the painters than among the carpenters, and these symptoms became increasingly prevalent with increasing cumulative solvent exposure. On only one of 12 psychometric tests, block design, did the painters perform worse than the carpenters, and in this test the painters' performance deteriorated with increasing cumulative exposure. For the majority of the psychometric tests, and for the coordination tests, there were no differences between the painters and carpenters, but the painters with "low" exposure tended to show better, and "heavily" exposed painters worse, results than the carpenters. The 52 painters with the heaviest cumulative exposures and 45 carpenters were examined for psychiatric diagnosis according to DSM-III, with electroencephalography and auditory evoked potential, P-300. Three painters and two carpenters had diagnoses compatible with an organic mental disorder. There were no overall differences between the painters and carpenters, either for the visually examined electroencephalograms or the P-300 latencies. The excess of neuropsychiatric symptoms among the painters was probably causally linked to solvent exposure. However, these symptoms seemed only rarely, if ever, serious enough to entail a psychiatric diagnosis. Concerning other outcomes, the investigation may not lead to a determination of whether the exposure-response relationship among the painters, with no difference between the entire group of painters and carpenters, is caused by solvent exposure or by selection factors within the group of painters.
The serum activities or concentrations of aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (ALP), albumin, gamma-glutamyl transpeptidase (GGT), bilirubin (BIL), cholic acid (CHOL), chenodeoxycholic acid (CHENO), and transferrin with isoelectric point 5.7, and the urinary excretion of albumin were determined among male current or former house painters (n = 135) and house carpenters (n = 71) who had worked in their trades for at least 10 years before 1970. Workers who showed a value above the 90th percentile among the carpenters in at least one of the tests ASAT, ALAT, GGT, BIL, CHOL, or CHENO were regarded as showing "possible signs of liver dysfunction". Each participant's lifetime solvent exposure was evaluated by interview. The painters were divided into categories with low, intermediate, and heavy cumulative exposure during life (LTSE) or during the most exposed year (MEYSE). All participants stated none or slight recent exposure. The prevalence of possible signs of liver dysfunction increased with solvent exposure category according to LTSE as well as MEYSE with a numerically higher risk estimate in the heavy exposure category for MEYSE than for LTSE. ALP activity increased with exposure category according to both exposure estimates. This increase seemed to be due to an interaction between exposure to solvents and current or previous long term intake of medicines potentially toxic to the liver. None of these results was affected by whether or not the subjects had been exposed to solvents during the year before the investigation. The exposure to solvents was not significantly related to any other outcome variable. It is concluded that long term heavy exposure to solvents may elicit changes in conventional liver function tests indicative of a mild chronic effect on the liver. The findings also suggest that heavy solvent exposure during short time periods is a more likely cause of the findings than lifetime cumulative solvent exposure and that an interaction between solvent exposure and medicines potentially harmful to the liver may be important in the causation of the effects.
The incidence of alcoholism and the incidence of other neuropsychiatric diagnoses were compared between the 767 house painters and the 1212 house carpenters, born in 1925 or later, who were members of the Stockholm branches of their respective trade unions in 1965 and who had been members for at least 10 years before 1970. Four different outcome registers were used: (1) the alcohol crime register, which contained all persons who had broken any law regulating the handling and consumption of alcohol (follow up period 1972-6). (2) The register of diagnoses at early retirement (follow up period 1971-84). (3) The register of diagnoses at discharge from inpatient psychiatric care (follow up period 1968-83). (4) The register of causes of death (follow up period 1965-86). Exposures to solvents and consumption of alcohol were evaluated by interviews with samples of the cohorts. A high average cumulative exposure to solvents was found among the painters. The mean consumption of alcohol was similar in the two cohorts. The incidence of diagnoses of neuropsychiatric disorders was higher in painters than in carpenters in all registers. Alcoholism was the most common neuropsychiatric disorder diagnosed and showed the highest relative risk. The excess of alcoholism among the painters was, however, due singularly to painters who had several registrations in the alcohol crime register or diagnoses of alcoholism in multiple registers. Thus the study implies that excessive alcohol consumption or severe damage due to alcohol, or both, but not less severe problems, were more common in painters than in carpenters. This suggests an interaction between exposure to solvents and intake of alcohol causing an increase in diagnosis of alcoholism among painters.
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During 1976-77 a field investigation was carried out into skin diseases among house painters in Stockholm, Sweden. The study was divided into three stages: I. questionnaires investigation, II. examination of painters who reported skin diseases, and III. patch testing and final classification. Of the 2,622 painters registered on 30 November 1976, 2239 (85.4%) answered the questionnaire. Current dermatoses were reported by 373 painters (16.7%) and of these, 227 were examined by us, 40 had recently been examined, and 106 did not attend. Occupational contact eczemas were diagnosed in 87 cases, and it was doubtful if the dermatoses were occupational in an additional 56 cases. A prevalence of 3.9% was suggested, but this represents a minimum figure. Chloracetamide was found to be an important cause of occupational contact eczema. A personal and/or family history of atopy was common among the affected painters. Solvents were widely used for skin cleansing; there is a great need for continuous information on protective measurements, and on skin cleansing and care. It is concluded that field investigation give higher and probably more reliable prevalence figures for occupational dermatoses than data compiled from outpatient clinics.
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