Pyrrolopyridine and Isoindole as Potential Anticonvulsant Agents: Design, Synthesis, and Pharmacological Evaluation.

BACKGROUND AND OBJECTIVE: Phthalimide, as the rigid form of ameltolide, exhibits a phenytoin-like profile of drug-receptor interaction and is active in the MES model and inactive in the PTZ model as an anti-epileptic agent. In this research, based on the isosteric replacement, we reported the design, preparation, and antiepileptic activity of 13 new analogs of pyrrolopyridine and isoindole. METHODS: The designed compounds were prepared by condensing 3, 4-pyridine dicarboxylic anhydride, or 4-fluorophthalic anhydride with different aryl amines. MES and PTZ-induced seizure models were utilized to evaluate the antiepileptic effect of the prepared ligands. RESULTS: It was found that the prepared ligands have significantly affected both tonic and clonic seizures. In tonic seizures, the prepared compounds decreased mortality to a significant extent, and in clonic seizures, they significantly showed better frequency and latency. Compounds 9, 12, and 13 were the most potent ligands than phenytoin. CONCLUSION: It is concluded that the best distance between two aryl parts is two bonds, and the substitution of the nitro group at the meta position of the phenyl ring is better than the para position. Our research group has investigated this concept for designing newer compounds with better anticonvulsant activity.

Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes.

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35-50 kg/m2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 - 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY3-36 , and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

Occupational contact urticaria caused by cyclic acid anhydrides.

BACKGROUND: Cyclic acid anhydrides often cause allergic respiratory diseases, but contact urticaria because of these anhydrides has been considered rare. OBJECTIVE: We describe 21 patients diagnosed with occupational contact urticaria at the Finnish Institute of Occupational Health during the period 1990-2006. METHOD: Prick test with human serum albumin (HSA)-acid anhydride conjugates, determination of specific immunoglobulin E (IgE), and open application were used in the diagnosis. RESULTS: The majority of the patients worked in the manufacture of electrical machines and were exposed to an epoxy hardener containing methyl hexahydrophthalic anhydride. The largest prick test reaction was often noted for the acid anhydride the patient had been exposed to. The specific IgE results were mostly in line with the prick test reactions. Phthalic anhydride IgE was determined in 20 patients and was found positive in 19 patients. In open application, a positive test result often required the use of the undiluted hardener. CONCLUSIONS: Contact urticaria may be more common than previously believed. Prick tests with HSA-acid anhydride conjugates were a useful test method for detecting immediate sensitization to acid anhydrides. The determination of the specific IgE gave almost equal results. The open application test often had to be performed with the undiluted anhydride product to obtain a positive test result.

Burn center treatment of patients with severe anhydrous ammonia injury: case reports and literature review.

Anhydrous ammonia, a widespread industrial chemical, can cause severe inhalation and ophthalmic injuries, as well as cutaneous burns. We present five patients with ammonia injury treated at our burn center after an explosion in a warehouse. The challenges inherent in managing the pulmonary complications of this injury are emphasized.

[The working environment control of anhydride hardeners from an epoxy resin system].

Epoxy resins are widely used in adhesives, coatings, materials for molds and composites, and encapsulation. Acid anhydrides such as methyltetrahydrophthalic anhydride are being used as curing agents for epoxy resins. The anhydride hardeners are well-known industrial inhalant allergens, inducing predominantly type I allergies. In the electronic components industry, these substances have been consumed in large quantities. Therefore, safe use in the industry demands control of the levels of exposure causing allergic diseases in the workshop. We conducted a prospective survey of two electronics plants to clarify how to control the atmospheric level of the anhydrides in the work environment. Measurements of the levels of the anhydrides in air started according to the Working Environment Measurement Standards (Ministry of Labour Notification No. 46, 1976) in April 2000, along with improvements in the work environment. A value of 40 micrograms/m3 was adopted as the administrative control level to judge the propriety of the working environment control. A total of 2 unit work areas in both plants belonged to Control Class III. The exposure originated from manual loading, casting, uncured hot resins, and leaks in an impregnating-machine or curing ovens. In order to achieve the working environment control, complete enclosure of the source, installation of local exhaust ventilation, and improvement or maintenance of the local exhaust ventilation system were performed on the basis of the results of the working environment measurement, with the result that the work environment was improved (Control Class I). It became evident that these measures were effective just like other noxious substances.

A prospective study of the relationship between exposure and specific antibodies in workers exposed to organic acid anhydrides.

BACKGROUND: The exposure-response relationships for the induction of specific IgE and IgG were evaluated in a prospective study of workers exposed to organic acid anhydrides (OAAs). Special attention was paid to the modifying effects of atopy and smoking. METHODS: The subjects were 163 previously unexposed persons exposed to epoxy resins with hexahydro-, methylhexahydro-, and methyltetrahydrophthalic anhydride as curing agents. The levels of OAAs in air and of specific IgE and IgG in serum were recurrently monitored. The mean observation time was 32 (1-105) months. RESULTS: The mean combined OAA exposure of the subjects was 15.4 (< 1-189) microg/m3. Positive specific IgE was demonstrated by 21 (13%) subjects with a mean induction time of 8.8 (1-35) months. The incidence of sensitization was 4.1 cases/1000 months at risk. The relative risk (OR) for atopics was 5.4 (1.9-15.3; 95% CI). An exposure-response relationship was demonstrated by an increasing risk of sensitization with increasing exposure. CONCLUSION: An association between exposure and atopy, respectively, and the induction of specific antibodies against OAAs were observed. The risk for atopics was comparable with the risk for the subjects in the most exposed group.

Exposure assessment and sensitisation in workers exposed to organic acid anhydrides.

OBJECTIVES: To clarify whether the intensity of exposure to organic acid anhydrides (OAAs) is associated with the risk of sensitisation to these allergens. METHODS: The investigations were carried out in three different manufacturing plants (A, B, and C) where OAAs were used in the production of epoxy resins. Methyltetrahydrophthalic acid anhydride (MTHPA) was used in all three plants. The exposure assessment included stationary and ambient air monitoring (OAAs in the air) and biological monitoring (metabolites in urine). In plant A 20, in plant B 86 and in plant C 113 employees were examined by a physician (anamnesis, skin-prick test, specific IgE, spirometry). In plants B and C, the exposure areas were classified as high, medium, and low, without the results of the exposure assessment being known. RESULTS: The ambient air concentrations (in microg/m3) of MTHPA were 37.2 and 58.5 in plant A (number of samples n = 2), ranged from <0.5-26.2 in plant B (n = 5) and from 2.1-57.9 in plant C (n = 3) with stationary air collecting, and from 8-45 (n = 6), from < 4.7-35.7 (n = 3) and from 2-37.8 (n = 3) with personal air collection. The metabolites of OAAs in urine (in nmol/mmol creatinine) ranged from 5.7-645 (median of MTHPA: 346) in plant A, from < 1-213 (median of MTHPA: 10.1) in plant B and from 0.1-830 (median of the sum of the OOA metabolites: 108.6) in plant C. The prevalence of sensitisation was 35% in plant A, 21% in plant B and 29% in plant C. A higher prevalence in the highly exposed areas, however, could not be seen. Levels of IgE specific for conjugates of MTHPA were not associated with the metabolites in the end of shift urine. Levels of IgG specific for conjugates of MTHPA, however, were associated with the metabolites in the end of shift urine. CONCLUSIONS: The data showed that biological monitoring is a useful tool in the exposure assessment of OAAs. Comparing the prevalence of sensitisation and the results of biological monitoring, between the three plants, we found that sensitisation increased with increasing exposure. Within a plant a higher risk of sensitisation in persons working in highly exposed areas at the time of the examination could not be seen, possibly due to frequent job rotation.

Risk factors for bronchial hyperresponsiveness in workers exposed to acid anhydrides.

Risk factors for bronchial hyperresponsiveness have previously been established in the general community. In settings where occupational asthma is a risk, it has not been established whether occupational sensitization or measures of exposure are important. Bronchial responsiveness to histamine was measured in a cohort of 506 workers exposed to acid anhydrides. Skin-prick tests were performed with conjugates of phthalic, maleic and trimellitic anhydride with human serum albumin and with common inhalant allergens. Employment and smoking histories were recorded. Occupational exposure was measured using personal air samplers and estimates of past exposure made by retrospective exposure assessment. Three hundred and seventy workers (73%) had bronchial responsiveness measured (median age 39 yrs, range 18-77) and 46 (12%) of these were hyperresponsive (provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1; PD20) < or = 8 micromol). Twelve (3%) of these responsive workers had a skin-prick test reaction to an acid anhydride conjugate, 124 (34%) to a common inhalant allergen, and 148 (40%) were current smokers. Multivariate analysis showed that occupational sensitization, sensitization to a common inhalant allergen, age, and pack-years of smoking were independent risk factors for bronchial hyperresponsiveness. Of these only occupational sensitization was completely independent of baseline FEV1. It is concluded that sensitization to acid anhydrides is a significant risk factor for bronchial hyperresponsiveness. However, measures of personal acid anhydride exposure were not associated with bronchial hyperresponsiveness.

[The use of chemiluminescent studies of blood and urine for the evaluation of the health status in workers of oil processing industry]. / Ispol'zovanie khemiliuminestsentnykh metodov issledovaniia krovi i mochi dlia otsenki sostoianiia zdorov'ia trudiashchikhsia neftepererabatyvaiushchei promyshlennosti.

The authors present hygienic characteristics of work conditions, evaluation of health state in workers engaged into pyromellitic dianhydride production, therapeutic and prophylactic measures to the subjects in preventorium. The characteristics and evaluation are based on changes of free-radical oxidation parameters in blood and urine. The workers engaged into pyromellitic dianhydride production demonstrated significant changes in chemiluminescent parameters of blood and urine. Studies on chemiluminescence of blood and urine evaluate compensatory and metabolic resources, reveal premorbid condition and monitor the treatment in preventorium.

Prevention of occupational allergy caused by exposure to acid anhydrides.

This paper focuses on the prevention of IgE-mediated symptoms of the eyes and airways caused by exposure to acid anhydrides in the workplace. Acid anhydrides are widely used in the production of alkyd resins and as curing agents for epoxy resins. Heavy exposure to acid anhydrides causes severe irritation. However, reports of direct irritation of mucous membranes or skin are rare in recent years, since a package of multiple engineering controls has been introduced to reduce exposure. On the other hand, acid anhydrides are well-known industrial inhalant sensitizers and can cause occupational allergy even at very low exposure intensities. Therefore, safe use in industry demands both control of the level of exposure causing allergic diseases in the workshop and programmes for prevention of occupational allergy.

Stepwise health surveillance for bronchial irritability syndrome in workers at risk of occupational respiratory disease.

OBJECTIVES: Questionnaires, lung function tests, and peak flow measurements are widely used in occupational health care to screen for subjects with respiratory disease. However, the diagnostic performance of these tests is often poor. Application of these tests in a stepwise manner would presumably result in a better characterisation of subjects with respiratory disease. METHODS: Cross sectional data from workers exposed to acid anhydrides, to laboratory animals, and to flour dusts were used. Sensitivity and specificity were calculated from cross tables of different (combinations of) tests for bronchial hyperresponsiveness and bronchial irritability in the past four weeks (BIS). From sensitivity and specificity likelihood ratios were computed and change in probability of BIS was calculated. RESULTS: The prevalence of BIS was 7%, 7%, and 5%, respectively. In all groups questionnaire data provided excellent sensitivity but poor specificity, which was inherent on the broad definition of symptoms. Adding the forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio yields almost perfect specificity, and peak expiratory flow (PEF) variability is intermediate in populations in which smoking induced or non-allergic respiratory diseases predominates. In occupational groups in which asthma is a problem, adding PEF measurements will optimise sensitivity and specificity in detection of BIS. The probability of BIS for subjects with a negative combined test outcome was lower than the probability before testing. Subjects with a positive combined test outcome had a probability of BIS after the tests at least three times the probability before. CONCLUSIONS: Combined testing yields better sensitivity and specificity. An advantage of combined testing is an economy in the effort to screen for subjects with BIS. Combined testing resulted in more detailed estimation of the probability of BIS.

Risk factors for sensitisation and respiratory symptoms among workers exposed to acid anhydrides: a cohort study.

OBJECTIVES: To examine the relation between exposure to acid anhydrides and the risk of developing immediate skin prick test responses to acid anhydride human serum albumin (AA-HSA) conjugates or work related respiratory symptoms; to assess whether these relations are modified by atopy or smoking. METHODS: A cohort of 506 workers exposed to phthalic (PA), maleic (MA), and trimellitic anhydride (TMA) was defined. Workers completed questionnaires relating to employment history, respiratory symptoms, and smoking habits. Skin prick tests were done with AA-HSA conjugates and common inhalant allergens. Exposure to acid anhydrides was measured at the time of the survey and a retrospective exposure assessment was done. RESULTS: Information was obtained from 401 (79%) workers. Thirty four (8.8%) had new work related respiratory symptoms that occurred for the first time while working with acid anhydrides and 12 (3.2%) were sensitised, with an immediate skin prick test reaction to AA-HSA conjugates. Sensitisation to acid anhydrides was associated with work related respiratory symptoms and with smoking at the time of exposure to acid anhydride. When all subjects were included and all three acid anhydrides were taken into account there was no consistent evidence for an exposure-response relation, but with the analysis restricted to a factory where only TMA was in use there was an increased prevalence of sensitisation to acid anhydrides and work related respiratory symptoms with increasing full shift exposure. This relation was apparent within the current occupational exposure standard of 40 micrograms.m-3 and was not modified significantly by smoking or atopy. CONCLUSIONS: Intensity of exposure and cigarette smoking may be risk factors for sensitisation to acid anhydrides. Exposure is also a risk factor for respiratory symptoms. As there was evidence for sensitisation to TMA at full shift exposures within the occupational exposure standard this standard should be reviewed.

Retrospective exposure assessment for a cohort study into respiratory effects of acid anhydrides.

OBJECTIVES: To estimate past exposure to phthalic (PA), trimellitic (TMA) and maleic anhydride (MA) in three alkyd resin and one cushioned flooring factory to estimate exposure-response relations in a retrospective cohort study. METHODS: Personal exposure measurements were carried out in 1992 and quantitative and qualitative information on past exposure and production processes were collected. Job titles were ranked by decreasing exposure and amalgamated into job categories and exposure groups. Multiplication factors for back calculating past exposure levels were estimated with past exposure data, or if no such data were available these factors were estimated by a panel of occupational hygienists. Exposure levels were back calculated starting with the exposure levels in 1992. RESULTS: High exposures to PA were estimated to have occurred among workers operating the PA melting pots in factory 1 (estimated exposure in 1960-9 was 2480 micrograms.m-3). Highest concentrations of TMA were estimated to have occurred among the ink mixers in factory 2 from 1979 to 1986 (554 micrograms.m-3). Exposure in most other job titles was thought to be fairly constant over time for PA, TMA, and MA. CONCLUSIONS: Exposure to acid anhydride at these factories has fallen during the period covered by the study. However, it is estimated that in only one job in factory 2 did past exposure to acid anhydride exceed the current occupational exposure standard. Accuracy of the estimated exposure is limited by a paucity of reliable past exposure data.

[Allergic conditions for diseases of the respiratory tract from occupational exposure to acid anhydrides]. / Alergicznie uwarunkowane schorzenia dróg oddechowych spowodowane zawodowym narazeniem na bezwodniki kwasne.

Acid anhydrides are highly reactive, low molecular weight compounds that are used widely in industry. Work-related exposure to this group of substances may cause occupational asthma. Because of low molecular weight, these compounds are not able to induce antibody responses without conjugating with human proteins. Acid anhydrides may act as haptens when conjugated with human serum albumin (HSA). The induction mechanism of immediate and late bronchial hyperresponsiveness to acid anhydrides appears to be at least partly mediated by IgE antibodies. Other clinical syndromes, which may be caused by acid anhydrides such as pulmonary disease-anemia (PDA), and late respiratory systemic syndrome (LRSS) associated with TMA exposure, appear to be associated with IgG antibodies to TMA as well as with IgE. Significant cross-reaction occurs between different compounds of this group, particularly regarding IgE antibodies. As inhalational exposure to acid anhydrides may result in serious pulmonary disease, adequate protection of potentially exposed workers or their removal, if affected, from exposure is essential.