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The capacity of para-aminosalicylic acid (PAS) to lower initially high serum lipoprotein lipid concentrations was tested in a double-blind crossover study. Thirty patients who were on a lipid-lowering diet were treated with PAS (6 gm daily) for 4 wk. There was an average reduction of the serum triglyceride concentration of 28% (p less than 0.001) and of 12% of the serum cholesterol concentration (p less than 0.001) corresponding to a reduction of very low density lipoprotein (VLDL) triglycerides of 40% (p less than 0.001) and low density lipoprotein (LDL) cholesterol of 6% (p less than 0.05). In hypercholesterolemic patients, the LDL cholesterol reduction was 14% (p less than 0.001). In patients with hypertriglyceridemia type IV, the mean reduction of the VLDL triglyceride concentration was 47% (p less than 0.01), corresponding to a serum triglyceride reduction by 37% (p less than 0.01). In spite of the decrease of VLDL concentration, there was an unexpected reduction of the lipoprotein lipase activity in adipose tissue of 16% (p less than 0.02). The glucose tolerance and the serum insulin concentrations at fasting and after glucose injection were not changed.
The elimination of para-aminosalicylic acid (PAS) after the intravenous injection of 20 mg PAS sodium/kg was estimated in patients with liver disease, in uremic patients and in volunteers without damage of the liver or kidneys. The drug was estimated with a colorimetric and fluorometric method. In the volunteers, the half-lives obtained with the fluorometric method were significantly longer than those estimated with the colorimetric method. This is caused by the estimation of more PAS metabolites by the used fluorometric method. In the patients with renal insufficiency (dialysis patients) the elimination rate of unchanged PAS--estimated with the colorimetric method--was not altered, whereas the elimination of PAS and its metabolites extractable by ethyl acetate was markedly slowed in comparison with the results obtained with the volunteers. The clearance of the unchanged PAS was even increased in the uremic patients. The serum protein binding of PAS was lowered significantly in the serum of uremic patients. In patients with liver cirrhosis, acute virus hepatitis and cholangitis the elimination rate of the drug was not altered in comparison with the volunteers. The results show that the dose of PAS in patients with renal insufficiency may not be reduced. The therapeutic level of the drug cannot otherwise be reached in these patients.
The hypolipidemic effect of PAS-C-diet treatment was studied in 63 patients with Types IIa and IIb hyperlipoproteinemia for 6-36 months. Serum lipids and body weights of all patients were stabilized by a low cholesterol-saturated fat-refined carbohydrate diet before the initiation of an eight-week placebo-drug single-blind crossover study. During the placebo period the plasma lipids levels, mean +/- SD: cholesterol 355 +/- 63.5 mg%, triglyceride 141 +/- 68.7 mg%, and LDL-cholesterol 279 +/- 56.8 mg% were lowered to 274 +/- 53.1 mg+, 98 +/- 40.6 mg%, and 209 +/- 52.9 mg%, respectively (P less than 0.001 in each instance), with 7.5-11.0 grams of PAS-C/day given in one to three divided doses. In ten patients who have completed three years of treatment similar results were obtained. They showed no tendency to develop drug tolerance. Eight had watery diarrhea during the initial period which promptly subsided with interruption of drug therapy. Reintroduction of PAS-C in smaller dose (4.5 g/day) with gradual increment to effective dosage level was tolerated by all. No hematologic, hepatic, and ophthalmologic abnormalities were demonstrated by periodic monitoring. The hypoplipidemic effect of the drug was found to be diminished by alcohol and caloric excess.
The effect of para-aminosalicylic acid-C (PAS-C, 8 g/day) on lipid metabolism was studied on a metabolic ward in nine subjects with primary endogenous hypertriglyceridemia. During 2 wk on a basal isocaloric liquid formula diet (40% fat, 45% carbohydrate), PAS-C reduced plasma triglyceride (-41.9 +/- 18.9%, p less than .01, -x +/- SD), cholesterol (-22.8 +/- 12.9%, p less than .005), and a very low density lipoprotein triglyceride (p less than .001) and cholesterol (p less than .01) levels without changing the cholesterol content of low density or high density lipoproteins. Similar effects occurred on a fat-free, 85% carbohydrate diet. Decreases in very low density lipoproteins correlated with changes in both total triglyceride (r = .99, p less than .01) and cholesterol (r = .70, p less than .05). Treatment with PAS-C reduced the plasma triglyceride removal rate related to lipoprotein lipase (-14.6 +/- 14.1%, p less than .02), but did not alter plasma postheparin lipolytic activity or the apparent Km for substrate-enzyme interaction. Kinetic data obtained during the prolonged heparin infusion fit the linearized Michaelis-Menten model for subjects with endogenous hypertriglyceridemia. The reduction in the plasma triglyceride concentration during PAS-C treatment was a function of the decrease in triglyceride removal rate (r = .74, p less than .025) without alternation in the maximal removal capacity related to lipoprotein lipase. This suggests that under the steady state conditions of these studies, the decrease in plasma triglyceride concentration was due to a reduction in endogenous triglyceride production. Free fatty acid metabolism, glucose homeostasis, fat absorption, and thyroid function did not change. These results suggest that PAS-C lowers plasma triglyceride and cholesterol levels in hypertriglyceridemic subjects reducing endogenous very low density lipoprotein production and/or secretion into the circulation.
Accurate drug susceptibility testing (DST) is crucial for designing effective regimens for multidrug-resistant (MDR) and pre-extensively drug-resistant tuberculosis (pre-XDR TB). Sensititre MYCOTB enables simultaneous determination of minimum inhibitory concentrations (MICs) for multiple drugs, but its diagnostic performance varies across studies. This meta-analysis evaluated the diagnostic performance of Sensititre MYCOTB for key MDR and pre-XDR TB drugs. The protocol was registered in PROSPERO (CRD420251230599). PubMed, Cochrane, Google Scholar, Scopus, ONOS, Web of Science, ScienceDirect, and registries were systematically searched for studies published between 2010 and 2025. Studies comparing the Sensititre MYCOTB with reference DST for Mycobacterium tuberculosis complex (MTBC) were included. Bias assessment and pooled diagnostic accuracy estimates were generated. Fourteen studies, including 1,728 isolates, were analyzed. Rifampicin and isoniazid demonstrated high sensitivity (0.976 [95% CI: 0.94-0.99] and 0.977 [95% CI: 0.95-0.99]) and specificity (0.958 [95% CI: 0.84-0.98] and 0.957 [95% CI: 0.83-0.99], respectively) with low heterogeneity. Amikacin, kanamycin, and ofloxacin demonstrate good diagnostic accuracy, with high specificity (>0.98 [95% CI]). Moderate diagnostic accuracy was observed for ethambutol, streptomycin, ethionamide, and rifabutin. Cycloserine, moxifloxacin, and para-aminosalicylic acid showed inconsistent performance despite excellent specificity (>0.97 [95% CI]). Sensitivity analysis partially improved pooled sensitivity for moxifloxacin 0.801 (95% CI: 0.585-0.924) and para-aminosalicylic acid 0.76 (95% CI: 0.518-0.894), whereas cycloserine remained at 0.436 (95% CI: 0.190-0.725), although heterogeneity persisted. Sensititre MYCOTB DST demonstrates high diagnostic accuracy for MDR-TB and pre-XDR-TB drugs, while caution is required with cycloserine, moxifloxacin, and para-aminosalicylic acid. These findings support the integration of MIC-based testing into clinical decision-making.
The protein binding of 6 antituberculous drugs--ethambutol, ethionamide, isoniazid, para-aminosalicylic acid, rifampicin and streptomycin--to normal and kwashiorkor serum has been investigated. The binding of these drugs was mildly decreased in kwashiorkor serum, but not to such an extent as to be of therapeutic importance, except for streptomycin and possibly para-aminosalicylic acid (PAS). With streptomycin there was a 15% increase in the free component in kwashiorkor serum, while with PAS there was a 12% increase in the free component. Of interest is the observation that rifampicin is predominantly bound to the gamma-globulin fraction, both in normal and in kwashiorkor serum. Secondary binding, predominantly to the alpha 1-, alpha 2-and gamma-globulin fractions, was seen quite commonly in kwashiorkor serum in association with diminished albumin binding.
Tuberculosis of the male urethra is a rare lesion, with only 21 cases reported in the literature. Two patients with tuberculosis of the urethra, who presented with multiple periurethral fistulas and a periurethral abscess, are described. In both patients there was associated genitourinary tuberculosis. Mycobacterium tuberculosis could be isolated from the urine and the exudate of the perineal ulcers. Biopsy from the perineal ulcers demonstrated tuberculous granulation tissue with tuberculous bacilli. Treatment consisted of suprapubic cystostomy and a 2-year course of antituberculous drugs, consisting of streptomycin, para-aminosalicylic acid and isoniazid. The urethral fistulas healed with this treatment. The urethral strictures were treated with repeated urethral dilations.
From 1961 through 1968 the incidence of primary drug resistance was monitored among patients admitted to 22 participating hospitals. The patients were believed to have newly diagnosed, previously untreated, bacteriologically proved pulmonary tuberculosis. During the study period the level of primary resistance to isoniazid, streptomycin, and para-aminosalicylic acid remained very low; there was no indication that primary resistance to these drugs was increasing. Investigation of patient histories revealed that a significant proportion of persons initially believed to have been previously untreated actually had received prior chemotherapy. Resistance rates to both isoniazid and streptomycin were significantly higher among younger patients than among older patients. No relationship was found between race or sex and primary resistance rates. The low incidence of drug resistance found in this survey suggests that disease caused by virulent resistant organisms occurs infrequently.
A study of primary antituberculous drug resistance in Hawaii was conducted from 1957 to 1977 to determine the incidence of primary resistance with respect to time. A total of 1,869 initial cultures of Mycobacterium tuberculosis submitted to Leahi Hospital in Honolulu were screened to identify drug resistance. Of 256 patients who excreted resistant bacilli, only 55 had no history of previous antituberculous chemotherapy. The frequencies of primary drug resistance from July 1957 to July 1977 were as follows: streptomycin, 0.86 per cent; isoniazid, 1.2 per cent; para-aminosalicylic acid, 1.5 per cent. No strains were resistant to ethambutol or rifampin. A slight decrease in the incidence of drug resistance during a 20-year period was observed. This was especially significant because Hawaii's tuberculosis problem is principally confined to its foreighn-born population. Although no serious primary drug resistance problem was discovered, Hawaii possesses both the highest immigration rate and the highest incidence of tuberculosis in the United states. Therefore, there is a need for continued periodic monitoring of drug resistance in Hawaii.
A continuing study of the frequency of primary drug resistance among children treated at the Kings County Hospital Center of Brooklyn during the years 1973 through 1977 showed a high incidence of primary drug resistance to isoniazid (8.8 per cent) and to streptomycin (12.3 per cent). In contrast, there were no strains resistant to cycloserine, viomycin, ethambutol, or rifampin, and only one of 57 strains (1.8 per cent) was resistant to ethionamide, and one (1.8 per cent) was resistant to para-aminosalicylic acid. Comparison with previous studies begun in 1961 showed no significant increase in resistance to isoniazid during 3 prior periods of study and no increase in resistance to streptomycin during the last 2 periods of study. It must be emphasized that these findings relate only to the children of a local community, and do not reflect the prevalence of primary drug resistance elsewhere in this country or among different age groups.
Rifampicin, a potent antituberculosis agent, is frequently combined with other antituberculosis drugs, or with drugs belonging to entirely different classes which may be required during a long period of antituberculous treatment, and therefore has a potential for drug interactions of practical clinical importance. The absorption of rifampicin is markedly decreased when it is simultaneously administered with para-aminosalicylic acid granules, due to adsorption by an excipient, bentonite. Several clinical observations and investigations have indicated that rifampicin itself accelerates the metabolism of various other compounds, including oral anticoagulants, the contraceptive pill, oral hypoglycaemic agents and digitoxin. Rifampicin seems to be a potent inducer of drug metabolism in humans and it causes a proliferation of the smooth endoplasmatic reticulum and an increase of cytochrome P450 content in the liver. It also increases its own rate of desacetylation. However, of the test compounds hexobarbitone and tolbutamide, the metabolic clearance increased 2-to 3-fold following rafampicin treatment, whereas antipyrine clearance was unaltered. This indicates that there is a certain selectivity in the enzyme induction effect of rifampicin, although it reamins unclear which compound will and which will not be affected. Rifampicin may also possibly interfere with hepatic uptake of other compounds, but the clinical significance of this type of interaction has not been clearly demonstrated; On the other hand, oral probenecid significantly increases the serum level of rifampicin, probably due to a similar depression of hepatic uptake.
In 1975, a survey was carried out in Canada to determine the primary and acquired drug resistance of M. tuberculosis isolates to isoniazid (INH), para-aminosalicylic acid (PAS) and streptomycin. The results of this investigation were compared with those of the primary drug resistant study of Armstrong, undertaken in 1963-64. It revealed that primary drug resistance has increased from 4.9% to 6.3%. The increase is mainly due to immigrants having arrived in this country during the last 12 years. In these newcomers the primary resistance rate was 11.5%. Moreover, 57.8% of the immigrants examined in the survey were of Asian origin, with a drug resistance rate of 11.7%, while 15.6% had arrived from South Europe with a resistant ratio of 16.7%. In retreatment cases, the national average of drug resistance was 26.4%. Among the Canadian provinces, the highest drug resistance rate in retreatment patients (40%) was found in Quebec. While in primary resistance Streptomycin exhibited the highest incidence, in retreatment cases isoniazid resistance proved to be more frequent. In natives, the rates and patterns of primary and acquired resistance were very similar to those observed in other Canadian born patients.
The activity of N-acetyltransferase is shown to significantly rise after administration of theophylline and isoprenaline, but not of propranolol and N-acetylderivate of para-aminosalicylic acid to form during 30 minutes at a constant rate that increases following addition of cyclic AMP to the incubation medium. The capacity of the rat to acetylate paraaminosalicylic acid did not change under the effect of the mentioned agents.
A trial of chemoprophylaxis to prevent reactivation of tuberculosis in persons with inactive disease who had never had adequate chemotherapy was conducted in Canada in the mid-1960s. Preventive drug treatment consisted of either isoniazid (INH) alone or INH plus para-aminosalicylic acid (PAS), for a maximum of 18 months. Long-term evaluation in 1974 of 1571 treated patients and 834 control patients demonstrated clearly the substantial and sustained value of adequate chemoprophylaxis in reducing the risk of reactivation. Among those who took INH alone for 6 months or more the annual reactivation rate was 1.2 per 1000 persons, while among those who took INH plus PAS the rate was 0.38/1000. These rates were, respectively, 70 and 90% less than the average rate in the controls, 3.9/1000. Among those who underwent chemoprophylaxis for less than 6 months the annual reactivation rate was 3.7/1000, similar to that in the controls. Cost-benefit analysis showed chemoprophylaxis to be economically sound. Despite the recent increasing application of this preventive measure, there are still many persons living in Canada who could benefit substantially from a course of chemoprophylaxis.
Sodium para-aminosalicylate (sodium salt of 2-hydroxy-4-aminobenzoic acid, Na-PAS) lowers the oxygen affinity of normal adult human placental, heterozygous and homozygous sickle cell anemic whole blood at 37 degrees C. The reduction of oxygen affinity is related to the type of hemoglobin in the blood. The mean P50 +/- S.E. at pH 7.40 for normal, placental, heterozygoud and homozygous sickle cell anemic blood in 26.2 +/- 0.1, 20.8 +/- 0.3, 26.8 +/- 0.3 and 31.0 +/- 0.5 mm Hg; in the presence of 5.7 mmol of Na-PAS per liter of blood the P50 values are increased to 28.0 +/- 0.3, 22.9 +/- 0.8, 30.5 +/- 0.6 and 33.9 +/- 0.3 mm Hg, respectively. The Bohr effect in normal and placental blood at this Na-PAS concentration is essentially unchanged: in heterozygous and homozygous sickle cell anemic blood, the Bohr factor (deta log P50/deta pH) is reduced from -0.48 +/- 0.02 to -0.41 +/- 0.01 and from -0.53 +/- 0.03 to -0.48 +/- 0.01. The Hill constants (n) of normal and placental blood are not affected by Na-PAS. In homozygous and heterozygous sickle blood, high concentrations of Na-PAS (22.9 mmol/l) decrease the Hill constant from 2.55 to 2.35 and from 2.56 to 2.28, respectively. Na-PAS is more firmly bound to red blood cells than to plasma. The binding of Na-PAS is probably primarily ionic in nature since the drug can be almost completely removed from blood components by dialysis. The changes in oxygen affinity caused by Na-PAS are consistent with conformational changes (R leads to T) which enhance the presence of deoxyhemoglobin.
After efficient extraction by para-aminosalicylate, chopping, grinding and eventual sonication, the macropolyanions are transformed into their cetyltrimethylammonium salts. These have differing solubilities, strongly depending on ionic strength. The cationic detergent-macropolyanionic salts are solubilized by high salt concentration. Salt is then dialysed out, rendering the polyanions highly insoluble in a sequential fashion. The insolubilized components are determined quantitatively by monitoring turbidity, which in case of DNA is strictly proportionate to its concentration. This relation is not affected by other components. This makes DNA determination possible even in crude aqueous extracts. The method has been applied to different objects, such as bacteria, plants, animals, soil and activated sludge. The method may prove to be especially useful in research of environmental poisons e.g. in rivers, lakes or clarifiers.
A reduced response of a tumour to chemotherapy may be due to the host's drug metabolism. To test this hypothesis, we measured the metabolism of a model drug, para-aminosalicylate (PAS). Volunteers and cancer patients ingested a single oral dose (2 g) of PAS and we measured the plasma disappearance curve of the drug and its metabolite. In 7 patients suffering from lymphosarcoma, acute or chronic leukaemia and resistant to cancer chemotherapy, we observed low plasma PAS concentrations, an increase in PAS acetylation and an increased number (and a higher frequency) of abnormal liver-function tests. In 14 patients with malignant blood disease, yet responding well to chemotherapy, the metabolism of PAS is similar to that of healthy controls of the same age and sex. The plasma half-life of PAS is similar in sensitive and resistant patients, but slightly longer than in volunteers. Finally, in urine collected 120 min after drug administration, we observed the same results as in plasma. In conclusion, cancer patients resistant to chemotherapy do not metabolize the model drug PAS as volunteers or sensitive patients do, and this might be relevant to the terminal stage of the disease.