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PubMed1979

Canadian survey to determine the rate of drug resistance to isoniazid, PAS and streptomycin in newly detected untreated tuberculosis patients and retreatment cases.

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.

Aminosalicylic Acid↗

PubMed1991

Correspondence with a pioneer, Jürgen Lehmann (1898-1989), producer of the first effective antituberculosis specific.

Correspondence between the author and Lehmann provided evidence that the latter evolved the first effective antituberculosis drug, para-aminosalicylic acid (PAS), contrary to accepted belief that this honour belonged to Nobel Prize-winner Selman A. Waksman for his production of streptomycin. While both drugs appeared in 1943, successful animal and clinical trials of PAS preceded those of streptomycin. PAS has been discarded in modern treatment regimens because of gastric side-effects, but was available at a critical time to demonstrate the principle of multiple therapy in prevention of bacterial resistance in tuberculosis therapy. It probably saved streptomycin, which causes bacterial resistance and clinical regression within 3 months when used alone, from being discarded as an unsuitable drug of temporary benefit and a public health hazard.

Aminosalicylic Acid↗

PubMed1987

Augmentation of hepatic uridine-diphosphate glucuronyl transferase activity by antituberculous drugs in hamsters in vivo.

Changes in uridine-diphosphate glucuronyl transferase activity (UDP-GT) in liver homogenates of hamsters treated with different doses of isoniazid (INH), rifampicin (RMP), para-aminosalicylic acid (PAS) and hydrocortisone for several periods of time were studied and expressed as mg of bilirubin conjugated per g of protein per h. INH, RMP, PAS and hydrocortisone induced UDP-GT activity to a statistically significant degree. The optimum dose for high induction was 20 mg for INH, RMP and hydrocortisone, and 200 mg for PAS per kg of body weight. The optimum time of treatment for high induction was 10 consecutive days of intraperitoneal administration for all drugs examined. Such data, particularly for INH and RMP, indicate why patients who receive these drugs show no clinical jaundice, although they develop an hepatitis-like disease with elevation of serum transaminase of hepatic origin. This could be the result of stimulation of the hepatic smooth endoplasmic reticulum which produces rapid conjugation and therefore excretion of bilirubin. Similarly, the antituberculous drugs may cause liver dysfunction by inducing other liver enzymes.

Aminosalicylic Acid↗

PubMed1987

Neuromuscular abnormalities associated with hypothyroidism and lymphocytic thyroiditis in three dogs.

Various degrees of persistent or paroxysmal paresis involving only the hindlimbs or all four limbs were observed in 3 dogs with hypothyroidism and lymphocytic thyroiditis. Clinical features included lethargy, obesity, alopecia, insidious and progressive paresis, hypotonia, and slow segmental reflexes in 2 dogs. Obesity, alopecia, paroxysmal paresis, and behavior change were observed in the third dog. Laboratory tests indicated that thyroid function was less than normal in all 3 dogs. Abnormal electromyographic potentials and slow motor nerve conduction velocities were found in each dog. Muscle biopsy specimen abnormalities included selective type-II myofiber atrophy in all dogs, whereas one dog had angular atrophy of type-I and type-II myofibers indicative of denervation. A substance that stained with para-aminosalicylic acid was observed within vacuoles of type-I myofibers in one dog. Lymphocytic thyroiditis characterized by lymphocytic infiltration of excised thyroid glands was observed in all dogs.

Animals↗

PubMed1985

[Resistance of Mycobacterium tuberculosis. An 8-year survey in the Poitiers area].

We have studied in Poitiers area from 1977 to 1984 the resistance of 853 Mycobacterium tuberculosis strains to the main anti-tuberculosis drugs. The overall rate of drug resistance was showed to be steady over the years while the primary resistance rate has decreased. The only one drug resistance has concerned para-aminosalicylic acid, streptomycin and isoniazid. Foreigners, most of them Asian people or North-African people, often bear resistant tubercle bacilli (29,03%) compared with French people (9,29%). We encountered drug resistance phenomena essentially among less than 60 years old patients. Drug susceptibility tests remain indispensable for a good epidemiologic supervision at the time of relapses and among patients possibly infected with multiresistant germs.

Adult↗

PubMed1973

Controlled comparison of oral twice-weekly and oral daily isoniazid plus PAS in newly diagnosed pulmonary tuberculosis.

A controlled clinical trial was undertaken in 247 patients with newly diagnosed pulmonary tuberculosis to assess the relative efficacies of a fully supervised twice-weekly oral regimen of isoniazid plus PAS (para-aminosalicylic acid) and a standard self-administered daily regimen of the same drugs following an initial intensive phase of two weeks of daily streptomycin, PAS, and isoniazid. Among patients who had isoniazid-sensitive cultures initially and who attended the clinic regularly the numbers with a favourable bacteriological response at the end of the year of chemotherapy were 79 (88%) out of 90 for the twice-weekly regimen and 72 (87%) out of 83 for the daily regimen; the numbers of patients with considerable radiographic improvement were 54 (60%) and 53 (64%) respectively. Complaints of vomiting or diarrhoea that did not require a reduction of the PAS dosage were made on one or two occasions by 23(21%) out of 109 twice-weekly and 25 (23%) out of 108 daily patients, and on at least three occasions by 4 (4%) and 12 (11%) respectively. Finally, all five patients who had chemotherapy changed on account of hypersensitivity to PAS had been receiving the daily regimen, as also had one patient who died of agranulocytosis.

Adolescent↗

PubMed1967

A simple biological method for determination of small amounts of tuberculostatic agents in fluids.

The authors describe the use of the vertical diffusion test for determining the quantity of certain tuberculostatic drugs in body fluids and the degree of mycobacterial susceptibility to these drugs, using tubercle bacilli as test organisms. It is found to be a reliable assay method for isoniazid, para-aminosalicylic acid, ethionamide and ethambutol when carried out on a modification of Middlebrook 7H-10 solid medium containing 1.5% Oxoid Ion-Agar No. 2.As a drug-susceptibility test, it yields results expressed quantitatively in degrees of sensitivity or resistance and is therefore recommended for use only in laboratories not equipped for more comprehensive testing. The method may also be used for ascertaining the level of tuberculostatic activity of a patient's serum against his own mycobacteria.

Antitubercular Agents↗

PubMedDate not supplied

[Effect of theophylline and isoprenaline on N-acetylation activity in the rat liver].

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.

Acetylation↗

PubMed1976

Chemoprophylaxis in inactive tuberculosis: long-term evaluation of a Canadian trial.

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.

Aminosalicylic Acids↗

PubMed1976

Effect of sodium para-aminosalicylate on oxygen affinity in normal, sickle and fetal human blood.

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.

Adult↗

PubMedDate not supplied

Fractionated precipitation of acid macropolyanions by dialysis, a simple method for the estimation of DNA in complex biological samples.

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.

Animals↗

PubMed1977

P-aminosalicylate metabolism in cancer patients sensitive and resistant to chemotherapy.

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.

Acute Disease↗

PubMed1969

Intermittent chemotherapy for tuberculosis in an urban community.

A regimen designed for effective foolproof antituberculosis treatment, acceptable on a routine basis, was applied to all patients newly diagnosed at the Chest Clinic, Hammersmith Hospital, in 1963, 1964, and 1965. During the first three months of treatment patients received daily (six days a week) streptomycin 0.75 g. plus isoniazid 300 mg. plus sodium para-aminosalicylate (P.A.S.) 12 g. The P.A.S. was usually stopped when bacterial sensitivity reports made this possible. For a further 15 months streptomycin 1 g. plus isoniazid 600 mg. was given on three alternate days each week to complete a total of 18 months' treatment.Of the total of 140 patients (66% sputum-positive) 112 (80%) completed the planned 18 months with intermittent streptomycin plus isoniazid and a further eight completed treatment on alternative regimens (a total of 85%). The equivalent figures for one year are 88% and 94%. Excellent clinical and radiological results, together with sputum conversion, were achieved in 138 of the 140 patients (99%). Only two patients were lost from surveillance, because of failure to co-operate, before quiescence was obtained.It is concluded that the total efficiency of supervised intermittent treatment is greater than that of unsupervised daily regimens. Since 100% arrest of tuberculosis is possible with co-operative patients, less should not be accepted in developed countries.

Adolescent↗

PubMed1969