Improved specificity of the PABA test with p-aminosalicylic acid (PAS).

Until now use of the PABA test together with [14C] PABA to calculate the PABA excretion index has probably been the best adaptation suggested to enhance the specificity of this non-invasive pancreatic function test. Drawbacks of the method are the application of radioactivity, the fact that children, pregnant women, and patients with renal insufficiency have to be excluded from the test, and the possible interference of drugs and isotopes. We propose simultaneous administration of p-aminosalicylic acid (PAS) in the PABA test and quantification of the urinary PABA and PAS excretion with liquid chromatography. Urinary PABA and PAS excretion in six hours are comparable (69.5 +/- 8.4% and 65.6 +/- 18.4% respectively in five healthy volunteers). Application of the PABA/PAS ratio was compared with the urinary PABA excretion in 21 normal controls, 38 patients with pancreatic disease, and 42 patients without pancreatic pathology. The PABA/PAS ratio and the per cent PABA excretion correlated very well in pancreatic patients: (PABA/PAS ratio) = 0.0149 (% PABA) + 0.052 (r = 0.902). Use of the PABA/PAS ratio enhanced the specificity of the test from 76 to 89%.     

Improvement in the specificity of the PABA test (PFT) by combined PABA peptide/D-xylose administration and serum kinetic measurement?

To obtain higher specificity of peptide-PABA-test, an indirect pancreatic functions test, 150 mg N-BT-PABA together with 25 g D-Xylose in 300 ml tea were administered to a group of 68 persons. Maximal concentration of PABA and D-Xylose were investigated serum by time-concentration-curves 0, 60, 90, 120 and 150 min after test meal. Serum-PABA was found pathologically low in 18 of 20 patients with proofed chronic pancreatitis. In 16 of 17 patients with chronic pancreatitis serum-D-Xylose was normal. In a group of 39 patients, in which a pancreatic disease was excluded, PABA-serum-test showed no false-pathological results. In 7 patients with small-bowel diseases and pathological D-Xylose-test, PABA-serum-test was false-pathologically in 6/7 cases. By serum-PABA-time-concentration-curves there was a significant discrimination between patients with chronic pancreatitis and controls at 60, 90, 120 and 150 min (p less than 0.01), but early and late peak concentration of PABA was often found in the two groups. If the PABA-concentration was estimated only 120 min after test meal, diminished test-specificity was found. Peak-PABA-serum-concentration was significantly correlated with lipase output (p less than 0.001) and trypsin output (p = 0.01) at secretin-caerulein test, but PABA was only at low enzyme outputs pathological, showing a moderate sensitivity of test.     

Comparative trial of thiacetazone with isoniazid and paraaminosalicyclic acid (PAS) with isoniazid in the treatment of pulmonary tuberculosis in Nigerians.

A comparative trial of a combination of thiacetazone 150 mg with isoniazid 300 mg in a once daily dose and that paraaminosalicyclic acid 12 gm uith isoniazid 300 mg daily in divided doses was carried out on 72 specially selected patients with pulmonary tuberculosis over a period of 12 months. The result of the trial showed that patients treated with thiacetazone/isoniazid combination responded equally favourably to therapy as the patients treated with PAS/isoniazid combination. The result of sputum conversion was similar in both groups. Radiological changes after treatment showed a significant similarity in both groups. It was observed that the thiacetazone/isoniazid combination is no more toxic than the PAS/isoniazid combination. There was no case of blood dyscrasia during the trial. Of the 72 patients who started the trial, a total of 19 (26 per cent) patients defaulted before the end of the third month. However, the remaining 53 patients (74 per cent) completed the trial, and the final analysis was based on this number. It was concluded that thiacetazone (150 mg/day) was of similar efficacy when compared with PAS (12 gm/day) as a companion drug for isoniazid (300 mg/day) in producing sputum conversion, and radiological changes in Nigerian tuberculosis patients and is therefore to be preferred because of its relative cheapness and once-a-day administration.     

Biodegradable implants from poly-(alpha-hydroxy acid) polymers for isoniazid delivery.

SETTING: In vitro and in vivo study of an isoniazid (INH) drug delivery system. OBJECTIVE: To develop a system for the treatment of tuberculosis using a subcutaneous polymer implant with a large drug load released slowly over a long period. INH delivery by biodegradable poly-(alpha-hydroxy acid) polymers was evaluated using ground polymer and compression molded implants. DESIGN: Rate of drug release and structural stability of the implant in an aqueous environment were measured, as were in vivo evaluations of the duration of measurable levels of INH in serum and urine. RESULTS: Factors that influenced the suitability of an implant in an in vitro system included polymer molecular weight and crystallinity, polymer and drug particle size, drug loading dose, and press temperature and pressure. The implant characteristics that most closely approached optimal conditions include a polymer of 100% L-lactide with low intrinsic viscosity, polymer particle size <75 micron, and INH particle = 126-180 micron, INH loading dose not to exceed 46%, and press conditions of 70 degrees C and 345000 kPa. Studies of subcutaneous implants in rabbits and baboons show that INH is released from the implant for 15 to 26 weeks. CONCLUSIONS: An INH-containing polymer was developed that was structurally stable in an aqueous environment and that released INH over a period of at least 15 weeks. Studies with infected animals will be necessary to determine the dose required for prophylaxis and treatment of active disease.     

Perinatal carcinogenicity of isoniazid (INH) in swiss mice

Summary Tumorigenicity of isoniazid (INH) and hydrazine sulfate (HS) was studied in male and virgin Swiss mice. The INH and HS induced 50% und 84% lung tumors in males and 67% and 72% in females, respectively. Both chemicals induced lung tumors in animals of the F₁ generation that were exposed to INH or HS during intrauterine life, lactation, and in the postweaning period. Surprisingly, the F₂ generation from these F₁ animals, which were exposed to INH only during gestation and lactation, showed earlier and much higher tumor incidence than the parent generation.     

A study of the relationship between the resistance of Mycobacterium tuberculosis to isonicotinic acid hydrazide (isoniazid) and to thiophen-2-carboxylic acid hydrazide

Thiophen-2-carboxylic acid hydrazide (TCH) is used to distinguish TCH-sensitive bovine, 'Asian human' and 'African' strains from TCH-resistant 'classical' human strains of Mycobacterium tuberculosis. It has been claimed that this test cannot be applied to isoniazid-resistant strains as these also become resistant to TCH. Although such cross-resistant mutants were readily isolated in vitro, a study of the incidence of TCH resistance in a large series of INH-sensitive and -resistant strains isolated from patients indicated that the emergence of this type of mutant is the exception rather than the rule in vivo. Thus, the use of TCH for subdividing the species M. tuberculosis remains valid for epidemiological purposes, irrespective of the occurrence of isoniazid resistance.     

A case of isoniazid (INH)-induced pneumonitis]

A 58-year-old man was referred for the evaluation of a lung nodule on chest X-ray. On admission, chest X-ray showed a solitary nodule with cavitation in the left lung field. Histological examination revealed epithelioid cell granulomas and the diagnosis of pulmonary tuberculosis was made. He was treated with INH, ethambutol (EB), and rifampicin (RFP). On the 16th day of treatment, he developed dry cough and high fever. On the 20th day, dyspnea developed and PaO2 was decreased to 38.2 Torr. Chest X-ray showed new widespread infiltrates in both lung fields and bilateral pleural effusions. The size of the cavitary lesion was decreased. Transbronchial biopsy specimen showed slight interstitial thickening, lymphocyte infiltration, and multiple granulomas. Drug lymphocyte stimulation test was positive only with INH (230%). INH-induced pneumonitis was highly suspected. All drugs was discontinued and hydrocortisone 2400 mg daily was started. He soon became afebrile, and dyspnea and dry cough resolved. Chest X-ray film showed resolution of infiltrative shadows. He was subsequently successfully treated with streptomycin, EB, and RFP without any adverse effects. To our knowledge, this is the sixth reported case of INH-induced pneumonitis.