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A comparison has been made between 6- and 9-month regimens of streptomycin, isoniazid and pyrazinamide given daily, 3 times a week or twice a week from the start of chemotherapy, in the treatment of newly-diagnosed, smear-positive, pulmonary tuberculosis in Chinese patients. At 6 months the twice-weekly regimen was marginally inferior in that 5 (4 per cent) of 126 patients with drug-sensitive strains pretreatment had an unfavourable bacteriological status compared with only 2 (1 per cent) of 141 on the 3 times weekly and none of 137 of the daily regimen. Of a total of 211 patients treated for 9 months, only 1 of 74 on the twice-weekly regimen relapsed bacteriologically between 6 and 9 months. The bacteriological relapse rates in the first 6 months of follow-up after 6 months' chemotherapy were 13 per cent on the daily, 16 per cent on the 3 times weekly, and 18 per cent on the twice-weekly regimen, and after 9 months' chemotherapy they were 3 per cent, 4 per cent and 4 per cent respectively. All 33 relapses were with strains sensitive to isoniazid and streptomycin, and 76 per cent of them occurred in the first 3 months after the end of chemotherapy. Although patients with drug-resistant strains pretreatment fared less well, about two-thirds had a favourable bacteriological status at 6 months, and all 3 regimens given for 9 months had low relapse rates. The implications of these findings are discussed.

The effect of prolonged thiazide diuretic administration on renal urate handling was examined in 10 normal men, before and after 2 weeks of oral hydrochlorothiazide administration. Whereas urate excretion per unit of glomerular filtration rate (GFR) usually remained unchanged, urate clearance (C urate :GFR) decreased slightly but significantly after the administration of hydrochlorothiazide because of increased plasma urate concentrations in some subjects. To assess the relative importance of intact tubular secretion of urate in producing this response, each participant was given pyrazinamide (PZA), an agent that inhibits urate secretion. The decrement in urate excretion: GFR produced by PZA (PZA-suppressible urate excretion) did not change after the administration of hydrochlorothiazide, but the decrement in C urate : GFR (PZA-suppressible urate clearance) decreased significantly. Residual urate excretion rates and clearance values after secretory inhibition by PZA remained unchanged after hydrochlorothiazide was given. These results suggest that the excretion of secreted urate was blunted after prolonged treatment with hydrochlorothiazide. Whether this resulted from an inhibition of tubular secretion or from increasingly avid reabsorption of urate at a postsecretory tubular site presently is unclear.

The present study was undertaken to clarify the mechanism of the diabetogenic activity of streptozotocin. Experiments were conducted to determine the resistance of animals to the diabetogenic action of streptozotocin; to follow the time course of irreversible beta-cell damage, and to determine the influence on streptozotocin action of certain compounds. Streptozotocin, a broad spectrum antibiotic, with antitumoral properties, was shown to be diabetogenic in rats and mice, but not in cats, rabbits, or guinea pigs. Intravenous or intraperitoneal administration of 65 mg/kg body weight of streptozotocin to male Wistar rats evoked a tri-phasic blood sugar response. It induced an initial hyperglycemic peak with no apparent change in plasma insulin concentrations, followed by profound hypoglycemia caused by liberation of large amounts of insulin from the pancreas. Forty-eight hours after injection, the animals were completely diabetic. Light- and electron-microscopic exadminations during the first forty-eight hours after the injection of streptozotocin showed pyknosis, degranulation and marked degeneration of the beta-cells. 1egenerative and necrotic changes were also seen in a few alpha-cells. These streptozotocin-induced diabetic rats revealed polydipsia, polyuria, polyphagia and glucosuria, and decreased body weight. Blood sugar, plasma FFA and insulin concentrations were examined after oral administration of glucose (OGTT: 3g/kg). Blood sugar and plasma FFA were significantly elevated but plasma insulin concentrations were markedly decreased, so insulin treatments were most effective in these animals. It has been reported that nicotinamide prevents the diabetogenic activity of streptozotocin and the deformity action of 6-aminonicotinamide and 3-acetylpridine. Pre-treatment with picolinamide, methyl-nicotinamide, and nicotinohydroxamic acid also blocked its diabetogenic action, but nicotinic acid, mannoheptulose and glucose were ineffective. N-nitrosodimethylamin and ethyl-N-nitrosomethylcarbamate were devoid of diabetogenicity. It seems that streptozotocin interfers with NAD formation in the beta-cell. Functioning pancreatic islets cell tumors were observed on the rats both at 407 days after streptozotocin administration and at 473 days after streptozotocin administration with nicotinamide (500 mg/kg, i.p.).

Morphazinamide was shown to have an in vitro activity similar to an equimolar concentration of pyrazinamide. This activity was not due, as had been previously assumed, to pyrazinamide formed by hydrolysis from morphazinamide, since it was demonstrated in slide cultures containing tubercle bacilli which were incubated with freshly prepared dilutions of morphazinamide in acid medium for several successive periods of only 1 hour, during which time little hydrolysis occurred. A new method was used for measuring morphazinamide and pyrazinamide separately in plasma. In man, the estimated in vitro antibacterial activity was similar after approxmately equimolar oral doses of morphazinamide or pyrazinamide. However, it is uncertain whether the in vivo activity of morphazinamide is the same as its in vitro activity.

1 Dapsone, rifampicin, isoniazid and pyrazinamide were shown to penetrate readily into the sciatic nerves of the dog and sheep. 2 These findings suggest that the continued persistence of viable drug-sensitive leprosy bacilli in the peripheral nerves of patients treated for long periods with either dapsone or rifampicin is not due to inadequate intraneural drug penetration.

The relative contributions of volume expansion and increased fractional excretion of sodium to the uricosuria of saline infusion were assessed in 19 subjects by volume expansion with rapid infusion of 21 of hypertonic saline (3%), isotonic saline (0.9%), or hypotonic saline (0.45%). Urate excretion increased 385 mug/min (P less than 0.01) with hypertonic, 145 mug/min (P less than 0.05) with isotonic saline, and 294 mug/min (P less than 0.001) with hyptonic saline. When 150 meq of sodium chloride was administered as appropriate volumes of hypertonic, isotonic of hypotonic saline, the magnitude or uricosuria was correlated with volume load (r = 0.66, P less than 0.002). fractional excretion of sodium correlated with infusion volumes for all studies taken together (r = 0.35, P greater than 0.1). The relationship between fractional excretion of sodium and fractional excretion of urate was entirely attributed to their correlation with infusion volume. Both post-pyrazinamide urate excretion and pyrazinamide suppressible urate excretion increased with volume expansion.

Summary A variety of conditions are necessary in pyrazinamide sensitivity tests in order to cater for strains of different growth characteristics. A technique is described which employs stepped pH levels in two complementary media. Only one drug concentration is required.

Summary Eleven cases of far-advanced cavitated pulmonary tuberculosis, with organisms resistant to streptomycin, PAS and isoniazid, were treated with pyrazinamide plus oxytetracycline for at least three months. There was a fall in sputum positivity in ten of the cases with a subsequent rise in positivity coinciding with the emergence of pyrazinamide-resistant bacilli. No oxytetracycline resistance was encountered. Clinically there was some improvement in most of the cases, but there tended to be an “escape” from the effect of the drug in the second month of therapy after the emergence of drug-resistant organisms. No toxic effects attributable to pyrazinamide were noted. Oxytetracycline probably does not appreciably delay the onset of pyrazinamide resistance or prolong the short effectiveness of the drug when given alone.

In thirty-two studies on ten normal subjects, renal urate secretion and reabsorption have been estimated by noting the decrement in UV urate : C inulin produced by a maximally effective dose of pyrazinamide (TS ur ), a drug which markedly although probably not completely inhibits tubular urate secretion. In each subject studies were performed in the control state, after decreasing plasma urate with allopurinol, and following elevation of plasma urate levels by RNA loading. Urate reabsorption remained at an average of 98 per cent of filtered load at all plasma levels, thereby indicating progressive augmentation of reabsorptive transport velocity with increasing filtered loads. Also, tubular secretion per nephron was a direct function of plasma urate concentration. Although plasma urate levels ranged as high as 12.8 mg. per 100 ml., at no time was there evidence for attainment of a secretory or reabsorptive tubular transport maximum. A provisional normal standard was set forth, relating TS ur to plasma urate concentration through a regression treatment with appropriate confidence limits. These data suggest that normal man displays an augmented rate of bidirectional urate transport with increasing substrate availability. Due to the nature of this bidirectional transport system, an increase in secretory rate serves to increase net urate excretion and thereby provides the homeostatic mechanism which tends to minimize the hyperuricemic response to an increase in uric acid synthesis. The pyrazinamide suppression technic appears to provide a means of assessing the integrity of this homeostatic mechanism within the residual nephrons of the chronically diseased kidney or in patients who have gout.

The effect of ethambutol on uric acid metabolism was assessed in 14 patients, 8 with gout and 6 with tuberculosis. This antituberculous agent produces hyperuricemia by decreasing the renal clearance of uric acid. Although the exact mechanism responsible for this effect of ethambutol remains undefined, several characteristics were observed which distinguish the effect of this drug from that of other agents which produce hyperuricemia by altering the renal handling of uric acid.

SummaryPyrazinamide depresses Curate/GFR in the Dalmatian and non-Dalmatian dog. Stop-flow studies revealed unequivocal suppression of tubular secretion of urate in the Dalmatian and gave no indication of enhancement of tubular reabsorption of urate in the non-Dalmatian.

Beschrieben werden die Resultate, welche bei 125 patienten erreicht wurden, die wahrend mindestens 3 Monaten mit Pyrazinamid in Kombination mit einem oder mehreren von den bekannten Mitteln Streptomycin, PAS, INH behandelt wurden. Bei 64 von diesen 125 Patienten wurden vor Beginn der Therapie noch Tuberkelbacillen im Sputum gefunden. Bei gut 70% trat Sputumkonversion auf. Bei 78 Patienten konnten rontgenologische Besserungen nachgewiesen werden. Das Bestehen einer Resistenz gegen ein oder mehrere von den Mitteln Streptomycin, PAS, INH hat keinen deutlichen Einflus auf die Wirksamkeit des Pyrazinamid. Die Gefahr einer Leberschadigung kann unter strenger klinischer Kontrolle als gering gelten.

Pyrazinamide Up to now at the Carlo Forlanini Institute, about 100 patients have been treated with pyrazinamide.� Here we will report only a first group of 30 patients having undergone a whole regimen of therapy (four to six months), and for whom a number of biological tests were carried out that will be reported elsewhere. The above mentioned 30 patients (15 men and 15 women) were affected by various forms of pulmonary tuberculosis, of which 11 were moderately advanced (one essentially exudative, ten essentially productive) and 19 chronic (six essentially exudative, two with residual cavitation, one tuberculoma). Of these chronic forms, four (two productive, two exudative) showed some exacerbation phenomena at the start of pyrazinamide therapy. All patients had already received prior therapy with other antibiotics and antituberculosis chemotherapeutic agents, and most of them had presented tuberche bacilli in sputum more or less resistant to streptomyci isoniazid and PAS. Except for some cases without clinical findings, the objective auscultatory findings of the lungs were quite prominent. Patients were carefully selected so as to eliminate any that had evidence of hepatic dysfunction. The daily dose of the drug (divided into five times a day) was 2.5 gr. gradually reached at the fourth day of treatment. In addition to routine roentgenographic, planigraphic and laboratory examinations (B.U.N., F.B.S., urine, and sputum analyses), repeated controls were carried out. These were related to the peripheral blood count, serum electrophoresis, the phagocytosis index, MiddlebrookDubos test, P.B.I. urinary 17-ketosteroids, behavior of the specific proteases, serum lipase power, serum cholesterol, serum bilirubin, plasma fibrinogen, prothrombin time, colloidal serolabihity tests, hippuric acid and B.S.P. tests. In Table I the important clinical roentgenographic and laboratory results are summarized, before and after 80 days of therapy. The drug tolerance in the doses we used was generally good, except for appearance of arthralgic phenomena in three patients; in one, symp-�toms started after a few days’ treatment and were present in the articulations of the upper and lower members, but without tumefaction. It is to be noted that such arthralgic phenomena completely disappeared with

1. One hundred fourteen patients were treated with the combination INH-PZA for periods of one to 25 months. 2. Of eight showing no change on roentgen evaluation at the fourth month of treatment, it is considered significant that all eight had achieved bacteriological “conversion” and that five of the eight had persistent open cavity with negative sputum. Of 58 moderately and far-advanced cases, 22 showed marked improvement, 17 moderate improvement, 10 slight improvement, and only one showed worsening. 3. Of 55 treated at least four months with moderately and far-advanced disease, 80 per cent achieved bacteriological negativity during the first two months, with the vast majority doing so during the first month of treatment. An additional 13 “converted” during the third and fourth months. Four patients (7 per cent) remained positive, and they all became resistant to INH within two months. 4. Of 19 cases with a cavitary component 4 cm. or more, 11 became “open negative,” four became “closed negative,” and four remained “open, positive, resistant.” Evidence of hepatic toxicity was obtained in 15 per cent of 114 cases only by an abnormal liver function test. Clinical hepatic involvement as well occurred in an additional 4 per cent. There was one death with jaundice; its relationship to PZA is doubtful. All evidence of hepatic toxicity, clinical or laboratory, appeared in a scattered fashion during the first 10 months of treatment; no toxicity was detected in 12 cases receiving PZA for 10-25 months. 5. The achievement of bacteriological negativity with persistence of open large cavity appears to happen much more often with INH-PZA than with various combinations of SM, INH and PAS. 6. The major disadvantage of INH-PZA therapy is the hepatotoxicity of PZA which manifests itself in most of the cases only by abnormal laboratory tests. Because of this it is felt that INH-PZA should be used only in those cases in whom frequent liver function studies can be done, and that further effort should be directed towards finding more sensitive laboratory indices of early PZA toxicity.

Summary The minimal inhibitory concentration of rifamide in Dubos liquid medium without tween 80 for human type tubercle bacilli is 0·5 μg. or less. The bovine type is slightly more sensitive than the human type. Avian strains, photochromogens and nonchromogens are resistant. There is no evidence of cross-resistance between rifamide and other antituberculosis drugs. The intravenous rifamide and the oral rifampicin are similar in their inhibitory activity. Individual doses of 450 mg. or 600 mg. rifampicin before a meal are generally followed at two hours by serum levels of 16 or 32 μg./ml. At 12 hours they are 1 or 2 μg. and at 24 hours only a trace or nil.

Summary Seventy-eight patients with chronic disease were treated with ethionamide (1 g. per day), in 73 instances in combination with a drug to which the bacteria were still sensitive. In the remaining 5 instances no effective companion drug was available. Thirty-two of these patients were sooner or later unable to tolerate the drug. Results at three months have been analysed for 35 patients on ethionamide/PAS; 6 on ethionamide/pyrazinamide; 5 on ethionamide alone; 4 on ethionamide/isoniazid; 3 on ethionamide/streptomycin and 1 on ethionamide/cycloserine. In about half the cases some degree of initial ethionamide resistance was noted although patients had not previously received the drug. Drug resistance invariably rapidly developed or increased in patients treated with ethionamide alone, and resistance tended to develop or increase in a proportion of patients in whom ethionamide was accompanied by PAS or other drugs to which the organisms were initially sensitive. The value of the drug when combined with PAS appears to be limited by the inability of many patients to tolerate it in a dosage high enough to prevent the emergence of resistant organisms. Experience with ethionamide combined with other drugs was too small to permit firm conclusions to be drawn. The impressive radiological and bacteriological results obtained with ethionamide and PAS in a considerable proportion of patients with intractable disease suggests that ethionamide may prove a useful therapeutic agent.

Thirteen non-gouty and twelve gouty men to whose regular diet was added 4 gm. of ribonucleic acid (RNA) daily, developed increases in plasma uric acid, urinary excretion of uric acid and derived parameters, without significant differences in the mean increments in non-gouty and gouty subjects. Ten non-gouty and seventeen gouty men were given intravenous injections of 1.1 to 2.5 gm. uric acid to impose even greater demands upon the tubular mechanisms for transfer of uric acid, and again the mean increments in the urinary excretion of uric acid and uric acid clearance in non-gouty and gouty subjects were indistinguishable. Pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid, was found to suppress the urinary elimination of rapidly infused uric acid in gouty and non-gouty subjects alike. The data indicate that gouty subjects can excrete large extraneous loads of uric acid with as much facility as normal man, and support the view that this obtains also for the usually smaller and more slowly delivered endogenous uric acid loads natural to gout. The results thus argue against any intrinsic defect, peculiar to gout, in the renal mechanisms for excretion of uric acid. Briefly reviewed is the evidence that tubular secretion of uric acid occurs in non-gouty and gouty man, indeed that virtually all the uric acid appearing in the urine ordinarily derives from tubular secretion, hence virtually all the filtered uric acid ordinarily must be reabsorbed. It is pointed out that in this version of the filtration-reabsorption-secretion hypothesis there need be no simple relationship between the filtered and excreted uric acid, a dissociation found in gout that has been interpreted by others as indicating a primary tubular defect in transfer of uric acid. The implications of the filtration-reabsorption-secretion hypothesis in respect to other aspects of the renal regulation of uric acid are discussed in relation to excretion of uric acid in normal and gouty man under natural and artificial conditions of uric acid loading. The present study, limited to over-all clearances, gives no information as to the precise mechanisms or quantitative aspects of tubular secretion of uric acid in normal or gouty man, nor does it explain just how renal excretion of large and rapidly imposed uric acid loads is regulated.

Summary Patients with chronic pulmonary tuberculosis, whose sputum contains tubercle bacilli resistant to the standard drugs, streptomycin, PAS and isoniazid, are usually looked upon as having a poor prognosis with regard to cure of their disease in comparison with patients having acute disease and tubercle bacilli sensitive to the standard drugs. Accordingly, it is common to find a lack of enthusiasm by patient and physician to persist with treatment. Twenty-six patients with chronic tuberculosis, resistant to the standard drugs, received treatment with daily ethionamide (0·5 g. twice daily), pyrazinamide (2–3 g. daily in two doses) and cycloserine (0·75–1 g. daily in two doses). These three drugs formed a combination about which the patients had many complaints, and many alterations, reductions and interruptions of treatment occurred. 4 patients discontinued treatment early in the course of the investigation. Twenty-two patients persisted with long-term treatment. At the end of 3 months treatment, 20 of the 22 patients became sputum negative on smear and culture and after 7 months all 22 patients were negative. The aim is to give all patients 2 years chemotherapy. 17 have had, so far, 18 months treatment or more. 14 have remained sputum negative for 18 months or more, another 5 have been negative for 1 year or more, 1 died of a streptococcal empyema after being sputum negative for 11 months and 2 relapsed and became sputum positive again after being negative for 5 and 8 months respectively. These 2 patients failed to carry out instructions regarding continuation of treatment after leaving hospital. This high rate of sputum conversion among patients with chronic tuberculosis is likely to be obtained, not merely by the substitution of new anti-tuberculosis drugs for standard drugs, but by the development of a strong doctor-patient relationship of confidence and discipline. The tubercle bacilli from all patients were fully sensitive to ethionamide, pyrazinamide and cycloserine before the start of treatment. During the course of treatment, 1 patient developed definite evidence of resistance to ethionamide but he was rendered negative with a re-arrangement of chemotherapy. Resistance to pyrazinamide and cycloserine was not encountered in any patient. Our experience of side effects from the three drugs are described and the experience of others discussed. On the basis of this study we feel confident in saying that about 80% of patients with chronic pulmonary tuberculosis, resistant to the standard drugs, can be rendered sputum negative with the course of treatment outlined in this paper.

A twenty-three year old man was found to have low serum urate concentrations (0.9 to 1.8 mg/100 ml) during evaluation for recurrent urinary calcium oxalate stones. His urinary clearance of uric acid was markedly increased (30 to 46 ml/minute), and was only minimally decreased after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. No other renal tubular abnormalities were detected. His sister also was hypouricemic and had an increased renal clearance of uric acid. We suggest that this man had a genetically determined renal abnormality affecting tubular reabsorption of uric acid; a similar defect is present in the Dalmatian coachhound. The association of idiopathic hypercalciuria with the renal uric acid reabsorptive defect in this case is probably fortuitous.

PZA-INH併用により過尿酸血症を起こした肺結核患者79例について,血中尿酸値に対するProbenecid (PBC)の影響を観察し,更にPZAによつて惹起された関節痛に対するPBCの効果を検討した. PZA過尿酸血症の14例にPBCを連日2週間併用し,著明な血中尿酸値の下降を認めた.又PZAにPBC隔日長期併用例では, PZAによる過尿酸血症が抑制される成績をえた.関節痛発生の11例に過尿酸血症がみられ,血中尿酸値は平均8.2 (6.6～13.2)mg/dlであつた.関節痛はPBC非併用群42例中16.7%に発生をみたが,これに対してPBC併用群では関節痛の発生はなかつた.以上の如く, PBCはPZA過尿酸血症の抑制,関節痛の治療及び予防に可成りの効果が期待出来る.又PZA投与中の関節痛の発生は過尿酸血症と関係が深いが,その発生には他の要因のあることも無視しえない.

249 humane, 27 bovine, 20 photochromogene und 7 BCG-Stamme wurden mittels Niacin-Test (Konno, mod.Bonicke undLisboa bzw.Runyon u. Mitarb.), Nitratreduktase-Test (Virtanen, quantitative Modifikation nachBonicke u. Mitarb.), Hohe-Schicht-Agar-Test (Lebek, mod.Schmiedel 1960) und Pyrazinamid-Diffusions-Test (Schmiedel 1963) typisiert. 196 humane, 10 bovine und die 20 photochromogenen Stamme waren fur INH resistent (0,2–50 mcg/ml). Der Niacin-Test in der vonBonicke undLisboa modifizierten Form versagte bei 7% der humanen Stamme, uberwiegend bei schlecht wachsenden, INH-resistenten. Zwei der sieben BCG-Stamme reagierten positiv. Mit den ubrigen Testen gelang es—bis auf vier Stamme (1,3%)—alle Mycobakterienstamme eindeutig zu differenzieren. Bei diesen vier Stammen handelte es sich um drei human-bovine Mischkulturen und einen humanen, INH-resistenten, dysgon wachsenden Stamm. 52 Stamme der verschiedenen Typen konnten im Pyrazinamid-Diffusions-Test nicht getestet werden, da sie auf dem Serumagar (pH 5,6) nicht wuchsen. Kamen die Stamme zum Wachstum, dann waren die humanen und fast alle photochromogenen Stamme Pyrazinamid-sensibel und die bovinen und BCG-Stamme resistent.

The addition of chemotherapeutic agents to the armamentarium for the treatment of tuberculosis has been of inestimable value in decreasing morbidity and mortality. It has been largely responsible for the great progress in resectional pulmonary surgery, which otherwise usually would have been denied the patient. As is well known, however, bacterial resistance to the antimicrobial drugs has developed in a sizable tuberculous population and this may present an ever-increasing problem in the future treatment and retreatment of tuberculosis. Unless proper use of specific drug combinations is effected at all times to meet the particular problem at hand, the effectiveness of the drugs will be lost in a significant percentage of cases. Many workers are making great strides toward preventing resistance by application of carefully selected treatment schedules and well-timed definitive surgery. At present, a large backlog of patients is developing with open positive lesions harboring tubercle bacilli either proved or presumptively resistant to PAS, INAH and streptomycin. These are posing a special problem and require most thoughtful handling by the specialist team. Many reports now attest to the increased percentage of complications that occur whenever resection is attempted in the presence of tubercle bacilli resistant to the antimicrobial therapy. Coleman and Bunch1 early pointed out the increased incidence of major complications, especially bronchopleural fistulae, following surgery in patients with streptomycin resistant strains. Murphy2 reported satisfactory results in only 77.6 per cent of operations for cavitary lesions as compared to 94.7 per cent where closed lesions had been resected. Where sputa were positive, only 82.8 per cent of the patients had good results as compared with 94.4 per cent when the sputa were negative. Holland, Bell and Welles3 found similar results in 75 patients with open positive lesions. Of an original chemotherapy susceptible group, there was only one major complication in 19 resections as contrasted with five complications in nine resections in the presence of bacterial resistance. The retreatment group had three major complications in 22 resections if the bacilli were susceptible, but with resistant organisms there were nine major complications in 33 resections. Overall favorable results were achieved in

Summary A controlled comparison has been made of streptomycin plus pyrazinamide (46 patients) and streptomycin plus PAS (36 patients) in the retreatment of patients with pulmonary tuberculosis. The patients had either failed to attain bacteriological quiescence on isoniazid alone or had relapsed bacteriologically after attaining quiescence; all were excreting strains of tubercle bacilli resistant to isoniazid but sensitive to streptomycin and PAS at the start of the trial. The disease status at 1 year was assessed in 41 patients on pyrazinamide and 24 on PAS, and of these, 29 (71%) and 12 (50%), respectively, had bacteriologically quiescent disease. Seven patients (2 on pyrazinamide, 5 on PAS) had their treatment terminated for toxicity, 1 due to a pyrazinamide polyarthritis, 2 on account of hypersensitivity to PAS, and 4 (1 on pyrazinamide, 3 on PAS) because of streptomycin toxicity. Nine patients (2 on pyrazinamide, 7 on PAS) became unco-operative and stopped treatment, and 2 patients (on pyrazinamide) died, 1 of a non-tuberculous condition. Thus, streptomycin plus pyrazinamide was slightly more effective therapeutically than streptomycin plus PAS and was not more toxic or less acceptable to the patients.

Observations are presented on the behavior of populations of tubercle bacilli in the tissues of mice during the administration of antimicrobial drugs. The behavior of the populations during therapy with any particular drug was different depending upon whether the tubercle bacilli were subsisting in the lung or in the spleen. Moreover, the pattern of microbial behavior was distinctive and predictable for each drug studied. Changes in the size of the populations of tubercle bacilli in the tissues appeared to be a more sensitive reflection of drug influence than microscopic study of the number and character of the tuberculous lesions. Nevertheless, in untreated animals, pulmonary lesions evolved and progressed steadily to a fatal outcome despite the fact that the populations of tubercle bacilli had stabilized at a relatively high census early in the course of therapy. The uniform persistence of tubercle bacilli in the spleen throughout prolonged drug administration was demonstrated with every drug or multiple drug regimens except for pyrazinamide when accompanied by isoniazid. Cultures of the bacilli which survived in the tissues despite antimicrobial therapy were highly susceptible to the drugs employed when tested in vitro. Thus the survival of the tubercle bacilli in the tissues represented microbial persistence rather than drug resistance. When pyrazinamide and isoniazid were administered together, it was not possible to detect the microorganisms in the spleen or lungs of treated animals. A detailed investigation of this apparent abolition of microbial persistence forms the subject of an accompanying report.

われわれは初回治療肺結核患者にPZA・INH療法を実施して,その臨床成績を詳細に検討すると共に,本療法と他種化学療法の治療成績を比較検討し,概ね次の如き結論を得た. 1) 本療法はSM・PAS併用療法や三剤併用療法, INH単独療法に比し,治療初期に明らかに速効的な治療効果が認められる. 2) 本療法による病状の改善は概ね6カ月以内に終了する.従つて本療法による治療期間は6カ月が適当で,それ以後は他種療法に変更することが望ましい. 3) 本療法の特徴はA・B・E型のみならずC・F型の病変にもよく奏効すること及びKc型空洞に対する効果が三剤併用療法以上に優れていることである. 4) この様な結果から早期に病状の改善が認められる本療法は,初回治療例に対する治療法として甚だ有利な方法であると結論できる. 5) 1力年治療時の成績は三剤併用療法と殆ど選ぶところがない. 6) 本療法の副作用の主たるものは,肝機能障害,関節痛である.

The acute effects of intravenous (i.v.) probenecid and chlorothiazide on renal urate handling were investigated in paired studies in normal men. Uricosuric responses to these agents were compared in the same subjects, both without and with pyrazinamide (PZA) pretreatment. Assuming that PZA selectively inhibits the tubular secretion of urate and that uricosuric agents act by increasing the excretion of filtered urate, then the uricosuric responses (the increment in urate excretion or clearance) should have been unaffected by PZA. Defined in this manner, however, uricosuric responses to probenecid and chlorothiazide were significantly decreased after PZA pretreatment. In order to determine whether PZA diminished other renal actions of chlorothiazide, changes in sodium and inorganic phosphorus excretion were examined. Chlorothiazide produced equivalent natriuretic and phosphaturic responses after PZA pretreatment, indicating that PZA does not interfere with at least some of the renal actions of chlorothiazide. In separate studies, PZA depressed urate excretion by at least 68% during the maintenance of chlorothiazide-induced natriuresis and phosphaturia, suggesting that chlorothiazide does not diminish the anti-secretory action of PZA. The results suggest that probenecid and chlorothiazide may derive their uricosuric properties by facilitating the excretion of both filtered and secreted urate. Possibly, increased excretion of secreted urate might occur through modulation of urate reabsorption at a site distal to tubular secretion, rather than by the direct acceleration of secretory transport. However, PZA-induced interference with the actions of probenecid and chlorothiazide on renal urate transport mechanisms cannot be excluded as a possible explanation for the present results.

Marked hypocalcemia Hypomagnesemia, tetany, hypokalemic alkalosis and hypophosphatemia developed during conventional dose viomycin-pyrazinamide treatment of pulmonary tuberculosis in a middle-aged man. Recovery of renal potassium conservation required nine weeks, but serum calcium and magnesium normalized after three weeks of replacement therapy.

Summary Fifty-seven patients with chronic pulmonary tuberculosis and organisms sensitive to streptomycin were treated with daily streptomycin plus pyrazinamide, the majority attending a clinic daily for the therapy; all had previously been treated either with isoniazid plus PAS or with isoniazid alone. The streptomycin plus pyrazinamide regimen was stopped in 20 patients before the end of a year because the disease was active, and 1 more patient died. Of the 36 patients who completed 1 year's treatment, 32 had attained bacteriological quiescence and 1 more is considered to have done so. Sputum conversion was very rapid in those patients who attained bacteriological quiescence. Patients whose response was unsatisfactory usually had a clear 'fall and rise' in the bacterial content of the sputum associated with the emergence of strains highly resistant to streptomycin. Extensive or moderate cavitation, a large total extent of the radiographic lesion and heavily positive sputum on smear examination were relatively unfavourable prognostic signs. Age and sex were not of prognostic importance. Toxicity to streptomycin was not a problem. Liver toxicity to pyrazinamide was not encountered, but joint pains occurred in 15 patients 6 of whom had a gouty syndrome. Seven patients received the combination throughout pregnancy, without developing toxic manifestations. The study has shown the value of long-term daily streptomycin plus pyrazinamide, as an out-patient treatment in India, for tuberculous patients in whom a first course of chemotherapy has failed.

Summary Eighty-two patients with cultures of mammalian tubercle bacilli resistant to isoniazid (78 also resistant to streptomycin and 52 to PAS) admitted to National Jewish Hospital between December 1, 1960 and October, 1, 1962, are included in this study. They were treated with chemotherapy regimens consisting of ethionamide, kanamycin and either pyrazinamide or cycloserine. None of the primary drugs was included in the therapy regimens. Seventy-four of the 82 patients were treated continuously with antituberculosis drugs for at least 120 days. In 70 (94%) the sputum became negative on culture. Twelve patients later reverted to culture-positive. Fifty-eight (79%) of the 74 patients remained culture-negative, throughout the follow-up period. Of the 16 patients who remained or later became culture-positive, nine were again treated. Seven of the nine became culture-negative on a regimen usually consisting of at least two of the following drugs: ethambutol, capreomycin, ‘Isoxyl’. By January 1, 1964, 60 (81%) of the 74 patients who had had at least 120 days treatment were known to be still culture-negative the period of follow-up being from 21 to 37 months from the start of treatment. The incidence of toxic drug reactions does not contraindicate the use of these drug regimens. Whenever possible, pulmonary resection should be considered as soon as two consecutive sputums obtained two weeks apart are culture-negative. The availability of multiple-drug regimens suggests that the prognosis need not be poor in those patients with cultures resistant to the first-line drugs. If the second-line drugs are both properly selected and administered, the retreatment results should compare favourable with the nearly 100 per cent success initial therapy.

Populations of tubercle bacilli of human origin exposed in vivo to pyrazinamide and a companion drug, vanished from the tissues of the mouse in so far as could be determined by microscopy, culture, or guinea pig subinoculation. The vanishing did not represent a complete elimination of the tubercle bacilli from all the animals. 90 days after the completion of treatment, tubercle bacilli could be cultured from approximately one-third of the animals examined at that time. This complete disappearance of the tubercle bacilli thus meets the definition of a truly latent infection in that the infection is present but is hidden beyond the limits of diagnostic reach. All but one of the strains of tubercle bacilli which survived in the animals and were detectable in the posttreatment period, were susceptible to pyrazinamide when tested under appropriate conditions in vitro. Only two factors could be identified which were essential for the uniform occurrence of the disappearance of tubercle bacilli: the administration of the pyrazinamide in a high daily dosage for at least eight of a total of 12 weeks of antimicrobial therapy; and the concurrent or prior exposure of the microbial populations to isoniazid or in some cases to other antituberculous drugs. The observations suggest that the ability of pyrazinamide-containing chemotherapies to bring about the disappearance of a tubercle bacillus is closely related to the occurrence of some alteration in the bacillus, essential for maximal pyrazinamide action, in response to environmental influences, including other antituberculous drugs present in the environment.

Summary One hundred and nine patients with organisms resistant to at least two of the standard anti-tuberculous drugs were admitted to hospitals in Edinburgh between 1953 and 1958. In 71 patients there was resistance to two of the drugs only, and in 43 (61 per cent.) the sputum has become and has continued to be negative. The most effective combination was tetracycline 4–5 g. with isoniazid, but this failed in 40 per cent. Streptomycin and tetracycline gave poor results, the sputum becoming negative in only 2 out of 10 patients. In 38 patients there was resistance to all three standard drugs. In 16 (42 per cent.) the sputum became permanently negative. Viomycin and tetracycline, followed by operation, was the most effective regime, the sputum becoming negative in 38·3 per cent. Very poor results were obtained with regimes such as pyrazinamide and tetracycline, cycloserine and tetracycline, pyrazinamide and cycloscrine, and cycloserine alone. With organisms resistant to two of the standard drugs, a combination of pyrazinamide and the remaining standard drug seems to be the regime of choice. With resistance to all three standard drugs the most effective regime may be the triple regime of ethionamide, pyrazinamide and cycloserine, probably with viomycin in addition, followed by surgery.

A previously reported form of microbial persistence whereby large populations of tubercle bacilli can be made to "vanish" uniformly from the tissues of mice has been shown to occur generally throughout each group of animals subjected to the experimental procedure; it does not reflect the eradication of the bacilli in the majority of animals with their persistence and ultimate revival in only a minority. The one demonstrable alteration of the tubercle bacilli while "vanished" is that they are sterile. Thus, they are undetectable by cell-free culture, tissue culture, and blind animal passage, i.e. by any method based on microbial multiplication. Whether they have also undergone alteration in morphology and persist in some unconventional form cannot be stated. Acid-fast forms similar to tubercle bacilli can be detected in small numbers by intensified microscopic search of tissue homogenates but the relationship of these forms to the sterile bacilli that ultimately revive is unclear. Thus, the persisting tubercle bacilli are more correctly designated as being in a "sterile state" than one of true latency. The uniform induction of the sterile state is a specific phenomenon requiring the participation of both the nicotinamide derivative, pyrazinamide, and isoniazid. Once assumed, this sterile state is relatively stable and the time required for revival of the tubercle bacilli in the spleens in one-half the animals is seven months. This process can be speeded up by the administration of large doses of cortisone in the third or fourth month after sterilization but revival is not significantly affected by the administration of cortisone earlier.

Summary The late results, five years after the start of treatment, are given in 122 patients with far-advanced tuberculosis and cultures resistant to streptomycin, isoniazid and PAS. Thirty-nine had chemotherapy and early surgical treatment and 83 had chemotherapy alone (surgical treatment was used in four after a relapse). The following drugs were used: ethionamide (0·5 g, twice daily), pyrazinamide (0·5 g. three times daily), cycloserine (0·25 g. three times daily), viomycin (1 g. daily or 2 g, twice a week). Fifty-five of the 83 patients were treated initially with three of the secondary drugs for a minimum of three months and an average period of 12 months; treatment was then continued with two drugs. Fifty-three (96%) became negative on culture. In two patients the treatment failed initially; both had one of the drugs (viomycin) intermittently and, as discovered later, one had no appreciable concentration of ethionamide in the serum after either oral or rectal administration of the drug. Eight (14%) had a late bacteriological relapse. They did not take drugs regularly. In four of them the cultures became resistant to secondary drugs. Five became negative again with further treatment (two of them after surgery). Ten patients died, six of them after the sputum had become persistently negative. Twenty-eight patients had only one or two drugs initially: only 11 (40%) became negative, three of them after retreatment with three-drug combinations. Nineteen died and in 16 of these sputum was still positive. There was no significant difference between the three-drug and two-drug group in the severity of disease and other relevant factors. The difficulties of treatment with secondary drugs are emphasized. However, satisfactory long-term results can be obtained if some basic rules and principles of good chemotherapy are observed, and if the patients are willing to co-operate.

Nicotinamide adenine dinucleotide glycohydrolase (NADase) activity of mice liver was increased after infection with strains of tubercle bacilli either susceptible or resistant to pyrazinamide. Pyrazinamide and nicotinamide, as well as isoniazid, suppressed the increase of NADase associated with tuberculous infection with the bacilli susceptible to these drugs. Pyrazinamide and nicotinamide did not influence the increased NADase produced by bacilli resistant to these drugs. the effects of pyrazinamide and nicotinamide on the host metabolism in tuberculous infection with susceptible bacilli were likely due to their antimycobacterial activities and not their direct action on host metabolism.