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PubMed1989

Does pyrazinoic acid as an active moiety of pyrazinamide have specific activity against Mycobacterium tuberculosis?

The commonly accepted hypothesis explaining the mechanism of action of pyrazinamide (PZA) is based on the assumption that PZA-susceptible Mycobacterium tuberculosis strains produce pyrazinamidase, which hydrolyzes PZA to the antibacterial moiety pyrazinoic acid (POA). It is not clear whether POA has specific antimicrobial activity or the inhibition of growth caused by POA is due to its ability to lower the pH of the environment below the limits of tolerance of M. tuberculosis growth. We confirmed in this study that POA, depending on the concentration, lowered the pH of 7H12 broth (pH 6.0), which ranged from 5.8 at 120.0 micrograms/ml to 4.6 at 960.0 micrograms/ml. Therefore, we tested the inhibitory effects of different concentrations of POA in broth in which the final pH was adjusted to 5.6 by adding appropriate amounts of phosphoric acid or dipotassium phosphate. Under these conditions, we found a clear dose-response correlation, proving that POA does have specific antimicrobial activity. The MIC of POA at pH 5.6 was 240 to 480 micrograms/ml, 8- to 16-fold higher than the MIC of PZA under the same conditions and much higher than the concentrations achievable in humans. This suggests that the action of POA in an acid environment is a combined effect of its specific activity and its ability to lower the pH below the limits of tolerance of the target organism.

Culture Media↗

PubMed1990

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3.

Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The relative impotency of streptomycin against TB in MPs and the contrary greatly increased potency of pyrazinamide (PZA) have been attributed to the fact that these vacuoles are phagolysosomes and, therefore, acidic. Chloroquine (CQ) is a lysomotropic base which can be used to raise phagolysosomal pH. Consequently, it was tested for its ability to increase the anti-TB effectiveness of streptomycin and decrease that of PZA in cultured human MPs. MPs infected with virulent Erdman strain TB were incubated in medium with various combinations of the drugs. Samples were taken at 0, 4, and 7 days and lysed for CFU counts of viable TB on nutrient agar. As expected, CQ increased the effectiveness of SM, but unexpectedly, it did not decrease that of PZA. CQ alone was found to be able to inhibit intracellular TB. Because of this, it was also tested with isoniazid, 1,25(OH)2-vitamin D3, and 25-OH-vitamin D3. It significantly enhanced the anti-TB protectiveness of both isoniazid and 25-OH-vitamin D3. Some combinations of CQ and the various drugs tested were able to kill intracellular TB. These results suggest that CQ may be useful in the treatment of tuberculosis.

Adult↗

PubMed1992

Antagonism between isoniazid and the combination pyrazinamide-rifampin against tuberculosis infection in mice.

Mice that had been inoculated intravenously with 6.30 log10 Mycobacterium tuberculosis H37Rv 14 days earlier were administered one of three combinations of drugs, i.e., isoniazid (INH)-rifampin (RMP)-pyrazinamide (PZA), INH-RMP, and RMP-PZA, during an initial 2-month period to mimic the initial phase of chemotherapy for human tuberculosis and during a later 4-month period to mimic the continuation phase of chemotherapy. At the end of the initial phase, all three combined regimens were found to have been highly effective in terms of the number of CFUs in the spleens of infected mice. The bactericidal activities of INH-RMP-PZA and INH-RMP were similar, whereas that of RMP-PZA was significantly greater. The spleens of all of the mice that had been treated initially with INH-RMP-PZA were culture negative by the end of 6 months of treatment, regardless of the regimen employed during the continuation phase. However, after an additional period of 6 months without treatment, the proportion of spleen culture positivity, or relapse rate, was significantly smaller in the subgroup treated with RMP-PZA during the continuation phase than in the subgroups treated with INH-RMP-PZA or INH-RMP; the relapse rate did not differ significantly between the latter two subgroups. These results suggest that antagonism occurs between INH and the combination RMP-PZA during both the initial and continuation phases of chemotherapy, compromising the benefit conferred by the addition of PZA to the combined regimen. The preliminary pharmacokinetic analysis suggested that the pharmacological interaction between INH and RMP was very likely to be involved in the mechanism of antagonism, as concomitant treatment with INH had significantly reduced the peak serum level and the area under the serum concentration-time curve of RMP in mice.

Animals↗

PubMed1987

Evaluation of the renal mechanisms for urate homeostasis in uremic patients by probenecid and pyrazinamide test.

The tubular transport of urate was studied in 47 uremic patients and in 20 normal subjects using probenecid and pyrazinamide tests. There was a marked increase in urate excretion per nephron as the renal function deteriorated. Presecretory reabsorption of urate per nephron, which was almost complete in normal subjects, showed a diminution with increasing severity of chronic renal failure. Until the creatinine clearance had decreased to less than 10 ml/min, the secreted urate per nephron remained almost constant, while in the end stage of renal failure it was markedly decreased. With the progression of renal disease, the postsecretory reabsorption of urate per nephron diminished. In patients with a creatinine clearance less than 10 ml/min, it was 4 times lower than in normal subjects. These findings indicate that urate secretion does not contribute to the increase of urate excretion per nephron at any level of renal failure, whereas the impairment of both reabsorptive components accounts for the augmented urate excretion per nephron in uremic patients.

Absorption↗

PubMed1989

1,25(OH)2-vitamin D3 synergizes with pyrazinamide to kill tubercle bacilli in cultured human macrophages.

Pyrazinamide (PZA) is believed to be mycobactericidal in vivo. Because it is ineffective at neutral pH in vitro, it is thought to owe its in vivo activity at least partly to acting upon tubercle bacilli (TB) in the helpfully low pH of macrophage (MP) phagolysosomes. However, when it was tested in TB-infected cultured human MP, it was not bactericidal and was able only to slow intra-MP bacillary growth. Recent evidence has suggested that human MP need hormonal support from certain vitamin D metabolites to resist TB. This support was not provided in the culture medium of the earlier experiments in which the PZA was relatively ineffective. Here, PZA has been retested in MP cultured in medium supplemented with the hormonally active metabolite of vitamin D, 1,25(OH)2-vitamin D3 (1,25D3). The MP were infected with virulent TB and incubated in various concentrations of PZA. 1,25D3 was added to postinfection medium at 4 micrograms/ml. Inhibition or killing of intracellular TB was quantitated by counts of culturable TB from samples of lysed MP taken at zero, 4, and 7 days after MP infection. Previous evidence for the protectiveness of 1,25D3 alone for human MP against TB was confirmed. The weak inhibition of TB in MP by PZA alone also was confirmed. The two used together synergized to decrease concentrations of PZA which were inhibitory and to switch the action of PZA from weakly inhibitory to bacteriostatic or mildly bactericidal. 1,25D3 had no direct anti-TB effect, and it did not synergize with PZA in the absence of MP, as determined with acidified bacteriologic culture medium in the BACTEC radiometric system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide.

In a first experiment, the efficacy of a 6-month course of isoniazid (INH) alone in comparison with 2-month courses of rifampin (RMP) alone, RMP + pyrazinamide (PZA), or RMP + PZA + INH as preventive therapy of tuberculosis was evaluated in the mouse. To simulate the infected, non-diseased state of humans, a nonreplicating bacillary population of limited size was developed in the mouse. Mice were vaccinated intravenously with 2.74 log10 M. bovis BCG and infected a month later with 3.38 log10 M. tuberculosis. Treatment began 2 wk after infection when the mean size of the M. tuberculosis population was 4.98 +/- 0.26 log10 cfu in the spleen. After 2 months of therapy, the proportion of mice with positive spleen cultures was 100%, 50%, 0%, and 20% in those animals treated, respectively, with INH alone, RMP alone, RMP + PZA, or RMP + PZA + INH. After 6 months of therapy with INH alone, the proportion of mice with positive spleen cultures was 38%. In order to confirm the extreme activity of the combination RMP + PZA and to assess the value of 3 months of therapy with RMP, a second experiment was performed following similar procedures. On completion of treatment, the proportion of mice with positive spleen cultures was 100%, 20%, 0%, and 80% in those animals treated, respectively, for 6 months with INH alone, 3 months with RMP alone, or 2 months with RMP + PZA, or RMP + PZA + INH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Is pyrazinamide bactericidal against Mycobacterium tuberculosis?

Bactericidal activity of pyrazinamide (PZA) was tested at pH 5.6 in 7H12 broth against drug-susceptible M. tuberculosis strains. The highest tested concentrations of PZA, 500 and 1,000 micrograms/ml, killed no more than 76% of the bacterial population. These concentrations are more than 32 times greater than the minimal inhibitory concentration (MIC) and the achievable in vivo concentrations. Despite high clinical efficacy of PZA and its so-called sterilizing activity in mouse experiments, this drug is much less bactericidal in vitro than any other known antituberculosis drug.

Dose-Response Relationship, Drug↗

PubMed1977

Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months.

A comparison was made between 6-month and 9-month regimens of streptomycin plus isoniazid plus pyrazinamide given daily, 3 times a week, or twice a week in the treatment of newly diagnosed, smear-positive pulmonary tuberculosis in Chinese patients. At 6 months, the twice-weekly regimen was marginally inferior; treatment failed for 5 (4 per cent) of 126 patients with drug-susceptible strains before treatment compared with 2 (1 per cent) of 141 on the 3-times-weekly regimen and none of 137 on the daily regimen. The results for patients with pretreatment strains resistant to isoniazid, to streptomycin, or to both drugs were not as good, treatment failing for 10 (30 per cent) of 33 on the daily regimen, 15 (37 per cent) of 41 on the 3-times-weekly regimen, and 14 (39 per cent) of 36 on the twice-weekly regimen. In contrast, the relapse rates after chemotherapy were similar for patients with drug-susceptible and drug-resistance strains before treatment and for patients on the daily and intermittent regimens. By 30 months, 35 (21 per cent) of 167 patients with susceptible strains who were treated for 6 months and 10 (6 per cent) of 179 treated for 9 months had relapsed, all with strains still susceptible to isoniazid and streptomycin. The relapse rates for patients with resistant strains were 7 (24 per cent) of 29 and 1 (4 per cent) of 26, respectively. Drug toxicity was not a special problem.

Adolescent↗

PubMed1977

Bactericidal activity of streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide alone and in combination against Mycobacterium Tuberculosis.

Log-phase cultures of Mycobacterium tuberculosis in Tween-albumin medium were exposed to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide in concentrations in the range likely to be present in serum during treatment of patients. The bactericidal activity of the drugs was measured as the decrease in viable counts at 4 and 7 days. The activity of single drugs was highest for streptomycin and next highest for rifampin and isoniazid, but ethambutol only started to kill after 4 days. When exposed to 2 drugs, bactericidal synergism was found with streptomycin/isoniazid and isoniazid/ethambutol; additivity, with streptomycin/rifampin; indifference, with isoniazid rifampin and streptomycin/ethambutol; and antagonism, with rifampin/ethambutol and isoniazid/pyrazinamide. When cultures were exposed to the 3 drugs, isoniazid, rifampin, and ethambutol, marked antagonism was found between isoniazid and rifampin, whereas the addition of isoniazid or an increase in its concentration increased the bactericidal activity.

Drug Interactions↗

PubMed1985

The penetration of rifampicin, pyrazinamide, and pyrazinoic acid into mouse macrophages.

The degree of penetration of rifampicin, pyrazinamide, and its metabolite pyrazinoic acid in mouse macrophages was evaluated over a period of 24 h. Cell cultures were exposed to 14C-labeled drugs at concentrations corresponding to peak, trough, and intermediate serum concentrations observed in humans after administration of therapeutic doses. The study was carried out with dead, resident, and stimulated peritoneal macrophages. The results indicated that the 3 compounds penetrate macrophages rapidly. At the lower concentrations, uptake of the 3 drugs is practically complete. With increasing concentrations, the absolute amount in the intracellular compartment increased. Comparison of the degree of penetration of the 3 drugs into dead, resident, and stimulated macrophages seems to suggest that the process of transfer through the macrophage wall is of a passive nature and not related to the metabolic state of the cells. Analysis of the binding of the 3 drugs to intracellular proteins indicated that more binding sites are probably available for rifampicin than for the other 2 drugs.

Animals↗

PubMed1985

Killing of macrophage-ingested mycobacteria by rifampicin, pyrazinamide, and pyrazinoic acid alone and in combination.

A study was undertaken with the aim of assessing the killing capacity of rifampicin, pyrazinamide, and pyrazinoic acid on macrophage-ingested, live Mycobacterium tuberculosis. The 3 drugs were used at concentrations corresponding to the average peak levels observed in humans after administration of therapeutic doses that had been found to penetrate into macrophages in a previous study. The degree of killing was studied after exposure of the cell cultures to the individual drugs and their combinations for 3, 18, 24, 48, and 72 h. Comparing the degree of killing in the control, drug-free cultures with that observed in the drug-containing systems, over a period of 3 to 24 h, indicated that in these a greater, more rapid, although not statistically significant, killing of intracellular mycobacteria took place. At 48 h the degree of killing was similar in the control and in the drug-containing cell cultures. Between 48 and 72 h, however, a marked growth of intracellular mycobacteria was observed in the control cultures. This phenomenon was much less evident in the drug-containing cultures. No major increase in the killing effect with respect to that observed with the individual drugs was found after exposure of the macrophages to all possible combinations of the 3 drugs.

Animals↗

PubMed1986

Inhibition by pyrazinamide of tubercle bacilli within cultured human macrophages.

Pyrazinamide (PZA) is a unique antituberculosis drug because it is effective in vivo but not in mediums commonly used to culture tubercle bacilli. Consequently, it was employed to test the validity of an in vitro macrophage model of human tuberculosis for value as a correlate of clinical events. The drug was as active in the macrophage model as it was clinically, inhibiting virulent tubercle bacilli at concentrations at 20 micrograms/ml or higher. By contrast, it was ineffective in 7H9 bacteriologic culture medium, even at concentrations as high as 2,560 micrograms/ml. It could be either bacteriostatic or bactericidal against intramacrophage tubercle bacilli, depending on its concentration, the donor of the macrophages, and the length of exposure of the infected macrophages to the drug. The data presented suggest that the clinical effectiveness of PZA is determined by a complicated self-modulating sequence of interactions between it, tubercle bacilli, and host macrophages. Specific evidence was found that tubercle bacilli may replicate within human macrophages in non-acid-fast form, thus indicating that colony-forming unit counts are inherently more accurate than acid-fast bacilli counts in these experiments, and also suggesting that important changes in bacillary cell wall composition may occur among tubercle bacilli within infected human macrophages.

Adult↗

PubMed1986

Pyrazinamide is not active in vitro against Mycobacterium avium complex.

Strains of M. tuberculosis that elaborate pyrazinamidase are typically susceptible in vitro and in vivo to pyrazinamide (PZA). However, we found that 33 strains of M. avium complex (MAC), all of which were pyrazinamidase-positive, were resistant in vitro to a high concentration (100 micrograms/ml) of PZA when tested at low pH in 7H12 broth by radiometric (BACTEC) method. The drug was equally ineffective against these bacteria within cultured normal human macrophages. We conclude that the pyrazinamidase test is not suitable for susceptibility studies against M. avium complex. On the basis of our in vitro studies, which support earlier data, we believe that PZA is not appropriate for therapy of MAC disease.

Amidohydrolases↗

PubMed1988

The role of pyrazinamide in tuberculosis chemotherapy.

Pyrazinamide is an antituberculosis drug synthesized in the 1950s and formerly used only as salvage therapy. Recent developments have elevated it to a central role in tuberculosis chemotherapy as the essential addition to isoniazid and rifampin which makes it possible to successfully complete treatment in six months. This is accomplished with no increase in hepatotoxicity. The only substantial side effect of this drug given at the dosage and for the duration used in these six-month regimens is a polyarthralgia which is only bothersome and not sufficient to warrant interruption of therapy. More rarely, acute gout is produced. The early history and pharmacology of this now first line antituberculosis drug are reviewed herein.

Humans↗

PubMed1989

Effects of dietary pyrazinamide, tryptophan, or nicotinic acid and gamma-ray irradiation on levels of NAD and NADP in various organs of mice.

The effects of large amounts of tryptophan, pyrazinamide, or nicotinic acid in diets on the contents of total NAD (NAD + NADH) and NADP (NADP + NADPH) of various organs were investigated in mice with or without gamma-irradiation. Female C3H/HeN mice were fed one of the following 4 kinds of experimental diets for one week: 1) control diet (20% casein diet containing 3 mg niacin per 100g diet); 2) diet supplemented by 0.5% L-tryptophan (T-diet); 3) diet supplemented by 0.5% L-tryptophan (T-diet); 4) diet supplemented by 0.1% nicotinic acid (NA-diet). Half of the mice in each group were subsequently irradiated with 8 Gy of gamma-ray (60 Co) after 4 h of fasting. Then, the contents of total NAD and NADP in thymus, spleen, kidney, liver, and blood were determined in all animals. The results indicated that NAD content of spleen was higher in PT-group (21.5%) and NA-group (23.2%) than in that of control group. In thymus, however, NAD content of only the PT-group was significantly greater (13.1%) than control. NAD level of kidney was also significantly higher (32.6%) in PT-group. By gamma-irradiation, NAD contents of thymus and spleen of all groups tended to be decreased, but those of kidney and liver were not always reduced. In the latter two organs, significant NAD reduction was shown only in kidney of PT-group and in liver of PT- and NA-groups. Even after irradiation, NAD levels of spleen and thymus in PT- and NA-groups tended to be kept higher than those in irradiated control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

[Determination of the sensitivity of mycobacteria to pyrazinamide and nicotinamide (author's transl)].

Since pyrazinamide (PZA) has had a come-back in therapy of tuberculosis a simple and reliable method for sensitivity tests has been necessary. A comparison of resistance tests to PZA in acid Löwenstein-Jensen-medium and in fluid medium with those to nicotinamide (NSA) showed a clear superiority of the NSA method, recommended by BRANDER. Also in routine sensitivity tests the use of NSA instead of PZA has stood the test. Another advantage of the method is the possibility to integrate it in the simplified proportion method without any additional work.

Drug Resistance, Microbial↗

PubMed1991

Effect of simultaneous isoniazid administration on pharmacokinetic parameters of pyrazinamide.

Pyrazinamide (PZN) was administered to 10 patients of pulmonary tuberculosis (for 7 consecutive days) each day after an overnight fast. On 8th day serum levels and urinary elimination were measured at 2,4,6 and 8 hours. Simultaneous administration of isoniazid to same patients significantly decreased the peak serum concentration (Cmax). Although, time to peak serum concentration (Tmax) remained unaffected, serum half life (t1/2) prolonged, the elimination rate constant (Kel) and area under serum concentration time curve (AUC) decreased and apparent volume of distribution (Vd) and plasma clearance (Clp) of PZN increased significantly. However, the cumulative per cent dose of PZN excreted in urine was not changed significantly. Although, serum levels of PZN were decreased at 2, 4, 6, and 8 hours, PZN levels remained above minimum effective concentration thereby not affecting the therapeutic status of PZN administered in combination with isoniazid, if PZN is administered in moderate doses.

Adult↗

PubMed1991

[Pharmacokinetic aspects of tuberculosis therapy with a fixed combination of rifampicin, isoniazide and pyrazinamide].

The here described investigations show correspondingly that the administration of isoniazid, rifampicin and pyrazinamide in a fixed combination of the administration of the individual substances is bioequivalent under pharmacokinetic aspects. Further investigations on large populations of patients must, however, still confirm whether or not the advantages of the fix combination striven for or theoretically to be expected can be proved in practice.

Biological Availability↗