Administration Of INH Research Articles

Isoniazid-rifampicin induced lipid changes in rats

IntroductionIsoniazid (INH) and rifampicine (RIF) continues to be highly effective drugs in the chemoprophylaxis and treatment of tuberculosis. It is associated with hepatotoxicity in some individuals. Change in liver and serum lipids may be one of the reasons of hepatotoxicity. We examined isoniazid–rifampicine induced lipid changes in liver and serum of rats. MethodsIn a rat model of INH–RIF induced hepatotoxicity we evaluated the effect of oral administration of INH–RIF (50 mg/kg body weight /day each) on hepatic marker enzymes, total lipids, cholesterol, triglycerides and phospholipids in serum and liver of experimental rats after 28 days. Enzymes, total lipids and lipid fractions were measured according to standard methods. Results: Treatment with INH–RIF increased the hepatic marker enzymes after 28 days and altered the lipid levels in serum and liver. Administration of INH–RIF resulted in significantly increased liver and serum cholesterol and total Lipids as compared to control group, while triglycerides were significantly elevated in liver only. In contrast, phospholipids were significantly decreased in liver and no effect in serum was observed. ConclusionChanges in lipids (both in serum and liver) are likely involved in the pathogenesis of INH–RIF induced hepatoxicity in rats.

Inhaled insulin as adjunctive therapy in subjects with type 2 diabetes failing oral agents: a controlled proof‐of‐concept study

This controlled proof-of-concept study investigated inhaled insulin (INH) as adjunctive therapy to existing oral antidiabetic agents in subjects with type 2 diabetes. Twenty-four subjects with type 2 diabetes [19 men and 5 women, 56.1 +/- 6.6 years, body mass index 32.7 +/- 4.2 kg/m(2), glycosylated haemoglobin (HbA1c) 8.4 +/- 0.8% (mean +/- s.d.)] inadequately controlled by metformin and/or sulfonylureas were randomized to receive additional therapy with either INH administered preprandially using a metered-dose inhaler (MDI), or insulin glargine (GLA) injected subcutaneously at bedtime for 4 weeks. Both inhaled and injected insulin doses were titrated to predefined blood glucose (BG) targets. INH and GLA improved metabolic control to a similar extent. Mean daily BG decreased by 2.8 mmol/l in the INH group (p < 0.001) and by 2.4 mmol/l in the GLA group (p < 0.001). Accordingly, fasting BG (-2.7 vs. -3.6 mmol/l for INH vs. GLA), preprandial- and 2-h postprandial BG, HbA1c (-1.23 vs. -1.05%), body weight (-1.9 vs. -2.3 kg) and serum fructosamine were similarly and significantly reduced in both groups (p < 0.05). Triglycerides decreased significantly with INH (-1.15 micromol/l; p < 0.001) but not with GLA [-0.52 micromol/l; not significant (NS)]. Incidence rates of adverse events did not differ significantly, and there were no indications of respiratory tract irritation. In subjects with type 2 diabetes inadequately controlled by oral agents, preprandial administration of INH delivered by a MDI provided a comparable metabolic control to bedtime GLA and did not show any safety concerns during a 4-week treatment. These results warrant a more extensive investigation of preprandial treatment with INH in longer term studies.

Effect of Isoniazid on the Pharmacodynamics of Cefazolin-Induced Seizures in Rats

Both isoniazid (INH) and cefazolin (CEZ) can have serious adverse effects on the central nervous system (CNS), causing seizures. In this study, we investigated the effect of INH on the pharmacodynamics of CEZ-induced seizures in rats. Male Wistar rats pretreated with INH (150 mg/kg i.p.) or saline received an intravenous infusion of CEZ at 3.2 g/h/rat until the onset of seizures, then samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately. The administration of INH was associated with a reduction in the total dose of CEZ required to produce seizures. The concentrations of CEZ in serum, brain, and CSF in INH-treated rats at the onset of seizures were significantly lower than those in control rats. In rats coadministered with pyridoxine (150 mg/kg s.c.), the concentration of CEZ in CSF at the onset of seizures was significantly higher than that in rats administered INH only. These results suggest that INH potentiates the sensitivity of the CNS to CEZ-induced seizures, and that the increased sensitivity is associated with the inhibition of vitamin B(6) metabolism by INH.

Isoniazid and Rifampicin Treatment on Phospholipids and Their Subfractions in Liver Tissue of Rabbits

Although combined treatment of isoniazid (INH) and rifampicin (RIF) has been documented to induce hepatotoxicity and hepatocellular damage, their effect on liver tissue phospholipids is still unknown. Because phospholipids constitute an integral part of hepatocellular membrane, studies were conducted to evaluate the effect of individual and combined treatment of INH and RIF on liver tissue phospholipids in rabbits. Simultaneous administration (i.p.) of INH and RIF (group IV; n = 6), each at a dose of 25 mg/kg for 11 days, caused a significant elevation of phospholipids in plasma from day 5 till day 11. This treatment also caused a significant fall in total inorganic phosphorous, phosphatidylcholine (PC), and cardiolipin (CL) with concomitant increase in phosphatidylethanolamine (PE) and phosphatitylserine (PS) subfractions of phospholipids in the liver tissue of rabbits. Though INH-alone treatment (group II; n = 5) produced a significant fall in total inorganic phosphorous content in the liver tissue, the phospholipid subfractions remain unaltered. RIF-alone treatment (group III; n = 5) did not produce any alteration in phospholipids and their subfractions in liver tissue and plasma of rabbits, and they were comparable to saline-treated control (group I; n = 5). It is likely that simultaneous treatment of INH and RIF could cause choline deficiency, resulting in lowering of phospholipids in the hepatocellular membrane and obstruction of lipoprotein synthesis, culminating in liver injury.

Population pharmacokinetics of antituberculous drugs and treatment of Mycobacterium bovis infection in bongo antelope (Tragelaphus eurycerus isaaci).

After clinical illness, treatment, and death of a captive male bongo antelope (Tragelaphus eurycerus isaaci) caused by tuberculosis involving Mycobacterium bovis, four tuberculin test reactive captive bongos were treated for 6 mo with isoniazid (INH) and rifampin (RIF) and intermittent single doses of other medications before being euthanized. In all cases, postmortem examination indicated no evidence of active disease and cultures of multiple organs were negative. We present detailed pharmacokinetic (PK) data for amikacin (AMK), ethambutol (EMB), INH, pyrazinamide (PZA), RIF, and levofloxacin in four female bongos. Adequate absorption and serum levels were obtained after parenteral administration of AMK, EMB, and INH and after oral administration of INH and PZA. Parenterally administered drugs were well described by a one-compartment PK model with first-order absorption and elimination processes. Treatment with INH and RIF over a 6-mo period did not result in demonstrable adverse effects. Starting doses of 10-15 mg/kg, i.m., or 30 mg/kg, p.o., of INH, 50 mg/kg, p.o., of EMB, and 25 mg/kg, i.m., s.i.d., of AMK are recommended. The treatment is continued with at least two drugs to which the organism is susceptible for a total treatment length of 6-12 mo. Treatment may be an option to eradicate M. bovis from suspect animals, with carefully administered and monitored drug treatment.

Effects of pefloxacin on urinary and salivary concentrations of isoniazid in six healthy female volunteers.

The effects of pefloxacin (PFC), a fluoroquinolone antibiotic, on the urinary and salivary concentrations of Isoniazid (INH) were investigated in six healthy female volunteers 19 to 30 years of age. The presence of PFC increased the rate and extent of INH absorption and the rate of its excretion in the urine and saliva. There was an increase in the excretion rate constant (K) and a reduction in the half-life (t1/2) of INH in the presence of PFC. Four of the volunteers had t(1/2) values in the range of 1.55 to 2.43 hours and were considered to be fast acetylators, whereas two subjects with a t(1/2) in the range of 3.36 to 4.41 hours were considered to be slow acetylators. Concurrent administration of INH and PFC may lead to an increased INH toxicity based on the results of the present study.

非定型抗酸菌による骨関節炎の２例

The incidence of atypical mycobacterium (AM) infection is 2.71 out of a population of 100.000. Most were pulmonary infection and extra pulmonary infection counted 3%. Arthritis and osteomyelitis caused by AM is rare. We successfuly treated two patients with arthritis and osteomyelitis coused by AM.Case 1. A 62-year-old man with wrist pain and swelling for 6 years, was suspected as having RA. However, treatment for RA did not improve his symptom. He received synovectomy 3 times but synovitis recurred. Mycobacterium scrofulaceum was cultured from joint fluid. We started administration of RFP, INH, and SPFX with synovectomy. Eight months after surgery, no recurrence was seen and he returned to his original job.Case 2. A 45-year-old man suffered from a wound by a metal wire penetrating his right foot while mowing the lawn. He was treated with antibiotics, but he developed osteomyelitis of the right talus. Osteomyelitis was treated by curettage 3 times but recurred. A culture of the pus revealed mycobacterium fortuitum. He was successfuly treated with CAM, IPM, and CPFX administration combined with curretage and AMK cement beads insertion. This cement beads were replaced by the cancellous bone, and AMK and DKB impregnated hydroxyapatite 5 weeks later. Eight months after surgery, there was no signs of infection and he returned to his original job as a policeman.

ISONIAZID DOES NOT AFFECT BIOAVAILABITY OF CYCLOSPORINE IN RENAL TRANSPLANT RECIPIENTS

627 The incidence of tuberculosis is increasing worldwide. Transplant recipients are particularly predisposed to develop tuberculosis and Isoniazid (INH) is used in most anti-tubercular therapeutic and prophylactic protocols. Cyclosporine (CyA) bioavailability increases on concomitant use of drugs that inhibit hepatic cytochrome P-450 enzymes. There are reports expressing concern regarding the use of INH in patients treated concomitantly with CyA. Seven renal transplant recipients receiving CyA (SANDIMMUN NEORAL) in a dose of 3.9-5.7 mg/kg/day and requiring concomitant INH prophylaxis (300 mg/day) against tuberculosis were studied. Acetylation status was assessed before inclusion in the study protocol and only slow acetylators were studied. Whole blood CyA levels at 0,1,2,4,6 and 8 hours of last dose were estimated by RIA on days 0 and 14 of starting INH and total CyA exposure (AUC) and CyA clearance calculated. The pharmacokinetic parameters before and after INH administration are shown in the Table:TableEven after post INH Cmin, Cmax, Tmax, AUCs and CyA clearance values were adjusted for INH levels, the differences in the above pre and post INH parameters did not reach statistical significance. There was also no statistically significant correlation between INH levels and changes in Cmin, Cmax, Tmax. AUCs and CyA clearance before and after administration of INH. There was no significant change in the serum creatinine levels before (1.49±0.49 mg/dl) and after INH administration (1.44±0.53 mg/dl, p>0.05). There were no episodes of CyA toxicity or acute rejection during and upto 4 weeks of starting INH. We conclude that concomitant administration of INH and CyA is safe and is not associated with any appreciable alterations in bioavailability of CyA.

Impaired Immune Response by Isoniazid Treatment During Intravesical BCG Administration in the Guinea Pig

At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given on the 3 days around each BCG instillation.We found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of MHC Class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. When INH was administered during the last 4 of 6 BCG instillations, the immune response to BCG was still impaired. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder.In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.

Neurotoxicity of antituberculous drugs in a patient without active tuberculosis

Three months after the beginning of an antituberculous regimen with Isoniazid (INH, 5 mg/kg daily), Ethambutol (20 mg/kg daily), Rifampicin (675 mg daily) and vitamin B6 a 56-year-old patient presented with a mild sensory polyneuropathy and a bilateral retrobulbar neuritis which progressed to a severe optic atrophy. Multiple hyperintense foci were detected with NMR-imaging in the cerebral white matter suggestive of central demyelination. INH and Ethambutol are known for their neurotoxic effects but the suggestion was made that neurologic signs may not be due to drug neurotoxicity but could be induced by immunological processes initiated by the tubercle bacillus. In the patient reported the suspected tuberculosis of the urogenital tract could not be proved histologically. Most likely his neurological symptoms were therefore caused by the administration of INH and Ethambutol. Patients with a low serum zinc level and a slow acetylation of INH are reported to be at special risk, both factors being present in ...

Effects of bovine follicular fluid inhibin on serum gonadotrophin concentrations in ewes during oestrus.

Experiments were conducted with ewes to investigate the effects of an enriched bovine follicular fluid inhibin preparation (INH) on gonadotrophin secretion after the onset of oestrus. Administration of INH (10 mg) 1 h after the onset of oestrus did not significantly alter the preovulatory FSH and LH surges or the second FSH peak. To determine the effects of INH on the second FSH surge, ewes were treated with saline (N = 7) or INH (N = 10) at 4 h (10 mg) and 24 h (5 mg) after the peak of the preovulatory LH surge. The second FSH surge was delayed about 24 h (P less than 0.05) in ewes treated with INH; however, the delay did not alter the interval to the next oestrus. In a third experiment, 16 ewes were assigned to 4 groups in a 2 x 2 factorial with the main effects being ovariectomy at 4 h and INH treatment (10 mg) at 4, 20 and 36 h after the peak of the LH surge. Controls received sham ovariectomy and saline injection as appropriate. Ovariectomy resulted in a rapid increase in serum FSH but not LH and this was delayed (P less than 0.05) by INH treatment. These results indicate that inhibin has a selective inhibitory action on FSH secretion in ewes and suggests that the second FSH surge results from increased basal FSH secretion due to decreased endogenous inhibin levels.

幼児脊椎カリエスと思われる１症例について

In this paper we reported a female infant with spinal tuberculosis who developed motor disturbance of her both lower extremities at 11-month-old. On admission she couldn't move her lower extremities at all and her knee and ankle jerks were exaggerated with ankle clonus on the both sides. We made a diagnosis of spinal tuberculosis from hematological examination and the findings of her X-ray pictures, tomsgrams and CT. We began to treat with administration of Rifampicin and INH. The laboratory findings were normalized after one month and neurological abnormalities were completely recovered after three months of treatment.However, by the reasons of that there is no history of tuberculosis in the patient and her family, her mantoux reaction was negative, and the period between the beginning of treatment and normalization of laboratory findings was short, there were some difficulties in differential diagnosis between spinal tuberculosis and pyogenic osteomyelitis.

Effect of concomitant isoniazid administration on determination of acetylator phenotype by sulphadimidine.

The influence of concomitant administration of isoniazid (INH) on the acetylation of sulphadimidine has been studied in 6 healthy volunteers, previously identified as having the fast acetylator phenotype. INH was administered in a slow release form (500 mg tablet) 1 hour before the sulphadimidine. Acetylation of sulphadimidine was measured in plasma 6 h after its intake and in urine collected between 5 and 6 hours. INH significantly decreased the acetylated fraction of sulphadimidine in plasma from 69.0 to 54.0 and in urine from 85.9 to 81.2%. This was reflected in a significantly higher plasma concentration of unconjugated sulphadimidine and reduced urinary excretion of acetylated sulphadimidine. It is concluded that concomitant administration of INH inhibits acetylation of sulphadimidine. Fast acetylators at the border line of discrimination, may be misclassified if phenotyped with sulphadimidine during concomitant administration of INH.

Is isoniazid-hepatotoxicity induced by the metabolite, hydrazine?

The effects of rifampicin (RMP) on isoniazid (INH) metabolism in rabbits were examined from the viewpoint of extensive hepatitis. After the RMP pretreatment, no remarkable changes were observed in the plasma levels of INH as well as its metabolites, acetylisoniazid (AcINH), acetylhydrazine (AcHz) and diacetylhydrazine (DAcHz) with the exception of hydrazine (Hz). After an oral administration of INH or Hz hydrate, the stochastic examination showed that the AUC0-8hr values of Hz plasma levels in RMP pretreated groups were significantly less than those in the control rabbits. RMP treatment was also shown to induce rabbit liver cytochrome P-450 activity. Histological studies demonstrated that Hz causes more remarkable hepatic necrosis in rabbits pretreated with RMP than in the control rabbits. These observations could suggest that Hz is a key intermediate of INH-hepatitis through the transformation of some hepatotoxic species by microsomal oxidation that is facilitated by RMP.

Treatment of tuberculosis and other mycobacterial diseases.

In controlled clinical trials, several regimens have proven effective in treating tuberculosis. The drugs must be given in combination to avoid the emergence of resistant organisms. The simplest regimen is based on the administration of isoniazid and rifampin for 9 months. Ethambutol or streptomycin generally is added for an initial 2-8 weeks. Good results also have been reported using twice weekly administration of the isoniazid and rifampin after an initial 1 month of daily treatment. Relapse rates of less than 3% have been reported with these regimens. A table shows the recommended doses for the drugs. If neither isoniazid nor rifampin can be used, the patient needs to be given at least 2 and preferably 3 drugs to which his organisms are known to be susceptible. Additionally, these drugs must be administered for at least 18 months. Several circumstances are associated with a higher rate of drug resistant organisms and call for susceptibility studies: tuberculosis among individuals known to have a higher prevalence of drug resistance such as Asians or Hispanics; previous treatment; persistence of culture-positive sputum after 3 months of therapy; and exposure to drug resistant tuberculosis. The recommendations for the treatment regimen need to be changed in several special situations, including: infection with mycobacteria other than "M. tuberculosis;" tuberculosis in children; disease in organ systems other than the lungs; and the presence of certain patient characteristics, concurrent diseases, or the development of adverse drug reactions. Much scientific data supports the value of isoniazid (INH) in the prevention of tuberculosis. Isoniazid preventive therapy is recommended for several groups, listed in order of priority: household members and other close associates of potentially infectious tuberculosis cases; newly infected persons; persons with significant reactions to tuberculin skin test and abnormal chest roentgenograms; persons with significant reactions to tuberculin skin tests who are in special clinical situations; and tuberculin skin test reactors under age 35 with none of the other risk factors. Prior to administration of INH preventive therapy, it is important to: exclude bacteriologically positive or progressive tuberculous disease; question for a history of prior INH administration to exclude those who have had a adequate course of the drug; check for contraindications to the administration of INH for preventive therapy; and identify patients for whom preventive therapy is not contraindicated but in whom special precautions are indicated. Other drugs might be effective for preventive therapy, but as yet there are currently no data available documenting the efficacy of any drug other than INH.

Effect of chronic administration of inhibin and testosterone on spermatogenesis in adult male rats.

Inhibin (Inh) and testosterone (T) were administered to adult male rats for 32 days to evaluate their effect on spermatogenesis. Fifty micrograms of Inh was injected subcutaneously twice daily, and T was administered as Silastic implants 2.5 cm in length. Weights of testes and epididymides were significantly decreased in (Inh + T)- and T-treated groups, but not in Inh-treated rats. Although Inh alone could suppress both the testicular and the epididymal sperm count, maximum suppression was observed in the (Inh + T)-treated group. The effect on the epididymal sperm count, however, was pronounced. The accessory organ weights remained unaffected in all treated groups. Chronic administration of Inh and T results in partial impairment of spermatogenesis.

High Pressure Liquid Chromatographic Determination of Isoniazid and Acetylisoniazid in Human Plasma

Abstract A quantitative high pressure liquid chromatographic (HPLC) assay has been developed for the determination of isoniazid (INH) and acetylisoniazid (ACINH) in human plasma. Plasma samples were taken from a patient after oral administration of INH (with proven tuberculosis infection). A C18 reversed phase radial compression column was used to separate INH and ACINH from other plasma components. The analysis takes 10 minutes per sample and the lower limit of detection for each compound is 0.10 ug/ml plasma.

Diazepam interaction with antituberculosis drugs.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Isoniazid hepatitis in adolescents

Prophylactic isoniazid therapy is currently recommended for adolescents with positive tuberculin reactions because of the risk of activation of tuberculosis in this age group. Since this drug has been associated with hepatic dysfunction in adults, the present study was undertaken to evaluate its effect on liver function in teen-agers. Accordingly, liver function tests were performed on 178 adolescents prior to and following administration of INH. Abnormalities in SGPT values were encountered in 10% of these patients and occurred in the main within the first 10 weeks of testing, suggesting INH maybe hepatotoxic. However, jaundice was notably absent in the patients with enzyme elevations and prompted a further investigation into the possible effect of INH on bilirubin metabolism. Thus, Sprague-Dawley rats were given four daily injections of INH. These animals manifested increased hepatic bilirubin glucuronyl transferase activity when compared with control rats, supporting the hypothesis that enzymatic induction may be responsible for the absence of jaundice in our adolescent subjects.

Effects of Isoniazid on Psychomotor Skills Related to Driving

The effects of single oral dose of 751 mg INII, alone or in combination with 0.5 Gm/kg of alcohol, on psychomotor skills related to driving were investigated. Volunteer cadets (100) were tested with a battery of a choice reaction test, two coordination tests, and an attention test. Further, 50 drivers from motorized troops drove a simulator for 40 minutes. the experiments were double blind. Both INII and alcohol slightly elevated the subjective feeling of performance. At 30 minutes after the ingestion of the drugs, both INII and alcohol shortened reaction time, and INH also improved coordination at 90 and 150 minutes after drug intake. Both alcohol and INH impaired attention. No major interaction was observed between INH and alcohol in psychomtor tests. In simulated driving, INH antagonized the deleterious effect of alcohol on attention. The numbers of collisions at emergency were slightly increased after either drug. The numbers of drivers driving off the road were increased after alcohol and INH given together. After this combination, the small movements of the steering wheel characteristic of drunken drivers were significantly increased. Administration of INH, 10 mg/kg might cause some extra risks for driving in the very beginning of the treatment and in combination with alcohol. /Author/