INH Levels Research Articles

Hereditary Angioedema as a Cause of Recurrent Abdominal Pain

Purpose: A 38 year-old Caucasian female with past history of diarrhea predominant irritable bowel syndrome, was admitted with 5-day history of intermittent abdominal pain, fever, nausea, vomiting, and diarrhea. Upon presentation, her examination was remarkable for dehydration, and left lower quadrant tenderness. Laboratory tests revealed WBC 10,300/mm. All other laboratory tests including liver function tests, routine stool studies, were normal. CT scan of the abdomen revealed sigmoid and descending colonic diverticula with bowel wall thickening and pericolonic stranding consistent with acute diverticulitis. Patient was started on fluids and empiric antibiotics with levofloxacin and metronidazole, without clinical or radiologic improvement. Upon further questioning, it was found that multiple family members are diagnosed with hereditary angioedema. Testing of C4 complement and C1-esterase inhibitor confirmed the diagnosis of hereditary angioedema. Patient was started on Berinert (C1-esterase inhibitor) and noted symptomatic improvement within days. Hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by a quantitative or functional defect of C1 esterase inhibitor. Type I HAE is characterized by a low or unmeasurable level of C1 inhibitor, while in type II HAE, C1 INH levels are normal but dysfunctional. Clinically, HAE is characterized by marked diffuse edema involving the skin, mucous membrane, and visceral organs. GI involvement frequently occurs in patients with HAE, and may be the initial manifestation. Isolated abdominal symptoms may occur in up to 21% of patients with HAE. The jejunum, ileum, duodenum, stomach and the colon are affected in descending frequency. Small bowel edema and abdominal ascites are common during clinical evaluation. The presence of ascites may be an indicator for the severity of an attack. Abdominal imaging reveals wall thickening of the colon as well as moderate ascites. Edema of the GI tract can occur in both hereditary and acquired forms of angioedema. In ACE-inhibitor induced angioedema of the intestine, there is primary involvement of the small bowel while in hereditary angioedema, there is isolated involvement of the colon or the small bowel. Treatment of acute attacks of HAE with IV purified C1 INH along with anti-fibrinolytics drugs has been found to be effective. Prophylactic treatment of Danazol and Stanozolol, attenuated androgens, increase the synthesis of C1 INH and are found to be the most effective prophylactic treatment. Hereditary angioedema should be considered in the differential diagnosis of unexplained, episodic abdominal pain in young patients.

Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients

Isoniazid (INH) is one of the most important drugs of antitubercular treatment regime, and in some cases it causes hepatotoxicity. It is metabolized by hepatic N-acetyltransferase-2 (NAT2). To compare whether both methods, i.e., genotype NAT2 and phenotype test of measuring serum INH levels, are useful to identify acetylator status of patients on antitubercular treatment (ATT). A total of 251 tuberculosis (TB) patients on standard treatment were followed up to 6months for this study. NAT2 genotype was assessed by PCR with restriction fragment length polymorphism (RFLP) whereas serum INH levels were measured by fluorometry. Of the 251 patients, 50 (19.9%) developed ATT-induced hepatotoxicity. By phenotypic estimation, in the hepatotoxicity group, 17/50 (34%) were slow acetylators whereas 33/50 (66%) were fast acetylators. Genotypically, 19/50 (38%) were slow acetylators and 31/50 (62%) fast acetylators. By phenotypic analysis, in non-hepatotoxicity group, 46/201 (22.9%) were slow acetylators and 155/201 (77.1%) fast acetylators. By genotypic analysis, 30/201 (14.9%) were slow acetylators and 171/201 (85%) fast acetylators. Overall, slow acetylators (25.1%) measured phenotypically were not significantly different from slow acetylators (19.5%) measured genotypically. This study suggests that the acetylator status of TB patients can be detected by phenotypic method as efficaciously as by genotypic method. Therefore, phenotypic method can replace genotypic method to determine acetylating status as phenotypic method is simple and inexpensive.

Comparative population genetics of mimetic Heliconius butterflies in an endangered habitat; Brazil's Atlantic Forest

BackgroundBrazil's Atlantic Forest is a biodiversity hotspot endangered by severe habitat degradation and fragmentation. Habitat fragmentation is expected to reduce dispersal among habitat patches resulting in increased genetic differentiation among populations. Here we examined genetic diversity and differentiation among populations of two Heliconius butterfly species in the northern portion of Brazil's Atlantic Forest to estimate the potential impact of habitat fragmentation on population connectivity in butterflies with home-range behavior.ResultsWe generated microsatellite, AFLP and mtDNA sequence data for 136 Heliconius erato specimens from eight collecting locations and 146 H. melpomene specimens from seven locations. Population genetic analyses of the data revealed high levels of genetic diversity in H. erato relative to H. melpomene, widespread genetic differentiation among populations of both species, and no evidence for isolation-by-distance.ConclusionsThese results are consistent with the hypothesis that the extensive habitat fragmentation along Brazil's Atlantic Forest has reduced dispersal of Heliconius butterflies among neighboring habitat patches. The results also lend support to the observation that fine-scale population genetic structure may be common in Heliconius. If such population structure also exists independent of human activity, and has been common over the evolutionary history of Heliconius butterflies, it may have contributed to the evolution of wing pattern diversity in the genus.

Isoniazid Blood Levels in Patients with Pulmonary Tuberculosis at a Tuberculosis Referral Center

Background: Serum concentrations of isoniazid (INH) were evaluated in Iranian patients admitted to the Tuberculosis Ward of Masih Daneshvari Hospital, Tehran, Iran. Factors correlated to plasma INH levels were determined. Methods: Blood samples were obtained 2 h after ingestion of 5 mg/kg INH in 82 patients (1 sample/patient) on days 3–15 of treatment. The following variables were investigated: INH plasma level, duration of therapy, age, sex, weight, dose of INH administered and smoking status. Results: The average (±SD) age and weight of patients were 60.68 ± 18.53 years and 74.96 ± 7.15 kg, respectively. INH concentrations were low in 14.63% and high in 23.17% of the patients (INH reference range: 3–5 µg/ml). Plasma INH was statistically correlated with duration of INH administration (Kendall’s rank correlation, r = 0.66, p < 0.001) but not with other variables. Conclusion: Based on the result of this study, plasma INH concentrations were not within the therapeutic range for 37.80% of the patients on conventional therapy. Therefore therapeutic drug monitoring may be needed to optimize INH dosage, especially in patients with inadequate clinical response or toxicity to INH.

C1 inhibitor level on neonatal sepsis and its relations with clinical findings

Generalised oedema is a frequent finding during neonatal sepsis, but its aetiology remains uncertain. The objective of this study was to measure functional C1 inhibitor (fC1 inh) levels in newborns with culture-proven sepsis, compare the results with age- and gestational age (GA)-matched controls and correlate the results with the clinical course of the patients during infection, with regard to vascular leak and oedema formation. Newborns with blood culture-proven sepsis were included and samples for C1 inh levels were obtained before the beginning of antibiotic therapy and on the 3rd day of treatment. Body weight, urine output and other treatment modalities including volume boluses were recorded. Oedema formation as a sign of vascular leak was determined by calculating percent weight change over time. Age- and GA-matched newborns without infection were used as controls. No difference was observed between the patient and the control groups concerning fC1 inh levels. Percent weight change in the patient group was not correlated with the C1 inh levels. Despite studies suggesting the role of C1 inhibitor deficiency in vascular leak during sepsis in adults, there is no information in the literature regarding the C1 inh levels of healthy or septic newborns to date. In this study, fC1 inh levels were no different than controls, necessitating the consideration of other factors causing vascular leak and oedema during neonatal sepsis.

Is there a need for clinical guidelines in the United States for the diagnosis of hereditary angioedema and the screening of family members of affected patients?

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency of C1 esterase inhibitor (C1 INH) protein or function. Guidelines do not exist regarding diagnostic criteria or routine testing of family members of patients with HAE. Laboratory data for diagnosis include complement factor 4 level; C1 INH antigenic protein level, which is reduced in approximately 85% of patients with HAE; and C1 INH functional assay, which is considered an unreliable test in the United States secondary to inconsistent standardization of assays. To assess the shortcomings of diagnosing HAE and to determine whether family members of patients with HAE are being adequately screened. The top physician prescribers of danazol in the United States were screened via an Internet questionnaire focusing on the diagnosis and current management of HAE. To assess the patient perspective on HAE, affected individuals in the United States, the United Kingdom, France, Germany, and The Netherlands participated in the Web-based International Survey of Patient Experience of Hereditary Angioedema. All 80 physicians who completed the survey were allergist or immunologists with a mean of 7 patients with C1 INH deficiency in their practices. Almost 84% of physician respondents used C1 INH level and function for diagnosis, and 63.8% used complement factor 4 levels. A total of 313 patients with HAE completed the survey. Respondents noted that only 48% of immediate family members and 26% of extended family members had been tested. Guidelines could potentially alleviate delays in diagnosis and incorrect diagnoses and could lead to adequate screening of family members.

Hereditary Angioedema: Three Cases Report, Members of the Same Family

This current clinical case report highlights three cases of Hereditary angioedema (HAE) patients who are all members of the same family (father and his two daughters). The father has C1–INH deficiency, while his daughters have low C1–INH levels: the first possesses only 10% function and the second has low C1–INH level with 0% function. Of note, the second daughter was discovered to have HAE at the age of 2, thus making her the youngest known HAE case report in the English literature.

Hereditary Angioedema: Three Cases Report, Members of the Same Family

This current clinical case report highlights three cases of Hereditary angioedema (HAE) patients who are all members of the same family (father and his two daughters). The father has C1–INH deficiency, while his daughters have low C1–INH levels: the first possesses only 10% function and the second has low C1–INH level with 0% function. Of note, the second daughter was discovered to have HAE at the age of 2, thus making her the youngest known HAE case report in the English literature.

8. Hereditary angioedema

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death.

Variations in total phenolics during ontogenetic, morphogenetic, and diurnal cycles inHypericum species from Turkey

Several species ofHypericum are used in traditional Turkish folk medicine. Their most medicinally important secondary metabolites are the hypericins, hyperforins, and phenolics. Here, we determined the ontogenetic, morphogenetic, and diurnal variations in total phenolics contents fromH. aviculariifolium subsp.depilatum var.depilatum (endemic),H. perforation, andH. pruinatum. Plants of wild-growingH. aviculariifolium subsp.depilatum var.depilatum andH. perforatum, and greenhouse-grownH. pruinatum were harvested four times per day during their vegetative, floral-budding, full-flowering, fresh-fruiting, and mature-fruiting stages. They were then dissected into stem, leaf, and reproductive tissues to be dried separately and assayed. The highest level of phenolics inH. aviculariifolium subsp.depilatum var.depilatum andH. pruinatum was found in the leaves, whereas the floral buds produced the greatest amount inH. perforatum. Variations in contents from whole plants fluctuated diurnally, differing among species over the course of ontogenesis, reaching the highest level at floral-budding and tending to increase at mid-day inH. aviculariifolium subsp.depilatum var.depilatum. ForH. perforatum andH. pruinatum, contents also were the highest during floral development, although no diurnal fluctuations were observed in those species.

Molecular characterization of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from the USA

Drug-resistant tuberculosis poses a significant problem for treatment. The mechanisms of resistance to the front-line drug isoniazid (INH) are complex and can be mediated by katG, inhA and other unknown genes. To identify the percentage of INH-resistant strains with no katG or inhA mutation, this study characterized a panel of 28 clinical isolates of Mycobacterium tuberculosis and five mutants derived from H37Rv resistant to INH. Seventeen of 33 resistant strains (51 %) had katG mutations with 12 of the 17 strains having the most common KatG Ser315Thr mutation. Three of the 17 strains with the KatG 315 mutation had an additional mutation in the inhA promoter and were resistant to a high level of INH. Seventeen of the 33 INH-resistant strains (51 %) had inhA mutations. The most common inhA promoter mutation was -15C-->T and was present in 13 of the 17 inhA mutations. This promoter mutation occurred alone without katG mutations and was associated with a low level of INH and ethionamide resistance. However, other inhA mutations were associated with katG mutations. No mutations were found in the ndh gene. Three of 33 strains (9 %) had no mutations in katG, inhA or ndh, indicating that their resistance was due to a new mechanism of resistance. Detection of the KatG Ser315Thr mutation and the -15C-->T inhA mutation accounted for 76 % (25/33) of the INH-resistant strains and should be useful for rapid detection of INH-resistant strains by molecular tests.

Use of Smear-Positive Samples To Assess the PCR-Based Genotype MTBDR Assay for Rapid, Direct Detection of the Mycobacterium tuberculosis Complex as Well as Its Resistance to Isoniazid and Rifampin

Isoniazid (INH) and rifampin (RIF) are two of the most important antituberculosis drugs, and resistance to both of these drugs can often result in treatment failure and fatal clinical outcome. Resistance to these two first-line drugs is most often attributed to mutations in the katG, inhA, and rpoB genes. Historically, the identification and testing of the susceptibility of Mycobacterium tuberculosis complex (MTBC) strains takes weeks to complete. Rapid detection of resistance using the PCR-based Genotype MTBDR assay (Hain Lifescience GmbH, Nehren, Germany) has the potential to significantly shorten the turnaround time from specimen receipt to reporting of results of susceptibility testing. Therefore, the aim of the present study was to determine (i) the sensitivity and accuracy of the Genotype MTBDR assay for the detection of MTBC strains and (ii) the ability of the assay to detect the presence of INH and RIF resistance-associated mutations in katG and rpoB from samples taken directly from smear-positive clinical specimens. The results were compared with those obtained with the reference BACTEC 460TB system combined with standard DNA sequencing analysis methods for katG, inhA, and rpoB. A total of 92 drug-resistant and 51 pansusceptible smear-positive specimens were included in the study. The Genotype MTBDR assay accurately and rapidly detected MTBC strains in 94.4% of the 143 specimens and showed a sensitivity of 94.4% for katG and 90.9% for rpoB when used directly on smear-positive specimens. The assay correctly identified INH resistance in 48 (84.2%) of the 57 specimens containing strains with resistance to high levels of INH (0.4 microg/ml) and RIF resistance in 25 (96.2%) of the 26 specimens containing RIF-resistant strains.

Pharmacokinetic and pharmacodynamic behaviour of antitubercular drugs encapsulated in alginate nanoparticles at two doses

This study was designed to evaluate the pharmacokinetics and tissue distribution of free and alginate-encapsulated antitubercular drugs in mice at different doses. Alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) were prepared by controlled cation-induced gelification of alginate. The formulation was orally administered to mice at two dose levels (D1 and D2). A comparison was made in mice receiving free drugs at equivalent doses. Drugs were analysed by high performance liquid chromatography (HPLC). The average size of alginate nanoparticles was found to be 235.5 ± 0.0 nm with a polydispersity index of 0.44; drug encapsulation was 70–90% for INH and PZA, 80–90% for RIF and 88–95% for EMB. In the free drug groups, plasma levels of RIF and INH were higher and PZA and EMB levels were lower in the D1 group (per body surface area of mice) compared with the D2 group (recommended human dose). The plasma drug levels of all drugs were higher in the D1 encapsulated group compared with D2, resulting in higher values of area under the plasma drug concentration–time curve (AUC 0–∞). The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with free drugs. Drug levels were maintained at or above the minimum inhibitory concentration (MIC 90) until Day 15 in organs after administration of encapsulated drugs, whilst free drugs stayed at or above the MIC 90 up to Day 1 only irrespective of dose. The levels of drugs in various organs remained above the MIC at both doses for equal periods, demonstrating their equiefficiency. Alginate nanoparticles hold great potential in reducing dosing frequency of antitubercular drugs.

Urinary inhibin a (INH) and activin (ACT) in hypertensive disorders during pregnancy

Convincing evidence suggests serum INH and ACT levels are elevated in preeclamptic women. We hypothesized that urinary INH and ACT levels are also altered in parallel and have discriminative predictive value in pregnancy associated hypertensive disorders [chronic hypertension (crHTN), mild (mPE) and severe preeclampsia (sPE)].

Mutational and expression analysis of tbnat and its response to isoniazid

A gene (nat) encoding arylamine N-acetyltransferase (NAT) has been found in Mycobacterium tuberculosis. The gene is expressed and the enzyme is active in growing M. tuberculosis cells. N-Acetyltransferase acetylates and inactivates isoniazid (INH), which is a front-line drug used in tuberculosis (TB) therapy. In this study, it was shown that a previously reported G619A single nucleotide polymorphism (SNP) was conserved in two M. tuberculosis strain families found in the Western Cape Province of South Africa (strain families 3 and 28). Further sequence analysis of isolates in strain family 3 identified a new T529C SNP in NAT resulting in a histidine instead of a tyrosine at position 177. This SNP was found only in isolates from strain family 3, and this mutation affects the highly conserved tyrosine residue close to the active site. Using real-time PCR, the expression of M. tuberculosis nat (tbnat) was determined over a 28 day growth cycle of the M. tuberculosis reference strain (H37Rv). The expression of tbnat occurs early in growth and reaches maximum levels at mid-exponential phase. The exposure of INH-susceptible isolates to low levels of INH resulted in an increase of tbnat expression (reference strain H37Rv, which is wild-type for tbnat, and isolate 1430, containing both SNPs). An INH-resistant isolate (816) exposed to INH showed no change in tbnat expression. The increased expression in the susceptible isolates suggests that INH affects tbnat expression. tbnat may contribute to INH susceptibility, but in combination with other factors.

Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages

Microparticles prepared by the precipitation with a compressed antisolvent (PCA) process were evaluated for their potential in targeting an ionizable prodrug of isoniazid (INH), isoniazid methanesulfonate (INHMS), for sustained delivery of INH to alveolar macrophages (AMs). The charged prodrug was ion-paired with two different hydrophobic cations (tetrapentylammonium (TPA)— and tetraheptylammonium (THA)—bromide), and loaded separately into the poly( l-lactide) (PLA) microparticles. The drug/polymer particles were spherical in shape and between 1 and 3 μm in diameter. The choice of hydrophobic cations did not affect drug incorporation efficiencies or the release kinetics of INH from the microparticles. Using a sensitive liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay developed for INH, high level of INH was detected in NR8383, a rat AM cell line, following exposure of these cells to drug-loaded microparticles. To confirm the microparticles can target AMs in vivo, we compared the INH levels in lavaged bronchoalveolar macrophages by LC-MS/MS after the Sprague–Dawley rats were administered either INHMS in PLA microparticles by intra-tracheal instillation or INH solution by gavage or intra-tracheal instillation. As expected, only microparticles provided sustained and targeted delivery of INH to AMs. Most importantly, this method of delivery led to substantial reduction in the blood levels of acetylisoniazid (AcINH), a major and potential toxic metabolite of INH.

Disruption of a Cadherin Gene Associated with Resistance to Cry1Ac δ-Endotoxin of Bacillus thuringiensis in Helicoverpa armigera

A laboratory strain (GY) of Helicoverpa armigera (Hubner) was established from surviving larvae collected from transgenic cotton expressing a Bacillus thuringiensis var. kurstaki insecticidal protein (Bt cotton) in Gaoyang County, Hebei Province, People's Republic of China, in 2001. The GYBT strain was derived from the GY strain through 28 generations of selection with activated Cry1Ac delivered by diet surface contamination. When resistance to Cry1Ac in the GYBT strain increased to 564-fold after selection, we detected high levels of cross-resistance to Cry1Aa (103-fold) and Cry1Ab (>46-fold) in the GYBT strain with reference to those in the GY strain. The GYBT strain had a low level of cross-resistance to B. thuringiensis var. kurstaki formulation (Btk) (5-fold) and no cross-resistance to Cry2Aa (1.4-fold). Genetic analysis showed that Cry1Ac resistance in the GYBT strain was controlled by one autosomal and incompletely recessive gene. The cross-resistance pattern and inheritance mode suggest that the Cry1Ac resistance in the GYBT strain of H. armigera belongs to "mode 1," the most common type of lepidopteran resistance to B. thuringiensis toxins. A cadherin gene was cloned and sequenced from both the GY and GYBT strains. Disruption of the cadherin gene by a premature stop codon was associated with a high level of Cry1Ac resistance in H. armigera. Tight linkage between Cry1Ac resistance and the cadherin locus was observed in a backcross analysis. Together with previous evidence found with Heliothis virescens and Pectinophora gossypiella, our results confirmed that the cadherin gene is a preferred target for developing DNA-based monitoring of B. thuringiensis resistance in field populations of lepidopteran pests.

Decreased bioavailability of rifampicin and other anti-tb drugs in patients with advanced HIV disease

Background Malabsorption of drugs from the gastro-intestinal tract due to HIV enteropathy and concurrent infections could lower the bioavailability of anti-tuberculosis (TB) drugs in HIV infected individuals. Our aim was to study the pharmacokinetics of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) in HIV infected Indian subjects. The D-xylose absorption test was also performed in all the patients. Method We studied 13 patients with smear positive pulmonary TB, 13 with HIV & diarrhoea and 14 with HIV & TB. Rifampicin (450mg), INH (600mg), PZA (1500mg) and EMB (1200mg) were administered orally. The plasma levels of RMP and INH at different time points and urinary levels of all drugs/metabolites were estimated. Results A significant decrease in peak concentrations of RMP in HIV & diarrhoea and HIV & TB patients was observed when compared to patients with TB, the values being 3.23, 3.27 & 8.27μg/ml respectively (P<0.001). Significant decrease in AUC of RMP was also observed in HIV patients. The bioavailability of INH was reduced in rapid acetylators in HIV patients with and without TB. The urinary excretion of all four drugs/metabolites and D-xylose was reduced in both HIV groups of patients. Conclusion Patients with HIV & TB and/or diarrhoea have decreased bioavailability of first line anti-TB drugs. This could have implications for TB treatment of HIV infected patients. Clinical Pharmacology & Therapeutics (2004) 75, P29–P29; doi: 10.1016/j.clpt.2003.11.108

Exogenous oestrogen as an alternative to food allergy in the aetiology of angioneurotic oedema

Although frequently reported as an aetiology for chronic angioneurotic oedema or urticaria, food allergy is often a diagnosis proposed in the absence of more convincing evidence, as illustrated by the disappointing results of eviction regimens. We report a series of women with an initial diagnosis of food allergy, but in whom the role of oral contraceptives was subsequently demonstrated. Detailed medical history was obtained from 26 young women presenting with chronic angioneurotic oedema or urticaria initially attributed to food allergy, but in whom C1-esterase inhibitor (C1 INH) deficiency was demonstrated. We investigated the effects of oral contraception on C1 INH levels, C1 INH activity and clinical symptoms of these patients. Discontinuation of oral contraception induced an increase in C1 INH levels and C1 INH activity, associated with recovery or marked improvement of the clinical symptoms formerly attributed to food allergy. The relatively high frequency of women taking cyproterone acetate in this population appeared to be a remarkable finding. Replacement of the initial contraception containing ethinylestradiol by a progestogen maintained or even accentuated these good therapeutic results. Exogenous oestrogens, such as those contained in most oral contraceptives, may play an iatrogenic role in the aetiology of chronic angioneurotic oedema or urticaria.

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.