Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs.

Background & objectives: As the dosages recommended for children are based on weight, empirical and derived by extrapolation from the studies in adults, pyrazinamide (PZA) pharmacokinetics in children is likely to be different from adults. Limited information exists regarding the pharmacokinetics of PZA in paediatric patients of primary progressive disease (PPD) of lungs. This study aims to look at the changed pharmacokinetics of pyrazinamide in children with PPD of lungs by using reverse phase high-pressure liquid chromatography (HPLC). Methods: A total of 40 children (age range 5 to 13 yr) of PPD were receiving pyrazinamide (30 mg/kg/day). On 11th day of short course antitubercular therapy, blood samples (two per day from 11th to 13th day) were collected at 0 h (pre-dose), 1, 2, 3, 4, 8 and 24 h after pyrazinamide administration and concentration of pyrazinamide was estimated by reverse phase high-pressure liquid chromatography. The mean peak serum concentration, the time to reach mean peak serum concentration, total clearance, concentration at time zero, volume of distribution, terminal elimination rate constant, elimination half-life, total area under serum concentration-time curve were measured. Results: The mean serum concentrations of pyrazinamide were found higher than its minimum inhibitory concentration (20 μg/ml) required to inhibit the growth of tubercle bacilli from 1 to 8 h continuously. Interpretation & conclusions: Our results suggest that a dose of 30 mg/kg/day achieves much higher concentration of pyrazinamide as compared to its minimum inhibitory concentration (20 μg/ml). Therefore, lowering of pyrazinamide dosage is suggested in children for better patient compliance along with reduction in cost, side-effects and toxicity without compromising its efficacy.

Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs.

BACKGROUND & OBJECTIVE: As the dosages recommended for children are based on weight, empirical and derived by extrapolation from the studies in adults, pyrazinamide (PZA) pharmacokinetics in children is likely to be different from adults. Limited information exists regarding the pharmacokinetics of PZA in paediatric patients of primary progressive disease (PPD) of lungs. This study aims to look at the changed pharmacokinetics of pyrazinamide in children with PPD of lungs by using reverse phase high-pressure liquid chromatography (HPLC). METHODS: A total of 40 children (age range 5 to 13 yr) of PPD were receiving pyrazinamide (30 mg/kg/day). On 11(th) day of short course antitubercular therapy, blood samples (two per day from 11(th) to 13(th) day) were collected at 0 h (pre-dose), 1, 2, 3, 4, 8 and 24 h after pyrazinamide administration and concentration of pyrazinamide was estimated by reverse phase high-pressure liquid chromatography. The mean peak serum concentration, the time to reach mean peak serum concentration, total clearance, concentration at time zero, volume of distribution, terminal elimination rate constant, elimination half-life, total area under serum concentration-time curve were measured. RESULTS: The mean serum concentrations of pyrazinamide were found higher than its minimum inhibitory concentration (20 microg/ml) required to inhibit the growth of tubercle bacilli from 1 to 8 h continuously. INTERPRETATION & CONCLUSION: Our results suggest that a dose of 30 mg/kg/day achieves much higher concentration of pyrazinamide as compared to its minimum inhibitory concentration (20 microg/ml). Therefore, lowering of pyrazinamide dosage is suggested in children for better patient compliance along with reduction in cost, side-effects and toxicity without compromising its efficacy.

Clinico-immunological profile in juvenile rheumatoid arthritis--an Indian experience.

From a Pediatric Rheumatology Clinic 361 children diagnosed as juvenile rheumatoid arthritis (JRA) according to American Rheumatism Association-JRA criteria were studied retrospectively for their clinico-immunological profile. The mean age of onset in systemic, pauciarticular and polyarticular onset, JRA subtypes were 5.2, 6.8 and 7.2 years respectively. There was male preponderance in systemic and pauciarticular JRA. In seropositive polyarticular JRA, girls outnumbered boys. The frequency of occurrence of systemic, pauciarticular and polyarticular disease was 87 (24%), 108 (30%) and 166 (46%) respectively. The systemic onset disease was dominated by extra-articular manifestations in terms of fever (100%), rash (57%), hepatomegaly (51%) and lymphadenopathy (25%). The pauci- and polyarticular illnesses were commonly dominated by joint involvement, morning stiffness, and in few patients, by extra-articular manifestations also. The joints were involved symmetrically. Most commonly involved joints in order of decreasing frequency were knee, ankle, wrist and elbow in all the subtypes. Anemia and leucocytosis were observed in majority with higher frequency in systemic onset JRA. The rheumatoid factor (RF) was present in 15% of polyarticular JRA. RF was also present in 7 and 9% of patients with pauciarticular and systemic subtypes respectively. The antinuclear antibody was positive in only 3 out of 66 patients in whom the test was carried out. The demographic profile and trends in clinical features were similar to the studies reported on caucasian population with difference in the actual frequency of various clinical features.

Juvenile dermatomyositis.

The clinical profile of 7 children and their follow-up is described. There was female preponderance with mate to female ratio of 1:6. The median age of onset was 6 years. All the patients had skin rash, muscle weakness and abnormal enzyme profile. Muscle biopsy was performed in 6 and was abnormal in all of them. The electromyogram (EMG) was performed in 6 and was found abnormal in five. All the children responded well to corticosteroids. Two children received intravenous dexamethasone bolus and showed good response.

Tubercular lymphadenitis: clinical manifestations.

One hundred and thirteen children suffering from tubercular lymphadenitis proven histopathologically, were studied for clinical and laboratory features. Age distribution was equal in all age groups except during infancy when it was rare. Sex ratio indicates a male preponderance with male to female in the ratio of 1.5:1 (67:46). Family history of contact with known tuberculous patient was positive in 19 (17%) children, 44 (40%) had received BCG, and 98 (88%) were either normal nourished or had mild malnutrition. Cervical, axillary and inguinal nodes were found in 90 (80%), 14 (12%), and 8 (7%) children respectively. Epitrochlear node was found in only 1 child. 11 (10%) children had discharging sinus, all being in cervical group. The consistency of nodes was firm in 98 (87%), fluctuation was present in 15 (13%). In 87 (77%) lymph nodes were matted. Hepatomegaly of more than 2 cm was present in 13 (11%) and spleen was enlarged (> 2 cm) in 4 (4%) only: Mantoux test was positive in 96 (85%) children and chest X-ray was abnormal in 25 (22%) cases. Findings suggest that tubercular adenitis occurs in all age groups with equal frequency. It can occur in vaccinated children also. It may be a sole manifestation of tubercular infection. The cervical nodes are predominantly involved. There is no typical location of nodes in individual groups but multiplicity and matting of nodes are characteristic features of tubercular adenitis in children.

Isoniazid and acetylisoniazid kinetics in serum and urine in pulmonary primary complex with intermittent regimen.

Twenty patients, 1 through 13 years of age from Pediatric Tuberculosis Clinic of All India Institute of Medical Sciences, New Delhi, suffering from pulmonary primary complex (PPC) were investigated for serum and urine concentrations of isoniazid (INH) and acetylisoniazid (AcINH). Patients were put on an intermittent regimen - 2HR, 4H2R2, INH (H) was given in a dose of 10 mg/kg/day for first 2 months (the daily dose phase), followed by 20 mg/kg/dose in biweekly phase of regimen for rest of the 4 months, whereas, rifampicin (R) was given as 12 mg/kg in both daily as well as biweekly phases. In the biweekly phase of regimen, after 7 days of biweekly administration of drugs, INH and AcINH concentrations were estimated by HPLC at 0,1,3,5 and 7 hours in serum, and at 0-3, 3-6, 6-12 and 12-24 hour-intervals of drug administration in urine. Peak concentrations of INH and AcINH (Mean +/- SD) were 2.6 +/- 1.8 and 5.5 +/- 2.6 micrograms/ml in serum (Cmax), and 5.7 +/- 4.8 and 21.5 +/- 12.1 mg in urine, respectively. Time to achieve Cmax (Tmax), for INH and AcINH were 1 and 5 hours respectively while time of peak concentration in urine for INH was 3-6 hours and for AcINH 6-12 hours. The half-life (T1/2) of INH was 4.5 hours and area under serum-concentration time-curve (AUC0-7h) was 20.7 micrograms/ml/h (mean values). In biweekly phase (4H2R2) of regimen, just before administration of next dose, 0 hour (or 72 hours) concentration of INH was estimated at 0.47 +/- 0.3 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Tuberculous meningitis in children: manifestation of an immune compromised state.

Thirty children in the age group 0-4 years with tuberculous meningitis (TBM) were investigated for their immune status (cell-mediated and humoral). Twenty age, sex and nutritional status matched children were investigated on the same lines, who served as controls. Absolute T cell counts were significantly increased (3126 +/- 1623) (p < 0.01) in TBM, though T cell percentages were comparable (59.8% in TBM versus 54.44% in controls). Leucocyte migration inhibition (LMI) test positivity was high (93%) in TBM patients. Mean LMI index showed a highly statistically significant difference (p < 0.001) between the 'Before-therapy' (0.62 +/- 0.16) and 'During-therapy' (0.77 +/- 0.23) groups in TBM patients. Mantoux test positivity with 1 TU of PPD was low (53.0%) in TBM in comparison to LMIT positivity. In humoral immune response, quantitative function measured by EAC rosettes was not altered. However, there was a significant decrease in the levels of IgA (79.48 +/- 33.78 IU) (p < 0.01), IgG (115.01 +/- 32.56 IU) (p < 0.01) and IgM (148.50 +/- 51.88 IU) (p < 0.05) in TBM patients. There was no significant difference in the complement levels in the TBM and control groups. The results show a well developed CMI response but a poor humoral response in TBM and represent an inverse relationship between the CMI and humoral responses.

Serum concentrations of rifampicin and isoniazid in tuberculosis.

Ninety-four patients, 1-13 years of age suffering from different types of tuberculosis were investigated for serum rifampicin (RIF) and isoniazid (INH) concentrations using microbiological and fluorimetric methods, respectively. Of these, 64 (68.1%) had pulmonary primary complex (PPC); 20 (21.3%) progressive primary disease (PPD) and 10 (10.6%) tuberculous meningitis (TBM). Patients with PPC, PPD and TBM were given two-drug (6HR), three drug (2HRZ, 4HR) and four drug (2SHRZ, 4HRE, 3HE) regimens, respectively. RIF and INH were administered in a dose of 12 and 10 mg/kg/day, respectively. After 10-12 days of continuous therapy, their serum concentrations were estimated at 0, 2, 4, 6, 8 hours for RIF and 0, 1, 3, 5, 7 hours for INH. For RIF, the time to achieve maximum concentrations (Tmax) was 2 hours, range of mean of maximum concentration (Cmax) 3.38 to 3.88 micrograms/ml, terminal half life elimination (T1/2) 3.03 to 3.81 hours and area under serum concentration curve (AUC) 0-8 hours 24.7 to 28.3 micrograms/ml hours in different forms of tuberculosis. INH had a Tmax of 1 h, Cmax 4.38 to 8.17 micrograms/ml, T1/2 4.0 to 4.98 hours and AUC 0-7 hours 34.1 to 57.5 micrograms/ml hours. The concentrations achieved at 7-8 hours with these dosages were much above those required for therapeutic efficacy (minimum inhibitory concentration), being 50 to 250 times for RIF and 35-60 times for INH. We recommend pharmacokinetic studies with lower doses of RIF and INH for less toxic, equally effective and cheaper antitubercular chemotherapy.

Childhood tuberculosis in a referral centre: clinical profile and risk factors.

One hundred and ninety six children (age group 6 months to 12 years) attending the Pediatric Tuberculosis Clinic at AIIMS, New Delhi, over a period from January 1988 to December 1989 were analysed. Nearly 61% of children were malnourished (Grades III and IV). A positive family history was noted in nearly one third (33.7%) of cases while 41.3% of children had received BCG. A positive Mantoux test was noted in 77% of cases. The most prominent lesion on radiology was parenchymal (51.4%). In nearly two third of cases, both Mantoux test and X-ray chest was positive. A family history of tuberculosis and BCG vaccination was significantly associated with positive Mantoux test (p < 0.01). Fever and cough in older children (> 6 years) while weight loss in younger children (< 3 years) were the predominant symptoms. Most of the cases (82.1%) had pulmonary primary complex, the proportion being higher in older age group. The severe form of tuberculosis, i.e., progressive primary disease, military tuberculosis, etc., were significantly more in younger children. The various risk factors significantly associated with severe form of tuberculosis were very young children (< 3 years), no BCG vaccination, a negative family history and a negative Mantoux test.

Visual evoked responses in tuberculous children on ethambutol therapy.

Visual evoked responses (VERs) were recorded in 47 children, aged 3-13 years with tuberculosis, treated with ethambutol (20 mg/kg/day) as a part of the antitubercular regimen. VERs were evoked by monocular whole field stimulation, the stimulus being provided by a black and white checker-board pattern reversed every 560 msec and recorded before the commencement, 2, 4, 6, 9 and 12 months of therapy and between 3 to 6 months after stopping the drug. In the first 6 months of therapy the mean values of latency ranged from 92.8 to 101.3 msec in the 3 to less than 6 years age group and 88.5 to 100.3 msec in children 6-13 years of age. Between 6-12 months of therapy the mean values of latency were between 93.3 to 101.0 msec in the 3 to less than 6 years age group and 96.0 to 101.5 msec in the older group. Between 3-6 months after stopping therapy the means of latency ranged from 92 to 96 msec. The differences were not statistically significant at any point of time. Thus, children do not seem to be at greater risk for developing ethambutol inducted optic damage as compared to adults. Ethambutol in the above stated dose may, therefore, be recommended for inclusion in antitubercular chemotherapy in pediatrics without undue fear of subclinical toxicity.

Construction of growth reference standards for urban slum children in developing countries.

A cross-sectional sample of 2987 children in the age group of 1 to 10 years were selected from urban slums of Delhi for measurement of weight and height. Males and females were 53 and 47% respectively. Mean weight and height were calculated for both the sexes. Comparison of percentiles of weight and height with NCHS and ICMR standards showed that the 75th percentiles weight and height of the present study were comparable with 80 and 90% of 50th percentile of NCHS respectively. Hence, upper 25% of the sample arranged in ascending order of magnitude were used for the construction of reference standards of weight and height. Comparison of percentiles drawn from the top 25% of the sample demonstrated that 50th percentile of the present study corresponded to 80% of 50th percentile of the NCHS for weight and 90% of 50th percentile of NCHS of the height for both boys and girls. Also the 50th percentile of ICMR for weight and height for both the sexes. Standards constructed from such sample would be better suited for two important uses: (i) monitoring of Nutrition Programme, and (ii) to detect a child with abnormal growth at the earliest.