Intensive short-course chemotherapy in pulmonary tuberculosis

One hundred and twenty children with possible diagnosis of pulmonary tuberculosis were admitted in this study for evaluating the efficacy of short course chemotherapy regimens in childhood pulmonary tuberculosis and are under follow up. In only three patients smear was positive for AFB. In 74 cases culture for AFB was done of which 18 cases (24·3%) were found to be positive. Fortyone patients were put on a standard one year regimen consisting of streptomycin, isoniazide and ethambutol as a control group and seventy nine patients were put on short-course regimens, consisting of isoniazid, rifampicin and pyrizinamide. Out of these 79 patients, 39 were in a biweekly regimen consisting of isoniazid and rifampicin after initial intensive therapy with three drugs for two months. In majority of patients clinical improvement and in all patients bacteriological improvement was observed at the end of two months period. Marked radiological improvement at the end of therapy was seen in only about two-third patients. Relapse after stopping therapy occurred in one patient with associated tubercular cervical lymphadenitis.     

Phase II trial of branched peginterferon-alpha 2a (40 kDa) for patients with advanced renal cell carcinoma.

BACKGROUND: Peginterferon-alpha 2a (40 kDa), PEGASYS(TM) (PEG-IFN), is a modified form of recombinant human interferon (IFN)-alpha 2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase II trial was conducted in previously untreated patients with advanced renal cell carcinoma (RCC) to assess efficacy, toxicity and pharmacokinetic profile. PATIENTS AND METHODS: Forty previously untreated patients with advanced RCC were enrolled on this multicenter trial. The median age was 60 years and 63% had prior nephrectomy. PEG-IFN was administered at a dose of 450 micro g/week on a weekly basis by subcutaneous injection. Serial venous blood samples were drawn to assess concentrations of PEG-IFN. RESULTS: Five (13%) patients achieved a major response (four partial and one complete). The median time to progression was 3.8 months, and 63% of patients were alive at 1 year. The toxicity profile was mostly mild to moderate in intensity. Toxicity higher than grade 2 included neutropenia (six patients), fatigue/asthenia (four patients), nausea/vomiting (three patients) and elevated hepatic transaminase concentrations (four patients). Serum drug levels were studied in all patients; mean C(max) at week 1 was 19 ng/ml, and levels were sustained at close to peak over 1 week. With chronic dosing, drug concentration was increased 3-fold, and steady state was achieved in 5-9 weeks. CONCLUSIONS: The sustained maintenance of serum levels of PEG-IFN allows once-weekly dosing. The efficacy and tolerability profile was qualitatively similar to standard IFN-alpha, and adverse events were mostly mild to moderate in nature.     

Determination of metabolite pharmacokinetics for orally administered prodrugs

The theoretical evaluation of a pharmacokinetic precursor/metabolite model was accomplished utilizing an integral approach based on clearance. Particular attention was paid to prodrugs where a single active intermediate results directly from the parent drug. This model, however, can be utilized for any drug in which a single first-pass metabolic adduct results. Complete elucidation of the first-pass and metabolic systemic pharmacokinetics is possible when plasma and urine concentration data are available after only oral drug administration. The generality of the model does not require prior knowledge of whether the metabolite was formed systemically or presystemically, and only limited metabolic pathway profiling. The model was applied to the evaluation of the angiotensin-converting enzyme inhibitor prodrug pentopril.     

Determination of in vivo hepatic extraction ratio from in vitro metabolism by rat hepatocytes.

Using isolated rat hepatocytes, the in vitro intrinsic hepatic clearance of three drugs, namely, antipyrine (AP), propranolol (P), and CGS 13429 was determined. The hepatic extraction ratios of AP, P, and CGS 13429 were then calculated to be 0.10, 0.90, and 0.88, respectively. To determine the in vivo hepatic extraction ratio in the rat, AP, P, or CGS 13429 was infused separately at a rate of 40, 20, and 20 micrograms/min.kg, via jugular and hepatic portal veins. The steady state plasma levels of AP, P, and CGS 13429 were 5.30 +/- 0.33 micrograms/ml, 608 +/- 76 and 380 +/- 46 ng/ml after jugular vein (iv) infusions, and 4.96 +/- 0.46 micrograms/ml, 162 +/- 26, and 148 +/- 23 ng/ml after hepatic portal vein (hpv) infusions, respectively. The blood to plasma ratios of AP, P, and CGS 13429 were 1.0, 0.78, and 1.0, respectively. The in vivo hepatic extraction ratio, calculated as (Css,iv--Css,hpv)/Css,iv from steady state blood levels following iv and hpv infusions for AP, P, and CGS 13429, were 0.065, 0.73, and 0.61, respectively. These results suggest that in vitro metabolism studies by hepatocytes may have potential application, during drug discovery, to distinguish drugs of low and high metabolic hepatic extraction ratio in vivo.     

Prospective comparison of novel dark blood late gadolinium enhancement with conventional bright blood imaging for the detection of scar

Background

Conventional bright blood late gadolinium enhancement (bright blood LGE) imaging is a routine cardiovascular magnetic resonance (CMR) technique offering excellent contrast between areas of LGE and normal myocardium. However, contrast between LGE and blood is frequently poor. Dark blood LGE (DB LGE) employs an inversion recovery T2 preparation to suppress the blood pool, thereby increasing the contrast between the endocardium and blood. The objective of this study is to compare the diagnostic utility of a novel DB phase sensitive inversion recovery (PSIR) LGE CMR sequence to standard bright blood PSIR LGE.

Methods

One hundred seventy-two patients referred for clinical CMR were scanned. A full left ventricle short axis stack was performed using both techniques, varying which was performed first in a 1:1 ratio. Two experienced observers analyzed all bright blood LGE and DB LGE stacks, which were randomized and anonymized. A scoring system was devised to quantify the presence and extent of gadolinium enhancement and the confidence with which the diagnosis could be made.

Results

A total of 2752 LV segments were analyzed. There was very good inter-observer correlation for quantifying LGE. DB LGE analysis found 41.5% more segments that exhibited hyperenhancement in comparison to bright blood LGE (248/2752 segments (9.0%) positive for LGE with bright blood; 351/2752 segments (12.8%) positive for LGE with DB; p?<?0.05). DB LGE also allowed observers to be more confident when diagnosing LGE (bright blood LGE high confidence in 154/248 regions (62.1%); DB LGE in 275/324 (84.9%) regions (p?<?0.05)). Eighteen patients with no bright blood LGE were found to have had DB LGE, 15 of whom had no known history of myocardial infarction.

Conclusions

DB LGE significantly increases LGE detection compared to standard bright blood LGE. It also increases observer confidence, particularly for subendocardial LGE, which may have important clinical implications.

     

Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients.

The effects of a 48-hour 0.5 mg/kg/hr infusion of the thromboxane synthase inhibitor pirmagrel were studied in 10 renal allograft recipients with cyclosporine nephrotoxicity. Plasma concentrations reached a mean steady-state plasma level of 1798 +/- 481 ng/ml. Biphasic, rapid elimination of pirmagrel was observed with a distribution half-life of 6.7 minutes and a terminal half-life of 73 minutes. Plasma clearance and the volume of distribution of the drug were 300 +/- 87 ml/hr/kg and 497 +/- 232 ml/kg, respectively. The pharmacodynamic effects of pirmagrel were marked by a mean 96% suppression of serum thromboxane B2 (TXB2), which coincided with a suppression of urinary excretion of TXB2, 2,3-dinor-TXB2, and 11-dehydro-TXB2 of 85% +/- 8%, 91% +/- 5%, and 89% +/- 9%, respectively. Urinary excretion of all thromboxane metabolites measured at the end of 1 week after termination of infusion was returned to the baseline. In conclusion, pirmagrel caused effective and sustained suppression of all thromboxane derived metabolites in plasma and urine during continuous infusion in kidney transplant patients receiving cyclosporine.     

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B

BACKGROUND/AIMS: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/kg b.w., n=16) of recombinant human (rHu) IL-12 given s.c. once a week for 12 consecutive weeks. METHODS: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. RESULTS: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: at the end of the study HBV DNA clearance was greater in patients treated with 0.50 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-gamma, IL-10, neopterin and beta2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. CONCLUSIONS: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.     

Induction of quinidine metabolism and plasma protein binding by phenobarbital in dogs

Two porta-caval transposed mongrel dogs were studied for phenobarbital (PB) induction of quinidine disposition after separate quinidine infusions via normal intravenous route and via portal vein. The plasma concentrations of quinidine and of three metabolites measured (3-OH quinidine, quinidine N-oxide, quinidine 10,11-dihydrodiol) were quite similar between i.v. and portal vein infusions, suggesting that the liver extraction ratio for quinidine in dogs is very low. After PB pretreatment plasma quinidine concentrations at the end of a 10 hr infusion increased about twofold while the half-life decreased from a control value of about 16 hr to 6 hr. Plasma concentrations of the three major metabolites measured were also increased following PB treatment. Plasma protein binding for quinidine and two of its three measured metabolites (3-hydroxy quinidine and quinidine N-oxide) were increased after PB treatment. Pharmacokinetic analysis of the data showed a decrease in steady-state volume of distribution (Vdss) of quinidine from an average value of 153 L to 54 L after PB treatment, while the total clearance did not change (6.6 vs. 5.6 L/hr). This decrease in Vdss could be explained by an increase in plasma protein binding of quinidine after PB treatment. The unbound nonrenal clearance of quinidine was induced by PB treatment. The decrease in fraction free in plasma and increase in unbound nonrenal (hence total) clearance resulted in little or no change in total plasma clearance for quinidine. The formation rate constants calculated for two quinidine metabolites, 3-hydroxy quinidine and quinidine N-oxide, were increased after PB treatment, suggesting an induction in these two metabolic pathways. Only quinidine 10,11-dihydrodiol was found in the bile after quinidine infusion, and the biliary clearance of this metabolite was also induced after PB treatment.