Additive effect of indomethacin and methotrexate on suppression of growth in rats

The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth.     

Effect of tetrakis-μ-3,5-diisopropylsalicylatodiaquodicopper(II) on the status of reduced glutathione in freshly isolated hepatocytes

Effects of different concentrations of tetrakis--3,5-diisopropylsalicylatodiaquodicopper(II) (Cu(II)₂(3,5-DIPS)₄(H₂O)₂) on the reduced status of glutathione (GSH), the major nonprotein thiol in tissues, were investigated using freshly isolated hepatocytes. Cu(II)₂(3,5-DIPS)₄ below 100 M did not have any significant effects on either the GSH content or viability of the hepatocytes, but at 150–250 M it decreased both parameters after 1 h of incubation. The decrease in cellular GSH was not followed by an increase in the oxidized form of GSH (GSSG) in the cell suspension. The addition of deferoxamine with Cu(II)₂(3,5-DIPS)₄ to the hepatocyte suspension prevented depletion in GSH content and loss of cell viability by Cu(II)₂(3,5-DIPS)₄. Both GSH depletion and loss of cell viability were found to be Cu(II)₂(3,5-DIPS)₄ dose dependent. From these results, it appears that Cu(II)₂(3,5-DIPS)₄ penetrated the cell membrane and acted by decreasing the GSH level by forming a copper-glutathione complex.     

Relative pharmacokinetics of three amikacin brands in onco-hemotologic pediatric patients experiencing febrile neutropeina.

Three commercially available brands of amikacin were investigated in a parallel study design for the assessment of comparative pharmacokinetics in pediatric oncology patients with chemotherapy-induced neutropenic febrile episode. Amikacin concentration in serum samples was determined by fluorescence polarization immunoassay method using Abbott TDx system. Computer software, PK II was used for computation of pharmacokinetic parameters of amikacin. The serum concentration of all brands nonsignificantly (p > 0.05) varied at all time points, except at 1 and 2 hrs post dosing. At 1 hr post dosing, the serum concentration of brand II varied from rest of two brands. Whereas at 2 hr following I/V infusion, brands II and I were statistically different. Highest serum concentration of 38.69 +/- 1.45 microg/ml was observed in case of brand III while brands I and II showed lower but not significantly different serum concentration values, i.e., 36.30 +/- 1.65 and 37.89 +/- 1.32 microg/ml, respectively when compared with brand I. The other pharmacokinetic parameters of 3 brands found to have non-significant difference (P < 0.05) except, t(1/2)alpha and Cl of brands I and II that deviated statistically significant (p < 0.01). The relative bioavailability of brand II and III as compared with brand I, considered as standard 86.17 and 96.86%, respectively falls within the accepted limits of +/- 20% required for the bioequivalence of any two brands. Based upon findings of the present study, all these brands may be used interchangeably in oncology patients. Further studies, however are needed to determine whether the statistically elevated Cl value in brand II is of any clinical significance.     

Supraventricular arrhythmia: A complication of 5-fluorouracil therapy

5-Fluorouracil is an S-phase-specific, synthetic pyrimidine antimetabolite, which is used as a cytostatic agent for a variety of malignant lesions, either singly or in multidrug regimens. Gastrointestinal toxicity and myelosuppression are the most common adverse reactions, but, of late, clinical cardiotoxicity has been reported in both prospective and retrospective studies. We present our experience of clinical cardiotoxicity in five patients.     

Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects.

OBJECTIVE: To determine the amount of growth in vestibular schwannomas in Neurofibromatosis type 2 (NF2) patients from diagnosis through short-term (up to 2 yr) and long-term (up to 4 yr) follow-up. STUDY DESIGN: Retrospective magnetic resonance imaging (MRI) films were obtained on subjects enrolled in the NF2 Natural History study and examined for changes in vestibular schwannoma size over time. SETTING: Data were collected from nine foreign and domestic NF2 centers, including hospital-based, academic, and tertiary care centers. SUBJECTS: NF2 patients with MRI data and at least one follow-up examination within 9 months to 2 years of diagnosis were included; n=56 patients with 84 lesions for evaluation of growth. INTERVENTION: Routine, clinically obtained, magnetic resonance images were digitized and measured using image management software. Short-term follow-up was defined as up to 2 years (n=84 lesions), and long-term follow-up was defined as 3 to 4 years (n=29 lesions). OUTCOME MEASURES: Vestibular schwannoma size was assessed using anterior-posterior, medial-lateral, and greatest diameter linear measurements. RESULTS: Vestibular schwannomas increased in size (at least 5 mm) in 8% of the vestibular schwannomas across short-term follow-up. At long-term follow-up, 13% of the tumors had increased in size. On average, schwannomas increased in greatest diameter 1.3 mm per year across short-term follow-up. CONCLUSION: Slightly greater than 1 in 10 diagnosed NF2-related vestibular schwannomas increased in size by at least 5 mm by 4 years of follow-up, if still untreated at that time.     

Interspeaker variation in habitual speaking rate: additional evidence.

PURPOSE: The purpose of the present study was to test the hypothesis that talkers previously classified by Y.-C. Tsao and G. Weismer (1997) as habitually fast versus habitually slow would show differences in the way they manipulated articulation rate across the rate continuum. METHOD: Thirty talkers previously classified by Tsao and Weismer (1997) as having habitually slow (n = 15; 7 males, 8 females) and habitually fast (n = 15; 8 males, 7 females) articulation rates produced a single sentence at 7 different rates, using a magnitude production paradigm. Hence, the participants were not randomly assigned to conditions. RESULTS: Quadratic regression functions relating measured to intended articulation rates were all statistically significant, and most important, there were significant differences between the slow and fast groups in the y intercepts of the functions, for both males and females. CONCLUSIONS: This study provides a constructive replication of Tsao and Weismer (1997), showing a difference between slow and fast talkers with a new set of speech materials and in a new task. The findings appear to be consistent with a biological basis for intertalker rate differences.     

Right ventricular outflow tract after non-conduit repair of tetralogy of Fallot with coronary anomaly

BACKGROUND: A total of 25 patients with tetralogy of Fallot and an important coronary artery crossing the right ventricular outflow tract underwent complete repair without use of an extracardiac conduit between January 1990 and December 1994. Repair was exclusively done by the transatrial or transatrial-transpulmonary approach. Age of these patients ranged from 1 to 12 years (mean 3.6 years). Three of the patients had already received a systemic to pulmonary artery shunt. METHODS: All patients reporting for follow-up (n = 18) were subjected to transthoracic echocardiography and, if required, cardiac catheterization and angiography. Right ventricle to pulmonary artery gradients were noted preoperatively, at discharge following repair and at follow-up study. RESULTS: Mean follow-up was 40.6 months (24 to 62 months). Mean early postoperative gradient was 23.5+/-13.4 mm Hg and 4 patients had significant (> 30 mm Hg) gradients. Mean late postoperative gradient was 20.6+/-12.4 mmHg and 2 patients had gradients greater than 30 mmHg. All the patients were in New York Heart Association functional class I at the time of last follow-up. CONCLUSIONS: Acceptable gradients across the right ventricular outflow tract are achievable following repair of tetralogy of Fallot in the presence of anomalous coronary artery across the right ventricular outflow tract using the transatrial or transatrial-transpulmonary approach. Most gradients were found not to vary significantly on subsequent follow-up.     

Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1.

The cytochrome P450 family 1 (CYP1) is considered to be one of the xenobiotic-metabolizing enzyme families and is responsible for oxidative metabolism of polycyclic aromatic hydrocarbons. For example, mouse Cyp1b1 was originally identified as the enzyme responsible for oxidative metabolism of 7,12-dimethylbenz(alpha)anthracene (DMBA). A comparison of the kinetics of this metabolism by mouse and human CYP1B1 orthologs revealed the mouse enzyme to have a more favorable metabolism of DMBA, with a catalytic efficiency ratio (CER) of 0.23. However, CYP1 enzymes are also capable of metabolism of endobiotics, and in the present study, the metabolism of retinoids and lipid endobiotics by human CYP1B1 and mouse Cyp1b1 orthologs was compared. Both hemoproteins oxidized retinol to retinal and retinal to retinoate, but did not oxidize retinoate. The CYP1B1 to Cyp1b1 CERs were 13 and 26 for the two steps, respectively; the Cyp1b1 K(m(app)) values for retinoids were 20-fold higher. Human family 1 cytochromes P450 had unique regional specificities for arachidonate oxidation: the major metabolites of CYP1A1, CYP1A2, and CYP1B1 were 75% terminal hydroxyeicosatetraenoic fatty acids (HETEs), 52% epoxyeicosatrienoic fatty acids (EETs), and 54% mid-chain HETEs, respectively. CYP1A1 and CYP1B1 K(m(app)) values for arachidonate were about 30 microM, whereas CYP1A2 K(m(app)) was 95 microM. The major metabolites of arachidonic acid by Cyp1b1 were EETs (50%) and midchain HETEs (37%). The mouse ortholog had a CER for metabolite production of 64 due to a K(m(app)) of 0.5 mM for arachidonate.