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Introduction: Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs)., Objective: We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs., Methods: New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBM ® MarketScan ® database (USA, January 2008-December 2017). ARF was defined as a diagnosis on inpatient or emergency department claims. We estimated adjusted incidence rates, incidence rate ratios (IRRs), and incidence rate differences (IRDs) of ARF in patients initiating levetiracetam versus other ASMs., Results: Overall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17)., Conclusions: The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In some countries, including Sweden, no risk is considered to exist with the use of meclozine for nausea and vomiting in pregnancy (NVP), but in other countries warnings against use during pregnancy are given. Rat tests indicate a teratogenic risk and published epidemiological studies are of restricted size. Delivery outcome was studied in 16,536 women who reported the use of meclozine in early pregnancy and was compared with all 540,660 women who gave birth. Information on drug usage was obtained prospectively in early pregnancy. Risk factors for using meclozine were young maternal age, to have had a previous child, not to smoke, to have a low body mass index. The use of some other drugs (antihypertensives, thyroxine, anticonvulsants) decreased the use of meclozine. Maternal diagnoses of preeclampsia or diabetes were less frequent when the woman had used meclozine. The twinning rate was increased and the sex distribution of the infants low (female excess). Preterm birth, low birth weight, short body length, and small head circumference occurred at a reduced rate after meclozine use, notably for boys. Also the rate of congenital malformations was reduced. If anything, delivery outcome is better than expected when the mother used meclozine. These beneficial effects are probably secondary to NVP. Meclozine can apparently be used without risk at this condition.

The aim of this study was to investigate the effects of riluzole on the lesion induced by a permanent middle cerebral artery occlusion (MCAO) in rats. Riluzole at 4 or 8 mg/kg i.v. significantly reduced the cortical ischemic brain damage. With the most effective dose of 8 mg/kg, the time evolution of the lesion was assessed by T2-weighted magnetic resonance imaging (MRI) repeated on the same animals after MCAO. MRI obtained at 24, 48, and 72 hours after MCAO showed a progressive increase of the ischemic lesion, except in the cortex of the riluzole-treated rats (8 mg/kg i.v.). Furthermore, there was no difference between lesion volumes as measured by MRI or by histology. This study indicates that MRI may be a valuable method to quantify in vivo the neuroprotective profile of a drug.

In rat brain dynamic susceptibility contrast magnetic resonance (MR) images, vessels visible on the same scan plane as the brain tissue were used to measure the characteristics of the input function of the MR contrast agent gadopentetate dimeglumine. MR images were acquired 30 and 60 minutes after intravenous injections of 3 mg/kg and 15 mg/kg NG-Nitro-L-arginine methyl ester (L-NAME) (n = 9). The time of arrival (TOA) and the mean transit time corrected for TOA of the input function were increased by 3 mg/kg or 15 mg/kg L-NAME. The area of the input function was increased by 15 mg/kg L-NAME. In two animals, similar modifications of the input function induced by 20 mg/kg L-NAME were reversed by infusion of sodium nitroprusside. In two other animals, MABP was increased by phenylephrine to a similar extent as in L-NAME experiments, but did not induce the same modifications of the input function, showing that the action of L-NAME on the input function was not simply caused by an effect on MABP. These results show that the input function can be significantly altered by manipulations widely used in cerebrovascular studies. These input function changes have important implications for calculation of cerebral blood flow.

The creatine kinase reaction has been studied by 31P NMR in exercising human calf muscle. Quantitative analysis of high energy phosphates and saturation transfer study of the creatine kinase flux in the direction of ATP synthesis (Vfor) were performed at rest and during exercise. As expected, exercise induced a [PCr] decrease (from 28.5 +/- 0.9 to 21.9 +/- 1.5 mM, P < 0.01) matched by a Pi increase (from 4.5 +/- 0.2 to 8.9 +/- 1.8 mM, P = 0.06). pHi and [ATP] remained unchanged. Vfor did not change from rest (12.4 +/- 0.9 mM s(-1)) to moderate exercise and decreased at the highest exercise level (8.4 +/- 1.4 mM s(-1), P = 0.006). This observation differs from the prediction of the creatine kinase rate equation, showing an increase in the flux with exercise intensity. Computations suggest that this discrepancy arises from metabolite compartmentalization and/or from the reaction kinetics of a dead end complex stabilized by planar anions.

The herpes simplex virus thymidine kinase gene was transferred into C6 glioma cells by infection with a recombinant adenovirus. In vitro, a 10 microM ganciclovir concentration was able to kill 100% of the infected cells. For in vivo experiments, brain tumors were established by stereotactic injection of C6 glioma cells in the caudate nucleus of rats. Five days later, the recombinant adenovirus was inoculated into the tumors and the animals were treated by intraperitoneal injections of ganciclovir for 14 days. At the end of ganciclovir therapy, histological examination revealed a 28-fold decrease in tumor volumes in the treated animals, as compared with control animals. In long-term studies, the mean survival time of the treated animals were four-fold longer than that of control ones. Magnetic resonance imaging demonstrated an apparent complete tumor regression in 62% of the animals. However, late tumor recurrence was observed in the treated animals. Repeated inoculation of C6 glioma cells in the contralateral hemisphere of long-term surviving animals resulted in either tumor rejection or slowly growing tumors. These findings demonstrate the potential efficacy of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration in the treatment of rat gliomas.

To detect reperfused ischemia of the rat intestine, T2-weighted spin-echo images were acquired, followed by T1-weighted images before and after administration of polylysine-Gd-DTPA or Gd-DTPA. Before administration of the contrast agent, the reperfused intestine was hyperintense on T2-weighted images, and to a lesser extent on T1-weighted images. After administration of polylysine-Gd-DTPA, the reperfused intestine enhanced more than the normal one, giving a significantly better contrast-to-noise (CNR) ratio than on unenhanced images. Gd-DTPA induced the same enhancement of the reperfused and the normal intestine and the CNR was lower than on unenhanced T2-weighted images. Reperfused intestinal ischemia could thus be better detected on polylysine-Gd-DTPA-enhanced MR images than on unenhanced images or on Gd-DTPA-enhanced images.

Rationale and Objectives: To compare the magnetic resonance (MR) imaging characteristics of gadolinium-DTPA (Gd-DTPA), a low-molecular-weight contrast agent, and polylysine-Gd-DTPA, a macromolecular contrast agent, in two types of hepatocarcinomas (HCC) in the rat., Methods: T1-weighted spin-echo images were obtained in 13 rats with chemically induced HCC and 26 rats with Novikoff HCC before and 3 minutes to 60 hours after administration of either Gd-DTPA or polylysine-Gd-DTPA., Results: Three minutes after polylysine-Gd-DTPA administration, the tumor-to-liver contrast of the two types of HCC increased significantly (positive contrast for chemically induced HCC and negative contrast for Novikoff HCC). At 30 minutes and 60 hours, the tumor-to-liver contrast remained above baseline values in chemically induced HCC and returned progressively to baseline values in Novikoff HCC. No significant increase in tumor-to-liver contrast was observed after Gd-DTPA administration., Conclusions: These results suggest that polylysine-Gd-DTPA provides a higher and more prolonged increase in tumor-to-liver contrast than Gd-DTPA.

Background: The functional and metabolic effects of inhibitors of nitric oxide (NO) synthase on ischemic hearts have not been investigated. This work was designed to perform such a study in isolated perfused rabbit hearts submitted to low-flow ischemia., Methods and Results: After a 30-minute equilibration period, the hearts were submitted to low-flow ischemia for 60 minutes followed by reperfusion for 30 minutes. Functional and metabolic parameters were followed in hearts perfused with or without inhibitors of NO synthase or NO precursors, which were added 15 minutes before ischemia but were absent during reperfusion. Ischemic contracture was delayed and reduced in hearts perfused with 1 mumol/L L-N-monomethylarginine (L-NMMA) or 1 mumol/L L-N-arginine methylester, two inhibitors of NO synthase, but not with D-N-monomethylarginine, the inactive enantiomer of L-NMMA. The protection was suppressed by addition to the perfusate containing L-NMMA of 1 mmol/L L-arginine or 0.1 mmol/L sodium nitroprusside but not by addition of 10 mumol/L 8-bromo cGMP, a cGMP analogue. The functional protection by 1 mumol/L L-NMMA was related to a stimulation of glycolysis from exogenous glucose and a preservation of the glycogen stores. This resulted in a better maintenance of high-energy phosphates and a lower acidosis as measured by 31P nuclear magnetic resonance spectroscopy. During reperfusion, functional recovery was more than doubled, and enzyme release was halved in L-NMMA-treated hearts compared with controls. The functional and metabolic protection was maximal at 1 nmol/L to 1 mumol/L L-NMMA, ie, below the vasoactive concentrations of the inhibitor., Conclusions: Nonvasoactive concentrations of NO synthase inhibitors protect the heart against ischemic damage; this relates to a stimulation of glycolysis from exogenous glucose.