The effects of some beta-endorphin fragments with neuroleptic-like properties, i.e., tau-endorphin, des-tyr1-tau-endorphin (DT tau E), desenkephalin-tau-endorphin (DE tau E), in comparison with the dopaminergic antagonist haloperidol,- were studied on the EEG and behavioral alterations induced by beta-endorphin in the rabbit. beta-Endorphin administered i.c.v. (5-30 nmol) induced EEG nonconvulsive limbic seizures as well as EEG background and behavioral alterations which were antagonized by naloxone administered i.v. (1-2 mg/kg). Haloperidol, tau-endorphin, DT tau E and DE tau E were unable to prevent beta-endorphin-induced alterations when injected in a single dose i.v. (25-50 micrograms/kg), 15 min before beta-endorphin. Subchronic i.v. administration of DT tau E or DE tau E (25 micrograms/kg/day) for 4 consecutive days prevented completely EEG limbic seizures as well as EEG background and behavioral alterations induced by i.c.v. beta-endorphin injected 15 min after the fourth dose; however, haloperidol (30 micrograms/kg/day) administered with the same schedule as DT tau E or DE tau E was able to prevent only EEG epileptiform and EEG background alterations induced by beta-endorphin. tau-Endorphin administered i.v. for 4 consecutive days (25 micrograms/kg/day) did not consistently influence any of the beta-endorphin effects. Our results show that DT tau E and DE tau E, which are devoid of opioid activity, exert a strong antagonism on ictal seizures as well as on other EEG alterations and behavioral alterations induced by beta-endorphin, and suggest that the antagonism shown by these drugs and by haloperidol on the EEG effects induced by beta-endorphin are exerted at least in part through an indirect action, i.e., an interaction with the dopaminergic system.
Dichloroacetate (DCA) is an investigational drug that can stimulate mitochondrial energy metabolism by inhibiting pyruvate dehydrogenase kinase. We hypothesize that DCA could be used in high‐risk pregnancy to reduce perinatal mitochondrial deficiency and resulting cardiac dysfunction in at‐risk fetuses and are testing this postulate in a pregnant sheep model. DCA is metabolized by the enzyme glutathione transferase zeta1 (GSTZ1) to glyoxylate. GSTZ1 is not expressed in human fetal liver, but expression rises after birth. Furthermore, DCA inactivates GSTZ1, resulting in altered pharmacokinetics with repeated dosing. The objectives of this research were (1) to investigate the relative expression of GSTZ1 in maternal and fetal sheep liver from untreated controls close to full term (140 days gestation) and (2) to determine if treatment of sheep with DCA resulted in reduced expression of GSTZ1. We administered DCA intravenously to either the ewe or the fetus at daily divided doses of 25 mg/kg for three to five days prior to sacrifice 24 h after the last dose. We used samples of maternal and fetal liver to prepare cytosol and mitochondria and employed a custom‐made polyclonal antibody to rat GSTZ1 to measure expression relative to a single rat hepatic cytosol standard by Western blot. The sheep liver samples exhibited good cross‐reactivity to the rat antibody. Surprisingly, expression of GSTZ1 in the full‐term fetal liver cytosol fractions from controls was similar to that in the control maternal liver. Treatment with DCA resulted in reduced expression in both maternal and fetal liver cytosol fractions to less than 10% of the control values. In control fetuses, mitochondrial expression of GSTZ1 was 17.6 ± 7.6% of the cytosolic expression. In the DCA‐treated group, mitochondrial expression decreased and levels were undetectable in one‐half of the fetal sheep. These studies demonstrate that (1) GSTZ1 expression in liver cytosol and mitochondria in the late fetal period varies with animal species and (2) repeated treatment with DCA results in reduced GSTZ1 expression, which is likely to alter DCA pharmacokinetics. Support or Funding Information Supported in part by the US Public Health Service, grant R21HD91599 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Cisplatin was administered to seven patients with advanced cancer in divided doses of 40 mg/m2 body surface daily for 5 consecutive days. The pharmacokinetics of total Pt was studied on the days 1, 3 and 5 of infusion. The renal function was assessed through the parameters usually applied in the clinical practice (serum creatinine level, creatinine clearance, urinary volume). Pt pharmacokinetics and the renal function did not show modifications outside the normal range. However, on day 5 of treatment patients showed increased alpha-half life and AUC of plasma Pt, as well as decreased Pt total body clearance and Pt renal clearance, associated to a significant (although still within normal range) increase in serum creatinine and a decrease in urinary volume. Moreover, a correlation between Pt pharmacokinetics and renal parameters (measured as the difference between the values of days 1 and 5 of treatment) was also found: the increase in creatinine was directly related to a decrease in Pt renal clearance and inversely related to Pt peak level in urine, while the latter was inversely related to a reduction of Pt renal clearance. It was concluded that very high doses of cisplatin are well tolerated in patients, although some parameters might suggest early impairment of the renal function.
The effects of single intraperitoneal injection of two cholinesterase inhibitors, physostigmine (PHY; 0.01, 0.025, 0.05, 0.1, 0.2 mg/kg) and heptylphysostigmine (HEP; 0.5, 2, 6 mg/kg) on electroencephalographic (EEG) activity and flash visual evoked potentials (f-VEP) in the occipital cortex were compared in DBA/2 mice. EEG spectral analysis of awake periods showed that PHY at all doses and HEP at 2 mg/kg induced an increase of power in the 4.25- to 7-Hz frequency band. Furthermore, PHY at the higher doses and HEP at all doses induced a decrease of power in the 7.25- to 12-Hz frequency band, while the lower doses of PHY (0.01, 0.025 mg/kg) produced an increase of this band. EEG effects elicited by the two drugs were similar, when doses displaying analogous biochemical effects (acetylcholinesterase inhibition) were used (i.e. 0.01 and 0.025 mg/kg of PHY versus 0.5 and 2 mg/kg of HEP). PHY and HEP induced similar changes in f-VEPs. Amplitudes of early and late components (P1N1, N1P2, P4N4 and particularly N1P3) were enhanced, while amplitudes of middle components were depressed after all doses. The peak latency measures were generally delayed, even though, after the lower doses, a trend to a latency reduction was evident in late components. This finding might indicate a possible effect on stimulus speed diffusion by ‘low therapeutic’ doses, analogous to the ones used in men. Our data show that both drugs are effective in modifying EEG and f-VEP parameters connected with brain cholinergic function, although in a very narrow dose range.
