Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μM versus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F1 offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F1 offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F1 offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively)

Relationship of cardiac morphologic alterations and electrical performance of various types of endocardial pacemaker leads implanted in dogs

Fifty-one specimens of reactive endomyocardium adherent to the distal portion of dexamethasone-eluting and nonsteroid endocardial pacing leads implanted in either the right atrium or the right ventricle of dogs for 6-182 weeks were evaluated. Connective tissue sheaths formed from proliferated endocardium and organized thrombus. Sheaths contained fibroblasts, macrophages, lymphocytes and mast cells and were 0.1-1.0 mm thick around the distal stimulating electrodes. The myocardium adjacent to peri-electrode connective tissue sheaths had multifocal myofibrillar lysis, atrophy and interstitial fibrosis. Leads with porus-surfaced electrodes containing dexamethasome tended to have thinner peri-electrode sheaths than leads with smooth surfaced electrodes without dexamethasone. There was a significant positive correlation (r = 0.6) between the voltage stimulation thresholds and the thickness of the connective tissue sheaths around the stimulating electrodes. In controlled experiments, a pair of pacemaker leads with similar electrodes, one of which contained dexamethasone, was implanted into the right ventricle of each of twelve dogs and maintained for either 3 weeks (n = 6 pairs) or 6 weeks (n = 6 pairs). Electrical stimulation thresholds were lower and peri-electrode connective tissue sheaths were (1) thinner (P $\u3c$.005); (2) less cellular (P $\u3c$.025): (3) less severely infiltrated with leukocytes; and had (4) fewer mast cells (P $\u3c$.05) for leads with electrodes containing dexamethasone than for similar leads without dexamethasone. Correlations between peri-electrode connective tissue sheath thickness and electrical stimulation thresholds were similar for pacing leads in the 6 week duration experiment as for leads in the initial study, but both lead types in the three week duration study had higher electrical thresholds than could be explained on the basis of peri-electrode connective tissue thickness alone. In-vitro exposure to calcium ionophore of peri-electrode tissues from the 3 week-duration study resulted in higher concentrations of prostacyclin and lower concentrations of thromboxane B\sb2 in supernatants from tissues that had been adjacent to electrodes containing dexamethasone than from tissues from similar electrodes without dexamethasone

Hypothermic Aortic Arch Flush for Preservation during Exsanguination Cardiac Arrest of 15 Minutes in Dogs

BACKGROUND: Trauma victims rarely survive cardiac arrest from exsanguination. Survivors may suffer neurologic damage. Our hypothesis was that a hypothermic aortic arch flush of 500 mL of isotonic saline solution at 4 degrees C, compared with 24 degrees C (room temperature), administered at the start of prolonged exsanguination cardiac arrest (CA) would improve functional neurologic outcome in dogs. METHODS: Seventeen male hunting dogs were prepared under light N2O-halothane anesthesia. The animals were randomized into two groups: group I (n = 9) received 4 degrees C isotonic saline flush and group II (n = 6) received 24 degrees C flush. Two additional dogs received no flush. While spontaneously breathing, the dogs underwent normothermic (tympanic membrane temperature [Ttm] = 37.5 degrees C) exsanguination over 5 minutes to cardiac arrest, assured by electric induction of ventricular fibrillation. After 2 minutes of arrest, the flush was administered over 1 minute into the aortic arch by means of a 13 French balloon-tipped catheter inserted by means of the femoral artery. After 15 minutes of CA, resuscitation was with closed-chest cardiopulmonary bypass, return of shed blood, and defibrillation. For the first 12 hours after CA, core temperature was maintained at 34 degrees C. Mechanical ventilation was continued to 20 hours and intensive care to 72 hours, when final evaluation and perfusion-fixation killing for brain histologic damage scoring were performed. RESULTS: Three dogs in group I were excluded because of extracerebral complications. All 14 dogs that followed protocol survived. During CA, the Ttm decreased to 33.6 +/- 1.2 degrees C in group I and 35.9 +/- 0.4 degrees C in group II (p = 0.002). At 72 hours, in group I, all dogs achieved an overall performance category (OPC) of 1 (normal). In group II, 1 dog was OPC 2 (moderate disability), 3 dogs were OPC 3 (severe disability), and 2 dogs were OPC 4 (coma). Both dogs without flush were OPC 4. Neurologic deficit scores (NDS 0% = normal, 100% = brain death) were 1 +/- 1% in group I and 41 +/- 12% in group II (p \u3c 0.05). The two dogs without flush achieved an NDS of 47% and 59%. Total brain histologic damage scores were 35 +/- 28 in group I and 82 +/- 17 in group II (p \u3c 0.01); and 124 and 200 in the nonflushed dogs. CONCLUSION: At the start of 15 minutes of exsanguination cardiac arrest in dogs, hypothermic aortic arch flush allows resuscitation to survival with normal neurologic function and histologically almost clean brains

Hypothermic Aortic Arch Flush for Preservation during Exsanguination Cardiac Arrest of 15 Minutes in Dogs

BACKGROUND: Trauma victims rarely survive cardiac arrest from exsanguination. Survivors may suffer neurologic damage. Our hypothesis was that a hypothermic aortic arch flush of 500 mL of isotonic saline solution at 4 degrees C, compared with 24 degrees C (room temperature), administered at the start of prolonged exsanguination cardiac arrest (CA) would improve functional neurologic outcome in dogs. METHODS: Seventeen male hunting dogs were prepared under light N2O-halothane anesthesia. The animals were randomized into two groups: group I (n = 9) received 4 degrees C isotonic saline flush and group II (n = 6) received 24 degrees C flush. Two additional dogs received no flush. While spontaneously breathing, the dogs underwent normothermic (tympanic membrane temperature [Ttm] = 37.5 degrees C) exsanguination over 5 minutes to cardiac arrest, assured by electric induction of ventricular fibrillation. After 2 minutes of arrest, the flush was administered over 1 minute into the aortic arch by means of a 13 French balloon-tipped catheter inserted by means of the femoral artery. After 15 minutes of CA, resuscitation was with closed-chest cardiopulmonary bypass, return of shed blood, and defibrillation. For the first 12 hours after CA, core temperature was maintained at 34 degrees C. Mechanical ventilation was continued to 20 hours and intensive care to 72 hours, when final evaluation and perfusion-fixation killing for brain histologic damage scoring were performed. RESULTS: Three dogs in group I were excluded because of extracerebral complications. All 14 dogs that followed protocol survived. During CA, the Ttm decreased to 33.6 +/- 1.2 degrees C in group I and 35.9 +/- 0.4 degrees C in group II (p = 0.002). At 72 hours, in group I, all dogs achieved an overall performance category (OPC) of 1 (normal). In group II, 1 dog was OPC 2 (moderate disability), 3 dogs were OPC 3 (severe disability), and 2 dogs were OPC 4 (coma). Both dogs without flush were OPC 4. Neurologic deficit scores (NDS 0% = normal, 100% = brain death) were 1 +/- 1% in group I and 41 +/- 12% in group II (p \u3c 0.05). The two dogs without flush achieved an NDS of 47% and 59%. Total brain histologic damage scores were 35 +/- 28 in group I and 82 +/- 17 in group II (p \u3c 0.01); and 124 and 200 in the nonflushed dogs. CONCLUSION: At the start of 15 minutes of exsanguination cardiac arrest in dogs, hypothermic aortic arch flush allows resuscitation to survival with normal neurologic function and histologically almost clean brains

Suspended Animation for Delayed Resuscitation from Prolonged Cardiac arrest that is Unresuscitable by Standard Cardiopulmonary-Cerebral Resuscitation

Standard cardiopulmonary-cerebral resuscitation fails to achieve restoration of spontaneous circulation in ~50% of normovolemic sudden cardiac arrests outside hospitals and in essentially all victims of penetrating truncal trauma who exsanguinate rapidly to cardiac arrest. Among cardiopulmonary-cerebral resuscitation innovations since the 1960s, automatic external defibrillation, mild hypothermia, emergency (portable) cardiopulmonary bypass, and suspended animation have potentials for clinical breakthrough effects. Suspended animation has been suggested for presently unresuscitable conditions and consists of the rapid induction of preservation (using hypothermia with or without drugs) of viability of the brain, heart, and organism (within 5 mins of normothermic cardiac arrest no-flow), which increases the time available for transport and resuscitative surgery, followed by delayed resuscitation. Since 1988, we have developed and used novel dog models of exsanguination cardiac arrest to explore suspended animation potentials with hypothermic and pharmacologic strategies using aortic cold flush and emergency portable cardiopulmonary bypass. Outcome evaluation was at 72 or 96 hrs after cardiac arrest. Cardiopulmonary bypass cannot be initiated rapidly. A single aortic flush of cold saline (4°C) at the start of cardiac arrest rapidly induced (depending on flush volume) mild-to-deep cerebral hypothermia (35° to 10°C), without cardiopulmonary bypass, and preserved viability during a cardiac arrest no-flow period of up to 120 mins. In contrast, except for one antioxidant (Tempol), explorations of 14 different drugs added to the aortic flush at room temperature (24°C) have thus far had disappointing outcome results. Profound hypothermia (10°C) during 60-min cardiac arrest induced and reversed with cardiopulmonary bypass achieved survival without functional or histologic brain damage. Further plans for the systematic development of suspended animation include the following: a) aortic flush, combining hypothermia with mechanism-specific drugs and novel fluids; b) extension of suspended animation by ultraprofound hypothermic preservation (0° to 5°C) with cardiopulmonary bypass; c) development of the most effective suspended animation protocol for clinical trials in trauma patients with cardiac arrest; and d) modification of suspended animation protocols for possible use in normovolemic ventricular fibrillation cardiac arrest, in which attempts to achieve restoration of spontaneous circulation by standard external cardiopulmonary resuscitation-advanced life support have failed

Suspended Animation for Delayed Resuscitation from Prolonged Cardiac arrest that is Unresuscitable by Standard Cardiopulmonary-Cerebral Resuscitation

Standard cardiopulmonary-cerebral resuscitation fails to achieve restoration of spontaneous circulation in ~50% of normovolemic sudden cardiac arrests outside hospitals and in essentially all victims of penetrating truncal trauma who exsanguinate rapidly to cardiac arrest. Among cardiopulmonary-cerebral resuscitation innovations since the 1960s, automatic external defibrillation, mild hypothermia, emergency (portable) cardiopulmonary bypass, and suspended animation have potentials for clinical breakthrough effects. Suspended animation has been suggested for presently unresuscitable conditions and consists of the rapid induction of preservation (using hypothermia with or without drugs) of viability of the brain, heart, and organism (within 5 mins of normothermic cardiac arrest no-flow), which increases the time available for transport and resuscitative surgery, followed by delayed resuscitation. Since 1988, we have developed and used novel dog models of exsanguination cardiac arrest to explore suspended animation potentials with hypothermic and pharmacologic strategies using aortic cold flush and emergency portable cardiopulmonary bypass. Outcome evaluation was at 72 or 96 hrs after cardiac arrest. Cardiopulmonary bypass cannot be initiated rapidly. A single aortic flush of cold saline (4°C) at the start of cardiac arrest rapidly induced (depending on flush volume) mild-to-deep cerebral hypothermia (35° to 10°C), without cardiopulmonary bypass, and preserved viability during a cardiac arrest no-flow period of up to 120 mins. In contrast, except for one antioxidant (Tempol), explorations of 14 different drugs added to the aortic flush at room temperature (24°C) have thus far had disappointing outcome results. Profound hypothermia (10°C) during 60-min cardiac arrest induced and reversed with cardiopulmonary bypass achieved survival without functional or histologic brain damage. Further plans for the systematic development of suspended animation include the following: a) aortic flush, combining hypothermia with mechanism-specific drugs and novel fluids; b) extension of suspended animation by ultraprofound hypothermic preservation (0° to 5°C) with cardiopulmonary bypass; c) development of the most effective suspended animation protocol for clinical trials in trauma patients with cardiac arrest; and d) modification of suspended animation protocols for possible use in normovolemic ventricular fibrillation cardiac arrest, in which attempts to achieve restoration of spontaneous circulation by standard external cardiopulmonary resuscitation-advanced life support have failed