Mark Vogel

Pfizer · Pfizer Global Research & Development - Drug Safety R&D

Glomerulopathy and body weight gain were noted after chronic oral administration of a novel nonsteroidal dissociated agonist of the glucocorticoid receptor compound, fosdagrocorat, to beagle dogs fed an ad libitum diet. To further investigate the role of diet and treatment with either fosdagrocorat or the glucocorticoid comparator, prednisone, on r...

Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducte...

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. In the 2-year carcinogenicity study with tofacitinib, increased incidence of hibernoma (a neoplasm of brown adipose tissue [BAT]) was noted in female rats at ≥30 mg/kg/day (≥41x human exposure multiples). Thus, signaling pathways within BAT were investigated by measurin...

Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign aden...

Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine-exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article-...

Sphingosine-1-phosphate (S1P) is a major bioactive phospholipid, which binds to and activates a family of five G-protein-coupled receptors designated as S1P 1 (S1P1) through S1P5. The S1P1 receptor subtype, expressed primarily on lymphocytes, is known to play a critical role in the regulation of lymphocyte trafficking. S1P1 inhibitors result in the...

Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C(max)) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies...

Safety thresholds for chemical impurities and leachables in consumer products such as foods and drugs have helped to ensure public health while establishing scientifically sound limits for identification and risk assessment of these compounds. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group, a collaboration o...

n-Butyl maleate, also referred to as monobutyl maleate, is an ester of maleic acid, which is used as a counterion in the pharmaceutical industry. While substantial published data exist on short-term treatment, maleic acid-induced renal toxicity in the rat, no toxicity data are available on the monobutyl ester. This study evaluated the oral subchron...

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intend...

We tested whether inhibition of carnitine acyl-transferase-1 (CAT-1) during coronary artery occlusion can limit infarct size (IS) by suppressing accumulation of long-chain acylcarnitines (LCAs), potentially cytotoxic intermediates of fatty acid metabolism. The CAT-1 inhibitor 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) was administer...

Hemoglobin (Hb) solutions being developed as red cell substitutes may have vasoconstrictor activity. We tested whether different coronary constrictor activities of certain Hb solutions were due to differential inhibition of endothelium-dependent vasodilation. In buffer-perfused rabbit hearts with constant coronary flow, Hb increased coronary resist...

In buffer-perfused rabbit hearts, the coronary vasoconstrictor activity of pasteurized raffinose-crosslinked human hemoglobin (o-raffinose poly-Hb) was compared to that of the unmodified ultrafiltered red cell lysate (SFH) used as the starting material. Dose-response curves were generated by increasing perfusate Hb concentration from 10 to 200 mg/d...

Left ventricular aneurysm formation after myocardial infarction (MI) has been associated with elongation of infarcted tissue in response to wall stress. Such elongation most commonly occurs in acutely infarcted or partially healed regions during the early post-MI period; however, recent reports have indicated that mature (15-week-old) healed infarc...

Pressure-controlled intermittent coronary sinus occlusion (PICSO) has been shown to reduce experimental infarct size. To examine the role of PICSO in limiting the consequences of brief ischemia on left ventricular function, we studied the effect of PICSO in nine open-chest anesthetized dogs. PICSO was performed using a pump-inflated, balloon-tipped...

Hemoglobin solutions being developed as red-cell substitutes can constrict various vascular beds. We tested whether different coronary constrictor activities of certain Hb solutions were due to differential inhibition of endothelium-dependent vasodilation. In buffer-perfused rabbit hearts with constant coronary flow, Hb increased coronary resistanc...

Myocardial hypertrophy can result in increased sensitivity toward the development of mechanical dysfunction during hypoxia. Alterations in glycolytic metabolism may contribute to this. We studied the response to 15 minutes of hypoxia in hypertrophied (deoxycorticosterone-salt hypertension model) and nonhypertrophied rat hearts and examined the infl...

Coronary occlusion (CO) of 1 h or longer causes transmural myocardial infarction (MI) in the rabbit. We studied how reperfusion of an infarct affected myocardial blood flow (MBF) acutely and after 3 wk of healing. CO was performed in rabbits for 60 or 180 min (n = 22) followed by reperfusion, and MBF to normal and infarcted zones was determined by...

We have found that DBBF-Hb and Hb Ao have significantly less vasoconstrictor activity than unmodified Hb in the rabbit heart. In striking contrast to these findings, DBBF-Hb and unmodified Hb have comparable hemodynamic effects in the isolated kidney. We have demonstrated that lipophilic contamination of fraction V BSA causes vasoconstriction in th...

Hearts from rabbits with 8-16 weeks of alloxan-diabetes were compared with hearts from normal rabbits to determine whether diabetic myocardium is more sensitive to ischemic injury. In isolated buffer-perfused hearts, left ventricular developed pressure, diastolic pressure, time to peak pressure (TTPP), time to half-maximal relaxation (RT1/2), and p...

"Stroma-free" hemoglobin solutions (SFH) cause hemodynamic alterations indicative of vasoconstriction. We studied vasoconstrictor activity in isolated rabbit hearts and rat kidneys of unmodified SFH and of SFH modified by pyridoxylation or glyoxylation, with or without glutaraldehyde cross-linking. The purity and chemical composition of the solutio...

Stroma-free hemoglobin (Hb) solutions are being developed as blood substitutes. We previously described coronary vasoconstrictor activity of Hb solutions prepared by conventional methods. In the present study we assessed the constrictor activity of unmodified and covalently modified Hb solutions purified by ATP-agarose affinity chromatography. The...

Contributions of edema to left ventricular (LV) chamber stiffines and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase onco...

Many experimental studies of left ventricular diastolic properties have utilized isolated perfused hearts subjected to either global ischemia or hypoxia. The isolated perfused heart model (see Figure 18-1) has several advantages. The pericardium is removed and the right ventricle is vented; thus, any pericardial or right ventricular interaction eff...

A coronary vasoconstrictor effect of human stroma-free hemoglobin (SFH) was identified in isolated rabbit hearts perfused with Krebs-Henseleit buffer or whole rabbit blood at a constant coronary flow rate. In buffer-perfused hearts, SFH in concentrations of 5 to 200 mg/dl produced dose-related increases of coronary perfusion pressure. At a concentr...

Early reperfusion after a coronary occlusion may reduce myocardial infarct size, but late reperfusion into necrotic myocardium may alter post-infarction healing. In rabbits, we compared 1- or 3-week-old scars resulting from permanent coronary occlusion to those resulting from a 1- or 3-hour occlusion followed by reperfusion. Reperfusion at 1 hour p...

Storage of blood can depress erythrocyte 2,3-diphosphoglycerate (DPG) levels and thereby increase oxyhemoglobin affinity and potentially decrease capillary-to-tissue oxygen transport. We measured myocardial function and metabolism in isolated rabbit hearts with fixed coronary flow under basal conditions and during isoproterenol stress at 37 and 30...

Ischemic myocardial contracture is exacerbated by reperfusion. This study examines the extent to which intensification of contracture by reperfusion is due to metabolic reoxygenation phenomena or hydraulic erectile contributions of coronary perfusion to left ventricular (LV) stiffness. Isolated rabbit hearts, with fluid-filled LV intraventricular b...

Adequacy of healing after acute myocardial infarction may determine the incidence of postmyocardial infarction rupture and ventricular aneurysm. Accordingly, in 36 rabbits, from 1 to 8 days after coronary ligation, and in 18 shams, we measured collagen formation and mechanical resistance of the infarcted left ventricle to stretch and rupture. Proly...

Red blood cell storage can result in depression of erythrocyte 2,3,-diphosphoglycerate (DPG) levels, thereby increase oxy-hemoglobin affinity and potentially decrease capillary-to-tissue oxygen transport. We assessed the metabolic and functional effects which resulted from red blood cell storage by using an isolated rabbit heart preparation with an...

Movement of the necrotic wavefront after coronary artery occlusion (CAO) was defined in rabbits by comparing transient CAO (15, 30, or 60 min) and reperfusion to permanent CAO (n = 5-9/group). At 24 h after CAO the area of necrosis was determined by nitro-blue tetrazolium staining, and the transmural and circumferential extent of necrosis was evalu...

To separate the effects of coronary flow, perfusion pressure, and oxygen delivery on left ventricular diastolic compliance and diastolic wall thickness, isolated buffer and blood-perfused rabbit hearts with left ventricular volume controlled by a fluid-filled intraventricular balloon were subjected to the following interventions: complete global is...

The effect of ibuprofen, a nonsteroidal anti-inflammatory agent, on coronary vascular resistance in isolated perfused rabbit heart was studied. Ibuprofen had coronary arterial vasodilatory activity. An arterial concentration of 50 microgram/ml produced a half-maximal coronary vasodilator response. An ibuprofen concentration of 140 microgram/ml prod...

To clarify conflicting reports concerning the effects of ischemia on left ventricular chamber stiffness, we compared the effects of hypoxia at constant coronary perfusion with those of global ischemia on left ventricular diastolic chamber stiffness using isolated, perfused rabbit hearts in which the left ventricle was contracting isovolumically. Si...

A preparation is described in which feline hearts were perfused with arterial blood drawn from a blood-donor cat. Ventricular function was measured with a fluidfilled latex balloon within the left ventricle. Left ventricular developed pressure, maximum left ventricular dP/dt, ventricular compliance, and coronary blood flow changed only slightly dur...

This study was designed to determine the effects of dimethyl-propranolol (UM-272) on myocardial injury after global ischemia of isolated feline hearts. Untreated ischemic hearts developed contracture, resulting in a leftward shift of the diastolic pressure-volume curve. Active pressure development in perfused ischemic hearts was significantly depre...

Effects of methylprednisolone were studied on isolated, blood-perfused cat hearts subjected to 1 hr of normothermic ischemic arrest. Untreated hearts sustained decreases in peak ventricular pressure pulse, dP/dt, and ventricular compliance. Ischemic hearts also became edematous, gained sodium, and lost potassium and creatine kinase enzyme activity....

The basis for the rapid rate of inactivation of specific glucocorticoid binding capacity has been studied in cell-free preparations from L929 mouse fibroblasts, rat thymocytes, and rat liver. The particulate fraction sedimenting between 27,000 and 100,000 x g from all of these cell types contains an enzyme (or enzymes) that inactivates the steroid...

We have examined the rates of inactivation of glucocorticoid receptors in cell-free preparations from several rat tissues. The t1/2 of inactivation of the glucocorticoid-binding ability of thymus, heart, and kidney cytosols (37,000 X g supernatants) ranges from 2 to 4 hr at 0 degrees, whereas that of liver is much slower (15 to 25 hr). The rate of...

Methylprednisolone sodium succinate (50 mg/kg) was given 30 minutes before or after the start of a 90 minute occlusion of the left circumflex coronary artery (LCX) in one group of dogs. In a second group, methylprednisolone sodium succinate was given 15 minutes after permanent occlusion of the left anterior descending artery (LAD). Infarct size was...