Efficacy of common surgical compounds in preventing articular chondrocyte death from desiccation.

PURPOSE: Purpose of this study was to identify potential substances that prevent desiccation of chondrocytes. METHODS: Macroscopically normal bovine cartilage explants (n = 80) were exposed to room air, or covered with surgical lubricant, Lactated ringer (LR) or Seprafilm (Genzyme Biosurgery, Cambridge, MA) for 0, 30, 60 or 120 min. The viability of superficial chondrocytes was measured after 48 h of incubation in tissue culture media at 37 °C by Live/Dead staining. Chondrotoxicity was measured as the extent of cell death below the articular surface. Statistical analysis was performed with a two-way analysis of variance on the data set and a subsequent Tukey's post hoc test. RESULTS: Chondrocyte death correlated positively with the length of exposure, regardless of the treatment (p < 0.0001). The extent of superficial chondrocyte death was minimally lower in the LR (89.1 ± 2.6 %, 80.8 ± 1.2 %) and surgical lube (84.3 ± 1.8 %, 75.9 ± 2.7 %) groups than the control (82 ± 5.7 %, 65.6 ± 13.3 %) and Seprafilm group (77.6 ± 3.9 %, 63.3 ± 6.9 %) (p < 0.001) at the first two time points, with no significant difference between the latter groups. After 60 and 120 min, surgical lube resulted in less chondrocyte death than all other groups (70.4 ± 6.8 % and 60.9 ± 5.9 %, all p < 0.0001). CONCLUSION: The data suggest that depending on the expected length of exposure of the articular cartilage surface, different compounds appear to be protective. For exposures exceeding 60 min, surgical lubricant demonstrated the highest protective potential. Results from this study indicate that protecting exposed articular surfaces with surgical lubricant for orthopaedic procedures lasting more than 1 h lead to decreased chondrocyte death and suggest improved cartilage functional outcomes postoperatively.

Patient satisfaction after primary total and unicompartmental knee arthroplasty: an age-dependent analysis.

BACKGROUND: Patient-related outcomes have become the focus of increased attention when assessing knee arthroplasty. METHODS: We retrieved questionnaires from 485 (584 knees) patients at a minimum of 3years after undergoing primary knee arthroplasty. We excluded bilateral knee arthroplasty, leaving 141 UKA and 245 TKA who rated their satisfaction and expectation regarding pain, range of motion (ROM), daily living function (DLF), return to recreational activity (RRA) and ability to kneel (ATK) on a scale of 0 (worst) to 10 (best). We further collected data on pain level and the modified Cincinnati rating scale. Range of motion was documented pre- and postoperatively at a minimum of six months. The cohort was subdivided into three age groups and compared with each other (Group 1: <55, n=113; Group 2: 55-64, n=117; Group 3: 65+, n=155). RESULTS: Average satisfaction with pain, ROM and ATK for patients under 55 was higher for UKA than for TKA. Patients>65 with TKA were on average more satisfied than patients with UKA in these three items. However, patients under 55 with UKA were up to 2.9 times more likely to have their expectations met when compared to patients receiving TKA. Patients with UKA under 55 rated their joint as good/excellent in 96.0% versus patients in the same age group with TKA in 81.0%. CONCLUSIONS: We found that overall, younger patients who were treated with UKA demonstrated higher satisfaction scores in most subsets when compared with the patients of the same age group who received TKA.

Surgical treatment for early osteoarthritis. Part I: cartilage repair procedures.

Young patients with early osteoarthritis (OA) represent a challenging population due to a combination of high functional demands and limited treatment options. Conservative measures such as injection and physical therapy can provide short-term pain relief but are only palliative in nature. Joint replacement, a successful procedure in the older population, is controversial in younger patients, who are less satisfied and experience higher failure rates. Therefore, while traditionally not indicated for the treatment of OA, cartilage repair has become a focus of increased interest due to its potential to provide pain relief and alter the progression of degenerative disease, with the hope of delaying or obviating the need for joint replacement. This review of cartilage repair techniques will discuss currently available procedures, specifically pertaining to experiences in the setting of early OA. Level of evidence IV.

Surgical treatment for early osteoarthritis. Part II: allografts and concurrent procedures.

UNLABELLED: Young patients with early osteoarthritis (OA) represent a challenging population due to a combination of high functional demands and limited treatment options. Conservative measures such as injection and physical therapy can provide short-term pain relief but are only palliative in nature. Joint replacement, a successful procedure in the older population, is controversial in younger patients, who are less satisfied and experience higher failure rates. Therefore, while traditionally not indicated for the treatment of OA, cartilage repair has become a focus of increased interest due to its potential to provide pain relief and alter the progression of degenerative disease, with the hope of delaying or obviating the need for joint replacement. The field of cartilage repair is seeing the rapid development of new technologies that promise greater ease of application, less demanding rehabilitation and better outcomes. Concurrent procedures such as meniscal transplantation and osteotomy, however, remain of crucial importance to provide a normalized biomechanical environment for these new technologies. LEVEL OF EVIDENCE: Systematic review, Level II.

J-integral fracture toughness and tearing modulus measurement of radiation cross-linked UHMWPE.

Radiation and chemical cross-linking of medical grade ultrahigh molecular weight polyethylene (UHMWPE) has recently been utilized in an effort to improve wear performance of total joint replacement components. However, reductions in mechanical properties with cross-linking are cause for concern regarding the use of cross-linked UHMWPE for high-stress applications such as in total knee replacement prostheses. In this study, the fracture behavior of radiation cross-linked UHMWPE was compared to that of uncross-linked UHMWPE. The Rice and Sorensen model that utilizes mechanical parameters obtained from uniaxial tensile and compact tension tests was used to calculate the steady state J-integral fracture toughness, Jss, for radiation cross-linked UHMWPE. Jss decreased monotonically with increase in radiation dose. UHMWPE exhibited tough, ductile tearing behavior with stable crack growth when it was cross-linked using a gamma radiation dose of 0-50 kGy. However, in cross-linked UHMWPE irradiated to a dose of 100 and 200 kGy, unstable fracture occurred spontaneously upon attaining the initial crack driving force, J1c. This indicates that a high degree of cross-linking is less desirable for high-stress applications in orthopaedic implants. However, a substantial increase in J1c, even at a low degree of cross-linking, suggests that a low degree of cross-linking may be beneficial for resistance to delamination and catastrophic failure, both of which require an initiation step for the fracture to propagate in the material. This mechanical test should, however, be considered along with fatigue tests and joint simulator testing before determination of an appropriate amount of cross-linking for total joint replacement prostheses that experience high stresses.

[Interspecies comparison of healing standardazed bone defects with and without autogenous bone transplantation]. / Interspeziesvergleich zur Heilung standardisierter Knochendefekte mit und ohne autogene Knochentransplantation.

This study tries to establish a basis for comparison of animal studies regarding bone defect healing. Pigs, sheep and rabbits were operated on according to a standardized scheme where each received bilateral defects of the femoral condylus. One of the defects was filled with cancellous autograft, the other remained empty. Bone defect healing was followed with several different methods of investigation, the results were put into perspective with the help of a standardized score-scheme.

Selectivity of BMS-180448 on myocardial versus brain blood flow in dogs and ferrets.

Openers of adenosine triphosphate (ATP)-sensitive potassium channels relax vascular smooth muscle and protect ischemic myocardium. Cromakalim and BMS-180448 are examples of this class of compounds. They are equipotent in their cardioprotective activity, but cromakalim and related compounds are extremely hypotensive, an activity that limits their use. The effects of cumulative i.v. doses of BMS-180448 or cromakalim on hemodynamics and regional blood flow (radiolabeled microspheres) were evaluated in pentobarbital-anesthetized dogs and ferrets. Both compounds significantly reduced mean arterial blood pressure, cromakalim after 0.03-0.04 mg/kg in both species, and BMS-180448 only after 10 mg/kg in dogs and 30 mg/kg in ferrets. Neither drug affected cardiac output. BMS-180448, like cromakalim, increased blood flow in the heart, with augmented regional left ventricular blood flow occurring more in the subepicardium than in the subendocardium. The effect of BMS-180448 on myocardial blood flow, in both the dog and ferret, occurred at doses that were less hypotensive than those of cromakalim. The most striking difference between the actions of these agents was seen in the brain where cromakalim, but not BMS-180448, increased blood flow in all regions. The results of these studies further demonstrate the myocardium-specific vasodilator activity of BMS-180448. Moreover, the cerebral vasodilator effect of K(ATP) openers, which has been thought responsible for the occurrence of headache in clinical trials, has been found lacking in BMS-180448; this difference may represent a clear advantage in the pharmacologic profile of the agent.

Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448.

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.

Cardioprotection associated with preconditioning in the anesthetized ferret.

The cardioprotective effect of ischemic preconditioning (PC) was investigated in the anesthetized ferret model of myocardial ischemia followed by reperfusion. PC of 2, 5, or 10-min duration, followed by 10-min reflow, was studied in animals subjected to 60-min sustained LAD coronary artery ischemia followed by 5-h reperfusion. Infarct size was determined by tetrazolium staining. Sham PC ferrets had a mean infarct of 72% of risk zone. A 2-min or 5-min cycle of PC significantly reduced tissue damage to 54% (p < 0.05) and 44% (p < 0.01), respectively. Infarct reduction associated with 10-min ischemic PC was not significant (57% of AAR). The cardioprotective effects of 5-min PC were lost when sustained ischemia was prolonged to 75 or 90-min. Myocardial salvage afforded by 5-min PC was also abolished by both a) inhibition of ATP-sensitive potassium channels using either glyburide or 5-HD and b) blockade of adenosine receptors with the A1 selective agent DPCPX. In the absence of PC, activation of ATP-sensitive potassium channels with the cardiac-selective agonist BMS-180448 significantly (p < 0.01) reduced infarct size from 66% to 37% of the risk zone. Cardioprotection, or its loss, was not the result of hemodynamic alterations occurring during PC, drug administration, or the coronary occlusion and reperfusion phases. Based upon its body size and lack of extensive myocardial collateral circulation the ferret offers a usefull alternative small species for study of ischemia and reperfusion salvage. It is concluded in the ferret that: a) the threshold for PC is less than in either the rat, rabbit, or dog; unlike the dog and pig, the beneficial effects of PC are b) reduced when the ischemic PC interval is extended to 10-min or c) lost if sustained coronary occlusion is maintained for a period of 75-min or longer; and last, a role in PC for both d) ATP-sensitive potassium channels and e) adenosine A1 receptors can be demonstrated.

Dose-related cardioprotection by ifetroban in relation to inhibition of thrombosis and ex vivo platelet function.

The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.

Failure of aspirin to interfere with the cardioprotective effects of ifetroban.

The thromboxane receptor antagonist ifetroban ([1S-(1 alpha,2 alpha,3 alpha, 4 alpha)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]- 7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid) and aspirin were evaluated for direct and combined effects on myocardial infarct size in anesthetized ferrets subjected to coronary artery occlusion (90 min) and reperfusion (5 h). Aspirin (10 mg/kg) or vehicle was administered as an i.v. bolus dose at the 45th min of occlusion in an initial assessment of its cardioprotective potential in this species. In interaction studies, aspirin was injected i.v. 10 min prior to occlusion (10 mg/kg) and at the 45th min of ischemia (5 mg/kg) both with and without subsequent administration of ifetroban (0.3 mg/kg + 0.3 mg/kg per h) beginning at the 75th min of occlusion. Aspirin administration alone caused non-significant (P > 0.05) 5-7% reductions in tissue damage (19.8-21.8% of left ventricle) from that observed in vehicle-controls (20.4-22.9% of left ventricle). Ifetroban alone significantly (P < 0.05) reduced infarct size compared to vehicle treatment (13 +/- 1% vs. 23 +/- 2% of left ventricle), and this was not prevented by combination with aspirin (12 +/- 2% vs. 22 +/- 3% of left ventricle). In the absence and presence of aspirin, ifetroban reduced infarct size by 42% and 43%, respectively. Concurrently, thromboxane A2-generating capacity in blood (measured as thromboxane B2 in clotted serum) was decreased ca. 99% by aspirin treatment. Thus, virtually complete platelet cyclooxygenase inhibition by aspirin afforded no cardioprotective action in the ferret and, more importantly, this inhibition did not interfere with the myocardial salvage efficacy of ifetroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial salvage efficacy of the thromboxane receptor antagonist ifetroban in ferrets and dogs.

The effects of the thromboxane A2 (TXA2)/prostaglandin endoperoxide (TP) receptor antagonist ifetroban (BMS-180291) on infarct size (IS) resulting from coronary occlusion/reperfusion was determined in anesthetized dogs and ferrets. In dogs, ifetroban (1 + 1 mg/kg/h, intravenously, i.v.) or vehicle administration was initiated 10 min before left circumflex coronary artery (LCX) occlusion. In ferrets, the left anterior descending coronary artery (LAD) was occluded; after 75 min, a continuous infusion of ifetroban (0.3 + 0.3 mg/kg/h i.v.) or vehicle was started. After 90-min ischemia in both species, the LCX or LAD occlusion was released; reperfusion was continued for 5 h, at which time IS was determined. Regional myocardial blood flow (RMBF) before and during occlusion and during reperfusion were measured with radioactive microspheres. Ifetroban significantly decreased the extent of infarction to 39 +/- 5% of the area at risk (AAR) from 64 +/- 5% in dogs and to 15 +/- 2% of the left ventricle as compared with a control of 22 +/- 2% in ferrets. The protective effect of ifetroban in both species occurred with no increase in collateral BF or treatment-related alterations in peripheral hemodynamic status. Ifetroban, at the doses that reduced IS in ferrets, inhibited 99% of platelet TP receptors throughout the experiment, as measured by inhibition of the ex vivo platelet shape change response to U-46,619, a TP receptor agonist. Thus, doses of ifetroban causing profound TP receptor blockade also salvaged jeopardized myocardium in dogs and ferrets without changing collateral BF or peripheral hemodynamics.

Myocardial salvage efficacy of a thromboxane receptor antagonist, SQ, 30,741, in relation to inhibition ex vivo of platelet function in the ferret.

The myocardial salvage efficacy of a thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the reproducibility of infarct size resulting from a 90 min period of occlusion followed by 5 hr of reperfusion of the left anterior descending coronary artery in saline-treated control ferrets revealed a consistent mean level of tissue damage representing 23.1 +/- 1.4% of the left ventricle. In subsequent studies, ferrets were given the thromboxane receptor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct size from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inhibition of the ex vivo platelet shape change response to U-46,619. Drug administration was not associated with measurable alterations in mean blood pressure, heart rate or the rate-pressure-product. The importance of this finding to clinical utility and the mechanism of the observed cardioprotective action, however, remain unclear. These data indicate that the ferret represents a useful model for the assessment of the myocardial salvage efficacy of TP receptor antagonists and are consistent with attenuation of ischemic myocardial damage by doses of these agents which produce > 96% TP receptor blockade.

Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol.

Sotalol is a competitive beta adrenoceptor antagonist devoid of membrane-stabilizing activity and intrinsic sympathomimetic activity that has no preferential actions on beta 1 or beta 2 responses. No other tested receptor systems are affected by sotalol. In addition to having class II (beta blockade) effects, sotalol also has class III antiarrhythmic activity. It increases the action potential duration (APD) and prolongs atrial and ventricular repolarization. The effect on APD is independent of beta blockade; the same effect is seen with similar concentrations of the d stereoisomer of sotalol, which does not have beta-blocking activity. Sotalol prolongs the rate-corrected QT interval and ventricular and atrial refractoriness without affecting atrial, His-Purkinje, or ventricular conduction velocity. Atrioventricular nodal conduction is decreased, largely because of beta blockade. Sotalol increases the fibrillation threshold and decreases the defibrillation threshold. Sotalol is an effective antiarrhythmic in various animal models of arrhythmia (e.g., chloroform, hydrocarbon-catecholamine, ouabain, and coronary ligation). In addition, it reduces the severity and frequency of arrhythmias induced by programmed electrical simulation. By comparison, metoprolol is ineffective and d-sotalol is as effective as the racemate in this model, indicating that this effect is independent of beta blockade. Sotalol causes concentration-dependent increases in the contractility of isolated ventricular tissue that is not blocked by previous beta or alpha blockade or catecholamine depletion. The positive inotropic effect may be related to inhibition of time-dependent K+ current responsible for the increase in APD. Like propranolol, sotalol decreases contractile force, heart rate, arterial blood pressure, left ventricular dP/dt, and cardiac output in intact animals due to blockade of circulating catecholamines. Sotalol consistently reduces the heart rate to a greater degree than propranolol and causes significantly less cardiac suppression than propranolol at a given heart rate.

Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that inhibition of leukocyte function by administration of monoclonal antibody 60.3 (MoAb 60.3) improves electrophysiological recovery and decreases injury volume following transient focal cerebral ischemia in cats. METHODS: Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive either 2 mg/kg MoAb 60.3 (n = 8) directed at the CDw18 leukocyte antigen complex or an equal volume of diluent (sterile saline; n = 10) at 45 minutes of ischemia in a blinded fashion. RESULTS: Blood flow to the left temporoparietal cortex decreased to less than 5 ml/min/100 g with ischemia, but was minimally affected on the right side. Postischemic hyperemia occurred in the left caudate nucleus, whereas blood flow in other brain regions returned to control. No region demonstrated delayed hypoperfusion, and there were no differences between groups. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to less than 10% of baseline amplitude at 180 minutes of reperfusion in both groups. Left hemispheric injury volume, as assessed by 2,3,5-triphenyltetrazolium chloride staining, was not affected by drug treatment (mean +/- SE values: MoAb 60.3, 37 +/- 5%; placebo, 38 +/- 7% of hemisphere). CONCLUSIONS: Inhibition of leukocyte function with MoAb 60.3 does not afford protection from severe focal ischemia and reperfusion in cats.

Efficacy of a monoclonal antibody (MoAb 60.3) in reducing myocardial injury resulting from ischemia/reperfusion in the ferret.

The myocardial salvage efficacy of a monoclonal antibody (MoAb 60.3) directed at the CDw 18 membrane antigen complex essential for normal neutrophil function was evaluated in a ferret occlusion/reperfusion model. When infused i.v. over a 10-min interval beginning at the 45th minute of a 90-min occlusion at a fixed dose of 2 mg/kg, the antibody afforded 33 and 45% reductions in infarct size following reperfusion intervals of 6 and 24 h, respectively. Administration of that same dose via the left atrium over 1 h beginning at the 75th minute of occlusion and continuing until the 45th minute of reflow resulted in only a 14% reduction in infarct size. If MoAb 60.3 administration was withheld until the 5th-15th minute of reperfusion, the mean levels of salvage were 19 and 8%, respectively, following 6- and 24-h periods of reflow. Time-course hemodynamic data indicated that the monoclonal antibody caused no alterations in oxygen utilization that might be responsible for the levels of salvage observed.

Comparability of the electrophysiologic responses and plasma and myocardial tissue concentrations of sotalol and its d stereoisomer in the dog.

The relative plasma, myocardial, and skeletal muscle concentrations as well as activities of racemic and d-sotalol were assessed in both anesthetized and conscious dogs. In acute anesthetized experiments, the agents were infused i.v. over a 15-min interval at doses of 1 and 4 mg/kg. Arterial blood samples and punch biopsy specimens from the left ventricular myocardium and skeletal muscle (gastrocnemius) were taken at the completion of each infusion and at periodic intervals for the ensuing 3 h. The drugs were also administered over a 2-week dosing interval to conscious dogs at a dose of 5 mg/kg given twice daily. ECG alterations and venous blood samples were withdrawn on the 1st, 3rd, 7th and 14th day of drug administration. Myocardial and skeletal muscle samples were taken at killing on day 14. In anesthetized dogs, both forms of sotalol decreased heart rate, lowered arterial pressure, prolonged ventricular refractoriness, and caused measurable increases in the PR, QT, and QTc intervals in the absence of any effect on QRS duration. Similar effects on heart rate and QTc and lack of influence on the PR and QRS interval were observed in conscious animals. Tissue drug concentrations were closely correlated with plasma drug levels. Comparable mean steady-state tissue/plasma ratios of 2.26-2.94 were attained immediately following acute i.v. drug infusions. These were larger than those observed following chronic oral drug administration for 14 days. The data, however, clearly demonstrated the equivalence of the plasma and myocardial drug levels obtained in dogs following i.v. infusion of 1 mg/kg or oral administration of 5 mg/kg of dl- or d-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the ferret for a myocardial ischemia/salvage model.

Exploratory work was undertaken in the anesthetized ferret to determine if it is an applicable species for use as an in vivo ischemic model and suitable for recovery surgical procedures. Experimental protocols utilizing varying combinations of left anterior descending (LAD) coronary artery occlusion (30, 60, 90 min) and reperfusion (4, 6, 18-24 hr) were evaluated. The results indicated that a 90-min/6-hr combination led to the production of an infarct equivalent, or slightly greater, in size to that observed following coronary artery occlusion either with and without reflow during an 18-24-hr recovery period prior to sacrifice. A combination of 90 min occlusion/4 hr reperfusion yielded an infarct area ca. 50% of that associated with 6 hr interval of reflow. An occlusive interval of 60 min or less combined with any reperfusion interval lack reproducibility. The administration of saline in varying volumes by different routes (IV versus left atrial) had no influence on either the absolute or, more especially, the relative (i.e., as a percent of left ventricle) tissue damage provoked by a 90-min/6-hr occlusion/reperfusion maneuver of the LAD coronary artery. When evaluated as a reference standard, superoxide dismutase (SOD) infused via the left atrium at a dose of 5 mg/kg afforded a 36% reduction in the area of ischemic damage in this model. These studies demonstrated that the ferret represents a useful species for initial, rapid, and economic--both in terms of cost and drug substance utilization--in vivo myocardial salvage screening assessments. The model permits an interpretation of potential test agent efficacy, dosage requirements, and hemodynamic actions, and it is suitable for basing a go/no-go decision that continued experimental development in more labor intense preparations is warranted.

Pharmacology, pharmacodynamics and pharmacokinetics of sotalol.

Sotalol is a nonselective, water-soluble beta-adrenoceptor antagonist with no membrane-stabilizing activity or intrinsic sympathomimetic activity. Sotalol is, essentially, completely absorbed and is not metabolized. Consequently, bioavailability is close to 100%. Age and food have slight but unimportant effects on bioavailability. Cmax of sotalol is 2 to 3 hours with a t1/2 between 7 and 15 hours. Excretion of sotalol is primarily through the kidneys, with no metabolism by liver and no first-pass effect. Therefore, sotalol plasma levels and half-life are directly related to creatinine clearance and glomerular filtration rate. Appropriate dose adjustments must be made for patients with impaired renal function or increased renal blood flow, as in pregnancy. The beta-adrenoceptor antagonistic effects of sotalol are directly related to plasma levels, which, in turn, are directly related to dose. However, the beta-adrenoceptor antagonism t1/2 is longer than the sotalol plasma t1/2. As a consequence of its ability to prolong the action potential duration, sotalol also increases cardiac contractility in isolated ventricular, but not atrial, preparations by 20 to 40%. This positive inotropic effect is not blocked by beta or alpha blockade or reserpine pretreatment and seems to be related to sotalol's effects on cardiac ionic currents. Like the effects of sotalol on action potential duration, the positive inotropic effects are inversely proportional to rate. The hemodynamics of sotalol indicate a relative lack of direct cardiac depressant activity in both animals and humans. The typical hemodynamic effects of sotalol in normotensive humans, even with depressed myocardial function, are a reduction in heart rate with little or no change in blood pressure, a reduction in cardiac output with no change in stroke volume, and little or no change in pulmonary wedge pressure and left ventricular end-diastolic pressure or volume, and little or no change in ejection fraction either at rest or during exercise.