Design and synthesis of 2-oxo-imidazolidine-4-carboxylic acid hydroxyamides as potent matrix metalloproteinase-13 inhibitors.

A novel series of imidazolidinone-based matrix metalloproteinase (MMP) inhibitors was discovered by structural modification of pyrrolidinone la. Potent inhibition of MMP-13 was exhibited by the analogues having 4-(4-fluorophenoxy)phenyl (4a, IC50 = 3 nM) and 4-(naphth-2-yloxy)phenyl (4h, IC50 = 4 nM) as P1' groups.

Joint motion and surface contact area related to component position in total hip arthroplasty.

A three-dimensional computer model of a total hip replacement was used to examine the relationship between the position of the components, the range of motion and the prosthetic joint contact area. Horizontal acetabular positions with small amounts of acetabular and femoral anteversion provide the largest contact areas, but result in limited joint movement. These data will allow surgeons to select implant positions that will provide the largest possible joint contact area for a given joint range of motion although these are conflicting goals. In some component positions a truncated spherical prosthetic head resulted in smaller contact areas than a completely spherical head.

Uncemented press-fit total hip arthroplasty using the Identifit custom-molding technique. A prospective minimum 2-year follow-up study.

Fifty-three primary uncemented custom-molded Identifit (Depuy, Warsaw, IN) hip arthroplasties were evaluated prospectively at a mean follow-up period of 30 months. The custom technique provided the capability to reproduce the unique femoral offset, version, and height in each hip and to achieve high percentages of femoral canal fill. Surgical time for unilateral cases was a mean 153 minutes. Clinical results, however, were disappointing. Nine hips (17%) required stem revision for persistent thigh pain and limping. Of the remaining 44 hips, the mean Harris hip score was 83, and 20% experienced moderate to severe thigh pain and 50% had a limp. Radiographically, 65% of the stems had subsided and 27% had migrated into valgus. Survivorship analysis predicted an 80% stem survival rate at 43 months. A precise fit and fill of the femoral canal is not in itself sufficient for femoral implant stability in total hip arthroplasty surgery.

Uncemented total hip arthroplasty using the CLS stem: a titanium alloy implant with a corundum blast finish. Results at a mean 6 years in a prospective study.

An uncemented titanium alloy stem with a corundum blast finish and an uncemented titanium fibermetal mesh socket were implanted in a series of 57 hips. These prostheses were selected for use in the youngest, most active, and/or heaviest candidates for total hip arthroplasty. Fifty hips were available for study at a minimum 60 months. At a mean 6 years, 92% of the hips were rated good or excellent. The mean Harris hip score was 92. One patient experienced mild thigh pain. The corundum blast finish was associated with reliable implant stability. Survival analysis predicted a 96% rate of implant survival at 92 months. Loss of bone density was rated mild, minimal, or none in 88% of the hips. Three hips developed severe bone loss due to systemic disease. Polyethylene wear was measurable in 86% of the hips. Twenty hips developed focal proximal femoral bone erosions. One hip had endosteal cavitation distal to zone 7. The presence of proximal femoral erosions or endosteal cavitation correlated positively with the presence of measurable polyethylene wear. The limited and proximal distribution of femoral bone erosion despite evidence of extensive polyethylene wear suggested that bone apposition to the corundum blast finish resulted in a barrier to migration of wear debris.

Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Reduction of intracellular pH by tenidap. Involvement of cellular anion transporters in the pH change.

Tenidap [5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide], a novel antirheumatic agent, produces a rapid and sustained intracellular acidification when applied to cells in culture. To investigate the mechanism by which this change in ionic homeostasis is achieved, the acidification activities of structural analogs of tenidap were determined, and the movements of [14C]tenidap into and out of cells were explored. The acidification activity of tenidap was enhanced by lowering extracellular pH, suggesting that the free acid species was required for this process. Consistent with this requirement, a non-acidic analog of tenidap did not produce a change in intracellular pH (pHi). In contrast, multihalogenated derivatives of tenidap produced greater changes in pHi than did tenidap, and one analog produced a transient acidification from which the cell recovered; this recovery, however, was blocked by an inhibitor of the Na+/H+ antiporter. Fibroblasts incubated with [14C]tenidap achieved within 5 min a level of cell-associated drug that remained constant during longer incubations. Simultaneous addition of the electrogenic ionophore valinomycin or the P-glycoprotein inhibitor 4-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-N-[2-(3,4-dimethoxyphe nyl) ethyl]-6,7-dimethoxy-2-quinazolinamine (CP-100,356) caused a time- and concentration-dependent increase in the level of cell-associated [14C]tenidap; other agents tested did not promote this enhanced cellular accumulation. [14C]Tenidap accumulated by fibroblasts in the presence of CP-100,356 subsequently was released when these cells were placed in a tenidap- and CP-100,356-free medium. Importantly, several agents that are known to inhibit anion transport processes, including alpha-cyano-beta-(1-phenylindol-3-yl) acrylate, 5-nitro-2(3-phenylpropylamino)-benzoic acid, and meclofenamic acid, inhibited efflux of [14C]tenidap. In contrast, ethacrynic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid did not impair the efflux process. Likewise, tenidap analogs that produced a sustained intracellular acidification blocked the efflux of [14C]tenidap, but non-acidifying species did not. These data suggest that movements of tenidap into and/or out of cells is a facilitated process subject to pharmacological intervention. Together, the structural selectivity of the acidification response and the evidence of facilitated transport suggest that the pHi modulating activity of tenidap is dependent on its unique physicochemical properties. Due to the dependence of these physicochemical properties on environmental and cellular conditions, in vivo expression of the acidification activity is likely to occur only within restricted environments that favor this tenidap-induced process.

Thermal expansion modular femoral head extractor for revision total hip arthroplasty.

Removal of a prosthetic modular femoral head is sometimes desirable during revision hip arthroplasty. A femoral head extractor was designed to heat and expand the prosthetic femoral head, apply a gentle distraction load, and remove the femoral head without injury to the femoral neck, taper, or bone-prosthesis interface. The device was used clinically in six hip revision cases. In five hips with cobalt-chrome heads and titanium alloy tapers, femoral heads were removed successfully; femoral fixation was maintained and femoral components were not visibly damaged. In the sixth case, the female portion of the taper junction was contained in a long femoral head sleeve. Heating the ball did not adequately expand the sleeve to allow easy ball removal.

Titanium contamination of recycled Cell Saver blood in revision hip arthroplasty.

The use of Cell Saver blood during revision hip arthroplasty has many benefits, both medical and economic. After a review of the current literature, to our knowledge, no case of metallic debris has been reported in the blood after complete treatment with the Haemonetics Cell Saver (Braintree, MA) and appropriate filter system. A case of total hip revision of a loose, cemented acetabular component with a commercially pure titanium metal backing and a titanium alloy plasma-spray textured surface was undertaken. The titanium alloy femoral component was not visibly loose and was not revised. The joint lining tissues were black. Throughout the procedure, the operative site was suctioned with a double-lumen heparinized catheter that delivered blood and other materials to a Haemonetics Cell Saver 3 Plus. The reservoir and filter unit used were the compatible Bentley BCR-3500 (Baxter, Irvine, CA), a system capable of filtering particulates down to 20 microns. Prior to infusion of the salvaged blood, many large black clumps of material were observed mixed in the blood. Some measured 10 x 5 x 5 mm and could easily be seen macroscopically. Light microscopy demonstrated red blood cells with intermixed neutrophils, and black foreign material scattered as separate particles and within the cytoplasm of the scattered histiocytes. Energy dispersive analysis of the black material confirmed the composition as primarily titanium with minute quantities of copper, iron, phosphorous, and sulfur. A scanning electron photomicrograph of one of the specimens demonstrated a large conglomerate, approximately 2,000 microns in diameter, composed primarily of titanium and organic material.(ABSTRACT TRUNCATED AT 250 WORDS)

Hip arthroplasty using the cementless CLS stem. A 2--4-year experience.

Fifty-one Cementless Spotorno (CLS, Protek A. G. Berne) stems were implanted in 43 patients with either a Harris Galante (Zimmer, Warsaw, IN) socket or bipolar head. Patients were evaluated at a mean of 31 months. Eighty percent of the hips were in patients who were less than 50 years of age or weighed more than 80 kg. The CLS stem achieved initial stability by wedging a proximally fluted, straight stem into a retained bed of femoral trabecular and cortical bone. Distal canal fill was avoided. The postoperative mean Harris hip score was 95. Eighty percent of the hips were rated excellent, 16% good, 2% fair, and 2% poor. No stem required revision. Six percent had slight, occasional thigh pain. No patient had mild, moderate, or severe thigh pain. Six percent had a limp related to the operated hip. Fifty-three percent of the hips developed a radiographic appearance of bone apposition at the stem tip. Fifty-five percent of the hips had some reduction in proximal bone density. These changes suggested that as bone remodeling occurred, the initial proximal load transfer situation expected from the CLS stem design changed to include some distal load transfer resulting in proximal stress shielding. Ninety-four percent of the hips had either no change in femoral bone density or only patchy loss of density isolated to zone 7. A high dislocation rate was attributed to an unfavorable head-to-neck diameter ratio, a valgus neck shaft angle, and a patient population capable of excellent hip motion.

Technetium-99m-labeled platelets: comparison of labeling with a new lipid-soluble Sn(II)-mercaptopyridine-N-oxide and 99mTc-HMPAO.

Platelets pretinned with a neutral Sn(II)-2-mercaptopyridine-N-oxide (SN-MPO) were labeled with 99mTc and compared to those labeled with 99mTc-HMPAO. The conditions of labeling platelets, e.g. concentrations of platelets and Sn(II)-MPO, 99mTc in ACD-saline or ACD-plasma media, pH and incubation time, were optimized using canine platelets. Moderate labeling efficiency was obtained with 20 micrograms of tin(II) chloride and 30 min incubation with Sn-MPO and pertechnetate. The viability of labeled platelets was determined by platelet recovery and platelet survival times in Beagle dogs. The labeling efficiency with platelets from 43 mL of blood was 62.8 +/- 7.6%. The platelet recovery was 35.7 +/- 5.0% and exponential survival time was 34.6 +/- 3.1 h compared to 43.3 +2- 12.0% and 29.5 +/- 3.3 h for 99mTc-HMPAO-labeled platelets. These values were significantly (P less than 0.01) lower than 111In-labeled platelets. Biodistribution in dogs indicates lower retention in blood, spleen and liver after some initial 99mTc excretion in urine. The platelet deposition with 99mTc platelets (Sn-MPO method) on polyurethane angio-catheters was similar to 99mTc-HMPAO-labeled platelets. This study indicates that the platelets could be successfully labeled with pertechnetate in a cost-effective manner for the evaluation of thromboembolic complications.

Kinetics and quantitation of In-111 labeled platelet deposition on control and heparin-bonded polyurethane angio catheters in a dog model.

The dynamics of platelet deposition on control polyurethane catheters (CPC) and heparin-bonded polyurethane catheters (HBPC) were evaluated with In-111 labeled platelets (In-PLT) using a computerized gamma camera (CGC). Ten nonheparinized dogs (18-25 kg) had both femoral arteries catherized with 10 cm of CPC and HBPC (5 Fr.) 24 hr postinjection of 300-420 microcuries of In-PLT, and imaged for 3 hr with a gamma camera. Regional platelet deposition on three segments of catheters and the puncture site was determined. Catheters were harvested and radioactivity on the catheter segments (proximal: PROX, middle: MID, distal: DIST and puncture site: PS) of both was determined. From the platelet count in blood, and radioactivity in blood and segments of catheters, adjacent artery, and area of artery and catheter, the platelet-density [X10(3) (mean +/- S.D.)] on catheter and artery was calculated and tabulated. Proximal values were cath (CPC), 1289 +/- 1125; artery, 1355 +/- 587; cath (HBPC), 125 +/- 113; artery, 1149 +/- 1620. The middle values were cath (CPC), 1102 +/- 1109; artery, 1512 +/- 625; cath (HBPC), 132 +/- 108; artery, 1011 +/- 942. Distal values were cath (CPC), 780 +/- 584; artery, 132 +/- 108; cath (HBPC), 227 +/- 194; artery, 1457 +/- 1309. The puncture site values were cath (CPC), 106 +/- 382; artery, 1011 +/- 942; cath (HBPC), 164 +/- 135; artery, 1498 +/- 1240. The large standard deviation in retained platelets is due to embolization. The platelet-density and regional counts on catheter segments were lower with HBPC than CPC, as was the rate of platelet-deposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of platelet loss with indium-111 labeled platelets in a hollow-fiber membrane oxygenator and arterial filter during extracorporeal circulation in a pig model.

Platelet consumption in a hollow-fiber membrane oxygenator (HFMO) and arterial filter (AF) during cardiopulmonary bypass (CPB) was quantified in five pigs using Indium-111 labeled autologous platelets. Platelet labeling was performed 20-24 hours before CPB. After general endotracheal anesthesia, the pigs were systemically heparinized and were placed on CPB via a median sternotomy. After 3 hours of CPB, radioactivity was quantified with a gamma camera and an ionization chamber. The percent of injected dose (mean +/- SD) was 0.79 +/- 0.45 in the HFMO, 2.52 +/- 0.93 in AF, 4.3 +/- 1.2 in blood loss during CPB. Platelet consumption in HFMO during CPB was lower than in bubble oxygenators (19%) or silicone membrane oxygenators (12%) as observed in previous studies.

Early femoral component loosening in DF-80 total hip arthroplasty.

Forty-seven DF-80 total hip arthroplasties performed in 40 patients were evaluated to determine the incidence and causes of early femoral component loosening. With an average 37.1-month follow-up period, 48.9% of the femoral components developed bone cement-bone radiolucent lines worrisome for stem loosening. Twenty-three percent of the stems had subsided and 4.3% had been revised. Radiolucent lines were apparent very early (average, 8.8 months). Statistical analysis revealed positive correlations between the use of the larger (45-mm) offset stem and both the appearance of radiolucent lines and stem loosening. Being male and tall also were associated with stem loosening. The causes for early DF-80 femoral component loosening could not be defined with certainty. The results of this study and a review of the literature suggest that failure may be a result of early biologic weakening of the proximal cement-bone interface combined with a stem design that maintains proximal bone loading. Metal debris did not appear to be a factor in loosening of this titanium alloy stem.

Near normalization of metabolism of IDDM: comparison of continuous subcutaneous (CSII) versus intraperitoneal (CIPII) insulin delivery.

The effects of continuous insulin infusion given subcutaneously (CSII) and intraperitoneally (CIPII) on 24 h "metabolic" profile of four insulin dependent diabetic volunteers were assessed. When the insulin dose delivered is adjusted to achieve a near match of the peripheral plasma glucose profile, the 24 h profiles of free fatty acids, glycerol, lactate and beta-hydroxybutyrate and the hormones, insulin, glucagon, cortisol and catecholamines were identical. These results suggest that CIPII has no advantage over CSII in normalizing of the metabolism of the insulin dependent diabetic.

Exercise in insulin-dependent diabetes mellitus: the effect of continuous insulin infusion using the subcutaneous, intravenous, and intraperitoneal sites.

The metabolic response to exercise in insulin-dependent diabetic (IDD) man was assessed during continuous insulin infusion using the subcutaneous (CSII), intravenous (CIVII), and intraperitoneal (CIPII) routes. During the basal period, plasma glucose levels were higher with CIPII (153 +/- 17 mg/dl) than with CSII (117 +/- 13 mg/dl) or CIVII (118 +/- 17 mg/dl). Basal free insulin concentrations were similar for CSII (12.3 +/- 10 microU/ml) and CIVII (12.4 +/- 1.4 MicroU/ml) but lower in CIPII (8.5 +/- 1.0 microU/ml, P less than 0.05). Exercise on a stationary bicycle at 75 W for 60 min produced a decline of plasma glucose in each protocol that was significantly only during CIVII (55 +/- 11 mg/dl, P less than 0.01). Insulin levels remained unchanged throughout the study period in all protocols. In normals, insulin values decreased during exercise and remained below basal levels through the recovery period (P less than 0.05), while plasma glucose remained unchanged. Plasma glucagon and epinephrine levels were similar in all protocols and remained unchanged with exercise, while plasma norepinephrine tended to be higher than normal in all diabetic subjects. Significant differences between normal and diabetic subjects (P less than 0.05) were observed for blood ketone bodies, while blood lactate, glycerol, and plasma FFA were similar. Normalization of intermediary metabolites occurred only with CIVII. Continuous insulin infusion provides near-normal glycemic and metabolic control before, during and following exercise in IDD man. However, to produce normal blood concentrations of intermediary metabolites during exercise, the insulin infusion rate may be excessive in terms of its hypoglycemic effect. CSII appears to be a safe, accessible, and adequate method for treating diabetic man during exercise.