Articular spacers in two-stage revision arthroplasty for prosthetic joint infection of the hip and the knee.

Use of articular antibiotic-eluting cement spacers during two-stage revision arthroplasty for prosthetic joint infection (PJI) is a long-established and proven adjunctive technique during first-stage surgery. Articular spacers come in many forms, either static or dynamic. The authors present an instructional review of current evidence regarding their use. A total of 45 studies (for spacer use in PJI involving either hip or knee) were analysed for data regarding eradication rate, functional outcomes, mechanical complications and the impact on second-stage surgery. A large number of case series and retrospective cohort studies were retrieved, with only a small number of prospective studies (2). High levels of infection eradication were commonly reported (>80%). Outcome scores were commonly reported as indicating good-to-excellent function and pain levels. Second-stage procedures were often not required when dynamic spacers were used. Static spacers were associated with more mechanical complications in both the hip and the knee. In the hip, dynamic spacers were more commonly associated with instability compared to static spacers. Consideration should be given to the use of dual-mobility or constrained definitive acetabular components in these cases at second-stage surgery. The use of antibiotic-eluting polymethylmethacrylate articular spacers in two-stage revision for PJI of hip and knee arthroplasty achieves a high rate of infection eradication. Dynamic spacers may confer a variety of benefits compared to static spacers, with a similar rate of infection eradication.

Risk Factors for Revision of Polished Taper-Slip Cemented Stems for Periprosthetic Femoral Fracture After Primary Total Hip Replacement: A Registry-Based Cohort Study from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

BACKGROUND: Total hip replacement (THR) with a cemented polished taper-slip (PTS) femoral stem has excellent long-term results but is associated with a higher postoperative periprosthetic femoral fracture (PFF) risk compared with composite beam stems. This study aimed to identify risk factors associated with PFF revision following THR with PTS stems. METHODS: In a retrospective cohort study, 299,019 primary THRs using PTS stems from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) were included, with a median follow-up of 5.2 years (interquartile range [IQR], 3.1 to 8.2 years). The adjusted hazard ratio (HR) of PFF revision was estimated for each variable using multivariable Cox survival regression analysis. RESULTS: Of 299,019 THR cases, 1,055 underwent revision for PFF at a median time of 3.1 years (IQR, 1.0 to 6.1 years). The mean age (and standard deviation) was 72 ± 9.7 years, 64.3% (192,365 patients) were female, and 82.6% (247,126 patients) had an American Society of Anesthesiologists (ASA) class of 1 or 2. Variables associated with increased PFF were increasing age (HR, 1.02 per year), intraoperative fracture (HR, 2.57 [95% confidence interval (CI), 1.42 to 4.66]), ovaloid (HR, 1.96 [95% CI, 1.22 to 3.16]) and round cross-sectional shapes (HR, 9.58 [95% CI, 2.29 to 40.12]), increasing stem offset (HR, 1.07 per millimeter), increasing head size (HR, 1.04 per millimeter), THR performed from 2012 to 2016 (HR, 1.45 [95% CI, 1.18 to 1.78]), cobalt-chromium stem material (HR, 6.7 [95% CI, 3.0 to 15.4]), and cobalt-chromium stems with low-viscosity cement (HR, 22.88 [95% CI, 9.90 to 52.85]). Variables associated with a decreased risk of PFF revision were female sex (HR, 0.52 [95% CI, 0.45 to 0.59]), increasing stem length (HR, 0.97 per millimeter), and a ceramic-on-polyethylene bearing (HR, 0.55 [95% CI, 0.36 to 0.85]). CONCLUSIONS: Increased risk of PFF revision was associated with PTS stems that are short, have high offset, are used with large femoral heads, are made of cobalt-chromium, or have ovaloid or round cross-sectional shapes. Large increases in PFF risk were associated with cobalt-chromium stems used with low-viscosity cement. Further study is required to confirm causation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A developmental functional MRI study of spatial working memory.

Functional magnetic resonance imaging (fMRI) was used to examine patterns of cortical activity in children during performance of a spatial working memory task. Six children (8-10 years) and six adults (19-26 years) searched a linear array of four boxes for the appearance of a dot. In the visual blocks, participants made no response. In the motor blocks, participants were instructed to indicate the location of the dot on each trial using a button-press response. In the working memory blocks, participants were instructed to indicate at which location the dot had appeared 1 or 2 trials previously. Both children and adults showed activity in the left precentral and postcentral gyri, as well as the right cerebellum for the motor condition as compared to the visual condition. Comparison of the memory and motor conditions revealed reliable activity in the right superior frontal gyrus (BA 8), right dorsolateral prefrontal cortex (BA 10/46), right superior parietal cortex, and bilateral inferior parietal cortex for both adults and children. These results suggest that spatial working memory tasks activate very similar cortical regions for school-age children and adults. The findings differ from previous imaging studies of nonspatial working memory tasks in that the prefrontal activations observed in the current work tend to be more dorsal. Results are discussed in light of the significant behavioral performance differences observed between child and adult participants.

Vascular endothelial growth factor as a marker of tumor endothelium.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that is a primary stimulant of the vascularization of solid tumors. VEGF production is induced by oncogenic gene mutations in the tumor cells and by hypoxic conditions inside the tumor mass. Hypoxia and the locally increased concentration of VEGF lead to an up-regulation of VEGF receptor expression on tumor endothelial cells. Therefore, in the tumor microenvironment, there is an up-regulation of both VEGF and its receptor, leading to a high concentration of occupied receptor on tumor vascular endothelium. The VEGF:receptor complex presents an attractive target for the specific delivery of drugs or other effectors to tumor endothelium. In the present study, several hybridomas that secrete monoclonal antibodies against the VEGF:receptor (Flk-1) complex or against VEGF itself have been raised. Three of the antibodies (3E7, GV39M, and 11B5) bind with high affinity to the VEGF:Flk-1 complex in ELISA and to tumor endothelium in frozen sections of human tumors, rodent tumors, and human tumor xenografts. 3E7 and GV39M localize selectively to tumor endothelium after i.v. injection into mice bearing human tumor xenografts. Additionally, one antibody (2C3) was raised that blocks the interaction between VEGF and KDR/Flk-1. 2C3 inhibits VEGF-mediated growth of endothelial cells in vitro and localizes strongly to connective tissue in tumors after injection into mice bearing human tumor xenografts. These findings suggest that 3E7, GV39M, and 2C3 are candidates for targeting and imaging the vasculature or connective tissue of tumors.

Prophylactic ephedrine and hypotension associated with spinal anesthesia for cesarean delivery.

Hypotension commonly accompanies induction of spinal anesthesia for cesarean section. To determine whether intravenous ephedrine prophylaxis would benefit prehydrated obstetrical patients presenting for elective cesarean section, we studied 30 patients randomly assigned to one of three experimental groups. All patients were preloaded with crystalloid (15 ml/kg), given spinal anesthesia and positioned with left uterine displacement (LUD). During induction, all patients received a 2 ml intravenous bolus and intravenous infusion of the study drug or placebo. The control group (n=10) received a saline bolus and saline infusion, the bolus group (n=10) received an ephedrine bolus (10 mg) and a saline infusion and the infusion group (n=10) received a saline bolus and a two-stage ephedrine infusion (20 mg over 12 min). After induction of anesthesia, systolic blood pressure decreased in the first 5 min in all groups. Hypotension occurred in 6/10 control patients, 5/10 bolus patients and 5/10 infusion patients. The amount of supplemental ephedrine required to treat hypotension did not differ among groups. Although the efficacy of ephedrine prophylaxis for hypotension associated with spinal anesthesia for elective cesarean section cannot be established by the small number of patients studied, this practice does not appear to be clinically relevant at the doses studied.

Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy.

We have characterized a murine IgM monoclonal antibody, TEC-11, that recognizes endoglin and may be suitable for targeting cytotoxic agents to human tumor vasculature. TEC-11 strongly stains endothelial cells in a broad range of solid human tumors while staining endothelial cells in the majority of normal, healthy adult tissues relatively weakly. Human umbilical vein endothelial cells (HUVECs) in sections of the umbilical vein react weakly with TEC-11, whereas proliferating HUVECs in tissue culture react strongly and uniformly. HUVEC cultures grown to confluence and then rested contain two subpopulations having high and low levels of endoglin expression. Flow cytometry revealed that a significant proportion of cells with high endoglin expression are cycling, having markedly increased levels of cellular protein, RNA, and DNA by comparison to low endoglin-expressing cells, which appear to be noncycling. Taken together, the increased binding of TEC-11 to tumor vasculature and to dividing as opposed to noncycling HUVECs in vitro suggests that endoglin is an endothelial cell proliferation-associated marker. An immunotoxin [TEC-11.deglycosylated ricin A chain (dgA)] composed of TEC-11 and dgA was 3000-fold more potent at inhibiting protein synthesis in proliferating HUVEC cultures than in confluent cultures. The confluent cells were no more sensitive to TEC-11.dgA than they were to an isotype-matched immunotoxin of irrelevant specificity. These findings suggest that TEC-11.dgA might have therapeutic value in the treatment of solid tumors in humans by selectively killing dividing endothelial cells which are prevalent in such tumors.

Latex versus iodinated contrast media anaphylaxis in the cardiac cath lab.

A 65-year-old man had bypass surgery 10 years previously with pulmonary artery catheter monitoring. Shortness of breath and mitral regurgitation necessitated repeat left and right heart catheterization using a pulmonary artery catheter. Before any iodinated contrast media exposure, the pulmonary artery catheter was inserted and within 2 min the patient developed anaphylaxis associated ventricular fibrillation. It was discovered that the pulmonary artery catheter used in the cath lab had a latex balloon and that the patient had been exposed to latex 10 years ago. Latex induced anaphylaxis is rarely considered in the differential diagnosis of patients with hypersensitivity reactions in the cath lab, intensive care unit, and operating room. The principal reason for failure to recognize the latex balloon as a potential allergen is that most health professionals are not aware that almost all pulmonary artery catheters contain a latex balloon. The risk of an allergic response to latex is 0.8% for the general population. Others at high risk include those who have had multiple surgical procedures and interventions with repeated latex exposure. Five to 10% of all U.S. health professionals and those performing household duties wearing latex gloves have an allergic response to latex. Latex hypersensitivity is an IgE dependent reaction, while iodinating contrast medium reaction is an IgE independent reaction. If latex hypersensitivity is suggested by pre-procedural history or if the patient falls into a high-risk group, pre-procedural skin testing and/or latex IgE radioallergosorbent (RAST) should be performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac electrophysiologic and antiarrhythmic actions of tedisamil.

The Class III electrophysiologic and antiarrhythmic actions of the bradycardic agent tedisamil were assessed in vitro and in vivo. In ferret isolated right ventricular papillary muscles, tedisamil increased effective refractory period (ERP) in a concentration-dependent manner, with a 25% ERP increase achieved with 3.0 microM tedisamil, and a 133.4% +/- 28.8% increase in ERP achieved at the high 100 microM concentration tested. In anesthetized dogs, the cumulative i.v. administration of tedisamil significantly increased ventricular relative refractory period (VRRP) and ventricular effective refractory period (VERP) as well as electrocardiographic QTc intervals (100-1000 micrograms/kg i.v.). A 20msec increase in VRRP was achieved with 45.0 micrograms/kg i.v. tedisamil, and a 56.1 +/- 9.8 msec (40.1% +/- 8.1%) increase in VRRP was achieved at the highest dose tested (1000 micrograms/kg i.v.). In the same dosage range in anesthetized dogs, tedisamil produced significant hemodynamic effects, including reduction in HR (100-1000 micrograms/kg i.v.) and elevations in mean arterial pressure (1000 micrograms/kg i.v.), left ventricular developed pressure (1000 micrograms/kg i.v.) and the maximum rate of LV pressure development (100-1000 micrograms/kg i.v.). In anesthetized dogs studied chronically (8.2 +/- 0.6 days) after anterior myocardial infarction, tedisamil suppressed programmed stimulation-induced ventricular tachyarrhythmias (8/10, 80% suppression at 100-1000 micrograms/kg i.v.) and reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia (arrhythmic mortality 5/10, 50% tedisamil vs. 34/40, 85% vehicle control cohort; P = .027). The latter findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Substituent effects in the carboxypeptidase A catalyzed hydrolysis of substituted L,beta-phenyllactate esters.

The carboxypeptidase A catalyzed hydrolysis of an extensive series of substituted cinnamoyl-L,beta-phenyllactate esters has been investigated. Plots of kcat vs pH are sigmoidal in the pH range 5-9 with an average apparent pKaES of 6.6 +/- 0.1. The values of Km are pH independent in the range pH 5-8. Plots of log kcat/Km vs pH give pKaE values of 6.4 and 9.0 that do not vary significantly through the series. A plot of log kcat (pH 8) vs sigma, the Hammett substituent constant, is linear with a slope rho of 0.5, while log Km vs sigma has a slope of -0.4. The plot of log kcat/Km vs sigma is also linear with rho = 0.9. The Hammett plots are linear at both pH 6 and 8 with closely similar slopes, which indicates that the apparent pKaES near pH 6 does not reflect a change in the rate-determining step. The enzymatic reactions and the nonenzymatic OH- catalyzed hydrolysis reactions are affected alike by changes in the substituent groups; a plot of log kOH, the second-order rate constant for alkaline hydrolysis of the esters, vs log kcat/Km is linear with a slope of 0.9. There is little effect of changing the substituent group in the nonenzymatic pH-independent hydrolysis of the Zn(II) complex of corresponding 4-substituted cinnamic acid 6-carboxypicolinic acid anhydrides (rho < or = 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of heart rate and pulmonary artery pressure on Doppler pulmonary artery acceleration time in experimental acute pulmonary hypertension.

Chronic pulmonary hypertension in humans is characterized by shortening of the pulmonary artery acceleration time as measured by Doppler echocardiography, such that the higher the pulmonary artery pressure, the shorter the pulmonary acceleration time. Increases in heart rate are also known to produce decreases in the pulmonary artery acceleration time. To explore the relationship between mean pulmonary artery pressure, heart rate, and Doppler pulmonary artery acceleration time, experimental acute pulmonary hypertension was created in nine Duroc swine, either by infusion of Sephadex beads with embolization of the pulmonary arterial circulation or by partially occluding the main pulmonary artery 8 to 10 cm distal to the pulmonic valve. Pulmonary artery Doppler flow velocity recordings and invasive pressure measurements were made at baseline and at paced atrial rates ranging from 60 to 160 beats per minute, in 20-beat increments. The results in this acute animal model reveal that increases in heart rate produced significant decreases in Doppler pulmonary artery acceleration time at mean pressures below 25 mm Hg. However, with mean pulmonary artery pressures greater than 25 mm Hg, both heart rate and increases in pulmonary artery pressure had no significant effect on acceleration time.

Effect of machine parameters on variance display in Doppler color flow mapping.

In color Doppler flow studies, "variance" is an important display modality for diagnosing stenotic, regurgitant, and shunt lesions. Variance, a mathematical calculation based on the variation in the Doppler signal frequencies, has been reported to reflect the degree of flow disturbance. A wide-band pulsed Doppler spectrum results in a larger degree of variance. It has been suggested that variance area (green color or mosaic area) might provide useful quantitative information regarding the severity of stenotic, regurgitant, and shunt lesions. Since ultrasound machine settings may affect the color Doppler variance image, we evaluated in 101 free jet experiments the effect of packet size (eight versus four samples per line), pulse repetition frequency (3.9 versus 5.2 kHz), frame rate (11 versus 22 frames per second), system gain (+15 dB versus -15 dB), transmit power (high versus low), and moving target indicator (MTI) filter setting (high versus low) on variance display. The variance area was planimetered using an image analysis computer. The following machine parameters were inversely correlated with variance area: (1) packet size (p less than 0.01), (2) pulse repetition frequency (p less than 0.001), and (3) frame rate (p less than 0.05). Both system gain (p less than 0.001) and wall filter setting (p less than 0.01) showed a direct correlation with variance area. We conclude that machine factors must be standardized in evaluating stenotic, regurgitant, and shunt lesions by color Doppler variance display imaging.

Pitfalls in the display of color Doppler jet areas: combined variability due to Doppler angle, frame rate, and scanning direction.

UNLABELLED: The Doppler color jet area depicting a regurgitant or shunt lesion may be useful in estimating its severity. However, color jet area may be affected by technical factors. We studied the combined effects of Doppler angle, frame rate, and scanning direction on the Doppler color jet area of a free jet with 10-mL injection. RESULTS: (1) Angle effects: color flow area was 11.7 +/- 2.0 cm2 at a Doppler angle of 20 degrees , and 2.3 +/- 1.2 cm2 at an angle of 60 degrees , when other parameters were kept constant (frame rate = 12 frames/sec, reverse scanning direction). (2) Frame rate effects: with other parameters kept constant (Doppler angle = 20 degrees , reverse scanning direction), color flow area was 11.7 +/- 2.0 cm2 at a rate of 12 frames/sec and 6.5 +/- 1.8 cm2 at 6 frames/sec. (3) Scanning direction effects: with other parameters kept constant (Doppler angle = 20 degrees , frame rate = 9 frames/sec), color flow area was 7.3 +/- 1.1 cm2 with scanning in the reverse direction, and 20.5 +/- 1.6 cm2 with scanning in the forward direction. (4) Combined effects: In our in vitro studies, the maximum color flow area was 20.5 +/- 1.6 cm2, and the minimum area was 1.5 +/- 0.2 cm2 (nearly twelve-fold). CONCLUSIONS: Doppler color jet area correlated inversely with Doppler angle (P less than 0.01) and directly with frame rate (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosomal and protein evolution in morphologically similar species of Praomys sensu lato (Rodentia, Muridae).

Evidence of extensive chromosomal evolution in a biologically and economically important group of African murids of the Praomys/Mastomys complex was provided by examination of G- and C-band chromosomal data on P. coucha (2n = 32), P. fumatus (2n = 38), P. hildebrandti (2n = 32), P. jacksoni (2n = 28), P. misonnei (2n = 36), and P. cf. tullbergi (2n = 35). A coding system was developed for the chromosomal characters, and analyses were performed by a computer program to find the shortest tree with a minimum of 35 autosomal rearrangements (pericentric inversions, complex translocations, centric fusions, centric fissions, tandem fusions, euchromatic additions, and heterochromatic additions). The resulting phylogenetic hypothesis differs from traditionally accepted hypotheses regarding this complex group of rodents. The cytogenetic data show that 1) there is no support for the dichotomy of Mastomys/Praomys previously based on morphology, 2) the 2n = 32 species from eastern Africa (P. hildebrandti) is distinct from the 2n = 32 species from southern Africa (P. natalensis), and 3) there is a close association between P. jacksoni and P. cf. tullbergi. Polyacrylamide gel electrophoresis of liver membrane proteins demonstrated few differences in protein mobilities between species and even fewer between individuals of the same species taken from different habitats and localities in Kenya. Monoclonal antibodies produced against liver proteins of one species and tested for reactivity to other species confirmed the evolutionary similarity of species of this complex. This immunologic approach may provide a robust data set for future phylogenetic studies of muroid rodents.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal antibodies produced against antigenic determinants present in complex mixtures of proteins.

This overview provides information concerning the production of monoclonal antibodies (MAbs) against specific antigenic determinants present in complex mixtures of proteins. We review five specific techniques for the production of these antibodies (Abs): (a) So-called "shotgun," non-selective approach; (b) cascade procedure; (c) lymphocyte "panning"; (d) cyclophosphamide elimination of unwanted Ab producers; and finally (e) use of polyclonal antisera to extinguish unwanted antibody production. We discuss the relative advantages and disadvantages of these various procedures, and suggest alternative strategies by which specific MAbs might be generated.

Interaction of carboxypeptidase A with carbamate and carbonate esters.

The carbamate ester N-(phenoxycarbonyl)-L-phenylalanine binds well to carboxypeptidase A in the manner of peptide substrates. The ester exhibits linear competitive inhibition toward carboxypeptidase A catalyzed hydrolysis of the amide hippuryl-L-phenylalanine (Ki = 1.0 X 10(-3) M at pH 7.5) and linear noncompetitive inhibition toward hydrolysis of the specific ester substrate O-hippuryl-L-beta-phenyllactate (Ki = 1.4 X 10(-3) M at pH 7.5). Linear inhibition shows that only one molecule of inhibitor is bound per active site at pH 7.5. The hydrolysis of the carbamate ester is not affected by the presence of 10(-8)-10(-9) M enzyme (the concentrations employed in inhibition experiments), but at an enzyme concentration of 3 X 10(-6) M catalysis can be detected. The value of kcat at 30 degrees C, mu = 0.5 M, and pH 7.45 is 0.25 s-1, and Km is 1.5 X 10(-3) M. The near identity of Km and Ki shows that Km is a dissociation constant. Substrate inhibition can be detected at pH less than 7 but not at pH values above 7, which suggests that a conformational change is occurring near that pH. The analogous carbonate ester O-(phenoxycarbonyl)-L-beta-phenyllactic acid is also a substrate for the enzyme. The Km is pH independent from pH 6.5 to 9 and has the value of 7.6 X 10(-5) M in that pH region. The rate constant kcat is pH independent from pH 8 to 10 at 30 degrees C (mu = 0.5 M) with a limiting value of 1.60 s-1. Modification of the carboxyl group of glutamic acid-270 to the methoxyamide strongly inhibits the hydrolysis of O-(phenoxycarbonyl)-L-beta-phenyllactic acid. Binding of beta-phenyllactate esters and phenylalanine amides must occur in different subsites, but the ratios of kcat and kcat/Km for the structural change from hippuryl to phenoxy in each series are closely similar, which suggests that the rate-determining steps are mechanistically similar.

Bioactive conformation of 1-arylpiperazines at central serotonin receptors.

A number of 1-arylpiperazines have been characterized as direct-acting serotonin agonists. Conformational parameters of this class that may affect receptor recognition and binding have been examined through the analysis of X-ray data and synthesis of rigid analogues. Radioligand binding studies indicate that 2,3,4,4a,5,6-hexahydro-9-(trifluoromethyl)-1H-pyrazino[1,2-a]quinoline, an arylpiperazine that mimics the X-ray conformation of the serotonin agonist 1-(6-chloropyrazin-2-yl)piperazine, exhibits high affinity for serotonin receptors, suggesting that the two rings of 1-arylpiperazines are relatively coplanar in the bioactive conformation.

L-646,462, a cyproheptadine-related antagonist of dopamine and serotonin with selectivity for peripheral systems.

The selectivity, peripheral vs. central actions, of the antidopaminergic agent L-646,462 was assessed in two ways. First, elevation of prolactin in serum (peripheral) and homovanillic acid in the striatum were measured in rats. L-646,462 was found to have a central/peripheral activity ratio of 143, whereas comparable values derived for haloperidol, metoclopramide and domperidone were 1.4, 9.4 and 1305, respectively. Second, the ID50 values required to block apomorphine-induced emesis in beagles (peripheral receptor-mediated response) were compared with those required to block apomorphine-induced stereotypy (central receptor-mediated response) in rats. Central/peripheral ID50 ratios of 234, 9.2, 129 and 7040 were obtained, respectively, for L-646,462, haloperidol, metoclopramide and domperidone. The selectivity of L-646,462 for peripheral serotonin (5-HT) receptors in rats was determined by measuring its effectiveness in blocking 5-HT-induced paw edema (peripheral response) and 5-hydroxytryptophan-induced head twitch (central response); a ratio of 114 was obtained. This value agrees nicely with the ratio of 143 derived in the rat ( vide supra) for peripheral selectivity for dopamine receptors. L-646,462 is, therefore, selective in vivo, preferentially blocking dopamine and 5-HT receptors located outside the blood-brain barrier. With regard to dopamine-receptors, L-646,462 was about equipotent and more selective than metoclopramide, while being less potent and less selective than domperidone. Unlike metoclopramide or domperidone, L-646,462 also possessed a reasonably potent 5-HT receptor antagonist effect in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.