Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor.

The species specificity of a small molecule antagonist for the human CCR1 chemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitrile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and human CCR1, and was able to block the functional activation of these receptors. However, it failed to significantly displace radiolabeled macrophage inflammatory protein-1alpha (MIP-1alpha) binding to mouse CCR1 at concentrations up to 10 microM. These data suggested that the antagonist binding site is well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 were further characterized. CCR1 antagonist 1 blocked the increase in intracellular Ca(2+) stimulated by CCR1 agonists, but had no effect on N-formyl-Met-Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1alpha (SDF1alpha)-induced Ca(2+) mobilization, demonstrating functional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagonist of marmoset and rabbit CCR1 receptors, it should be possible to test its efficacy in animal models of disease.

Discovery of novel non-peptide CCR1 receptor antagonists.

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.

Restricted environmental stimulation technique improves human performance: rifle marksmanship.

This study controlled for relaxation and guided imagery confounds noted in much previous research on enhancement of human performance using the restricted environmental stimulation technique (REST). Dry flotation REST was used where subjects lay ("floated") on a salt-water-filled bladder in a sound-attenuated, light-free chamber. 9 men and 3 women in a rifle marksmanship training course, exposed to dry-flotation REST, showed significantly higher rifle marksmanship scores than the university students who as matched controls were exposed to relaxation (9 men and 3 women). Further, only the former showed a significant pre- to posttest improvement in scores, which suggests REST's positive effects on marksmanship go beyond the induction of relaxation by hypnosis. The results support hypotheses summarized in 1982 by Barabasz regarding potentiation by REST of internally generated imagery and subsequent improvement observed in a nonREST posttest environment.

Interference by antiarrhythmic agents with function of electrical cardiac devices.

The possible interference of drugs with the function of implanted electrical cardiac devices in two patients is described, and the literature on the interaction between these drugs and devices is reviewed. A 59-year-old woman had a permanent pacemaker implanted after diagnosis of tachycardia-bradycardia syndrome, and her drug regimen of digoxin, verapamil, and warfarin was supplemented with flecainide to prevent paroxysmal atrial fibrillation. A Holter monitor recording performed after five days of flecainide therapy showed the pacemaker was sensing and pacing normally. Approximately three weeks after pacemaker implantation and initiation of flecainide therapy, a Holter monitor recording showed high-grade atrioventricular block and failure of the pacemaker to capture. A chest roentgenogram showed that the pacemaker lead was properly placed. The pacemaker's pulse amplitude and pulse width were increased, and the device again functioned reliably. Six months later the pacing threshold was noted to have returned to normal. A 64-year-old man had a history of aborted sudden cardiac death from ventricular tachyarrhythmias. The patient received an automatic implanted cardioverter-defibrillator (AICD); at that time, a 15-J discharge was required to terminate induced ventricular fibrillation (VF). Three years later, the AICD was replaced; the energy required for VF termination with the new unit was 16 J. Seven months after implantation of the new unit, the patient had several episodes of ventricular tachycardia (VT). Moricizine therapy was initiated. An electrophysiologic study (EPS) three days later showed that a larger shock (28 J) was required to terminate VF and that the pacing threshold had increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of drug therapy for treatment of hypertensive urgencies in the emergency department.

Oral nifedipine (N) and clonidine (C) are often used in the treatment of hypertensive urgencies; however, until recently, there were no comparative studies using the same patient population. The authors reviewed the records of hypertensive patients treated in the emergency department between October 1, 1987 and September 30, 1988. Selected patients had a diastolic blood pressure (DBP) of greater than 115 mm Hg without evidence of acute end organ damage. Patients were stratified into three treatment groups: N, C, and group 3 (G3). G3 received a variety of drug therapies but not exclusively N or C. Systolic blood pressure (SBP), DBP, mean arterial pressure (MAP), percent decrease in MAP (%MAP), time to lower blood pressure, admissions, and discharges were evaluated. Efficacy and safety were defined as reaching a DBP less than 110 mm Hg but %MAP of no greater than either 25% or 40%, respectively. Thirty-five N, 32 C, and 27 G3 patients were identified with no statistical difference between groups in race, gender, pretreatment SBP, DBP, or MAP. N, C, and G3 significantly reduced SBP, DBP, and MAP (P less than .01). Comparing N, C, and G3, no differences were observed in %MAP, admissions, discharges, efficacy, or safety. Time required to decrease blood pressure differed between all three groups (44 +/- 32 N v 77 +/- 57 C v 152 +/- 94 min G3) (p less than .05). These results indicate that N, C, and a variety of drug therapies are equally effective and safe in the treatment of hypertensive urgencies.

Acute interstitial nephritis associated with mezlocillin, nafcillin, and gentamicin treatment for Pseudomonas infection.

Two patients developed acute interstitial nephritis (AIN) following treatment with mezlocillin sodium. Diagnosis was made by renal biopsy. Gallium 67 citrate scanning was abnormal in both. All patients were receiving multiple-drug therapy, but AIN has either not been described with the other drugs, or the temporal relationship between the AIN and termination of other drug therapy makes a causative relationship unlikely. All were infected with Pseudomonas aeruginosa. A role for the infecting organism or drug synergism in contributing to the renal disease cannot be excluded.

Balance and tissue distribution of vanadium after short-term ingestion of vanadate.

Forty-six female Sprague-Dawley rats (170-200 g) were randomly assigned to one of six treatment groups receiving 0.1, 5.0, or 25.0 ppm dietary vanadium with either normal (0.13 mEq/g) or high (1.82 mEq/g) dietary potassium. Supplemental vanadium was administered as sodium metavanadate. These diets were fed for 2 weeks, and all feces and urine collected. At the end of the treatment period, brain, liver, renal cortex and medulla, whole blood, and plasma were obtained and analyzed for vanadium by atomic absorption spectrophotometry, as were the urine and feces samples. Tissue vanadium concentration increased significantly (P less than 0.00001) with increasing food vanadium content, but were not affected by dietary potassium in spite of the polyuria induced in animals on the high potassium diets. The highest vanadium concentrations were found in the renal cortex and the lowest, in the brain. Although urinary vanadium excretion was higher in animals fed the high potassium diets, a relatively small percentage of ingested vanadium was excreted in the urine. Rats fed diets containing no supplemental sodium metavanadate (0.1 ppm vanadium) were in negative vanadium balance, but their growth was not inhibited. Animals receiving 5.0 and 25.0 ppm vanadium diets retained 39.7 +/- 18.5% of ingested vanadium and excreted 59.1 +/- 18.8% of ingested vanadium in the feces. These values indicate greater absorption and retention of ingested vanadium than found In previously reported investigations.