Porphyrin and phthalocyanine antiscrapie compounds.

The transmissible spongiform encephalopathies (TSEs) are fatal, neurodegenerative diseases for which no effective treatments are available. The likelihood that a bovine form of TSE has crossed species barriers and infected humans underscores the urgent need to identify anti-TSE drugs. Certain cyclic tetrapyrroles (porphyrins and phthalocyanines) have recently been shown to inhibit the in vitro formation of PrP-res, a protease-resistant protein critical for TSE pathogenesis. We now report that treatment of TSE-infected animals with three such compounds increased survival time from 50 to 300%. The significant inhibition of TSE disease by structurally dissimilar tetrapyrroles identifies these compounds as anti-TSE drugs.

Requirement for both micron- and submicron scale structure for synergistic responses of osteoblasts to substrate surface energy and topography.

OBJECTIVE: Surface roughness and surface free energy are two important factors that regulate cell responses to biomaterials. Previous studies established that titanium (Ti) substrates with micron-scale and submicron scale topographies promote osteoblast differentiation and osteogenic local factor production and that there is a synergistic response to micro-rough Ti surfaces that have retained their high surface energy via processing that limits hydrocarbon contamination. This study tested the hypothesis that the synergistic response of osteoblasts to these modified surfaces depends on both surface micro-structure and surface energy. METHODS: Ti disks were manufactured to present three different surface structures: smooth pretreatment (PT) surfaces with R(a) of 0.2 microm; acid-etched surfaces (A) with a submicron roughness R(a) of 0.83 microm; and sandblasted/acid-etched surfaces (SLA) with R(a) of 3-4 microm. Modified acid-etched (modA) and modified sandblasted/acid-etched (modSLA) Ti substrates, which have low contamination and present a hydroxylated/hydrated surface layer to retain high surface energy, were compared with regular low surface energy A and SLA surfaces. Human osteoblast-like MG63 cells were cultured on these substrates and their responses, including cell shape, growth, differentiation (alkaline phosphatase, osteocalcin), and local factor production (TGF-beta1, PGE(2), osteoprotegerin (OPG)) were analyzed (N=6 per variable). Data were normalized to cell number. RESULTS: There were no significant differences between smooth PT and A surfaces except for a small increase in OPG. Compared to A surfaces, MG63 cells produced 30% more osteocalcin on modA, and 70% more on SLA. However, growth on modSLA increased osteocalcin by more than 250%, which exceeded the sum of independent effects of surface energy and topography. Similar effects were noted when levels of latent TGF-beta1, PGE(2) and OPG were measured in the conditioned media. CONCLUSIONS: The results demonstrate a synergistic effect between high surface energy and topography of Ti substrates and show that both micron-scale and submicron scale structural features are necessary.

Phenytoin and chlorpromazine in the treatment of spasticity.

The efficacy of phenytoin sodium and chlorpromazine hydrochloride in the reduction of spasticity was evaluated in both open and controlled studies. In each study, the majority of patients exhibited both objective and subjective signs of improvement. Reduction of motor tone in spastic muscles, as well as improvement in functiional status, was observed. Most patients experienced greater benefit from the combination of phenytoin and chlorpromazine than from either drug alone. The use of the drugs in combination permitted decreased chlorpromazine doses and reduced unwanted side effects such as lethargy and somnolence. These drugs may exert their action by suppressing fusimotor efferent as well as afferent discharged from muscle spindles. The results suggest that the fusimotor system is an important pharmacologic target in the treatment of spasticity.

Suppression of decerebrate rigidity by phenytoin and chlorpromazine.

In cats decerebrated by a midcollicular section, decerebrate rigidity developed that was not alleviated by phenytoin even in doses as great as 60 mg per kilogram. Chlorpromazine that depresses decerebrate rigidity in a dose-related fashion requires 1.5 to 2.0 mg per kilogram to exhibit an appreciable effect. In the presence of 20 mg per kilogram phenytoin, however, as little as 0.1 mg per kilogram chlorpromazine markedly reduces decerebrate rigidity. This drug combination did not impair neuromuscular transmission nor did it severely impair motor coordination in cats. Although phenytoin depressed muscle spindle discharges, this peripheral suppression was insufficient to abolish the rigidity. Phenytoin with or without chlorpromazine may be of value in suppressing muscle rigidity in some disorders of upper motor neuron lesions.

Spinal cord contusion in the rat: somatosensory evoked potentials as a function of graded injury.

A weight-drop technique was used to produce mild, moderate, or severe spinal cord contusive injury in rats. At 4 weeks after injury, somatosensory evoked potentials (SEPs) were recorded with silver ball electrodes placed over the somatosensory cortex of anesthetized rats to measure the response to sciatic nerve stimulation. Both SEP area and amplitude were measured and were highly correlated with each other. Both indices of the SEP correlated inversely with the height of the weight drop and directly with the degree of residual function assessed at 4 weeks after injury. Measures of residual function consisted of a motor score, inclined plane test, and a combined behavioral score based on several neurologic functions. No correlation between latency of the SEP with degrees of contusive injury was observed. The data indicate that the SEP can be used as one criterion in the assessment of the severity of a lesion in a rat model of a graded spinal cord injury.

Antiextensor effects of 3,3-diphenyl-n-propylamine in the mouse.

Diphenylpropylamine has antiextensor activity in the MES test and worsens clonic seizures produced by pentylenetetrazol. The drug also prevents tonic hindlimb extension produced by large doses of pentylenetetrazol. Diphenylpropylamine appears, therefore, to be a phenytoin-like compound. However, unlike most antiextensor agents, diphenylpropylamine has neuroexcitatory effects and antagonizes barbital-induced loss of the righting reflex.

Effects of calcium channel blocking agents on neostigmine-induced fasciculations.

Male Sprague-Dawley rats were anesthetized with pentobarbital and prepared for monitoring contractions of the gastrocnemius muscle evoked by stimulation of the sciatic nerve. Animals received atropine prior to a dose of neostigmine of 0.02 mg/kg i.v. The effects on contractile strength and the number of fasciculations in a 2-min period were assessed. Pretreatment with phenytoin, 20 mg/kg, reduced the number of fasciculations to 32% of control without altering contractile strength. Both nifedipine and nitrendipine, 1 mg/kg each, virtually abolished fasciculations without altering twitch strength. Verapamil, 4 and 8 mg/kg, depressed fasciculation frequency to 50% of control without affecting pre-neostigmine twitch height. The dihydropyridine calcium blocking agents did however reduce the neostigmine-induced augmentation of contraction strength. These data suggest that a calcium-mediated current at presynaptic motor endings participates in the generation of repetitive nerve terminal discharges leading to muscle fasciculations.

The influence of heart rate on ouabain cardiotoxicity in cats with spinal cord transection.

The dose, serum level and ventricular content of ouabain needed to produce cardiotoxicity were examined in control cats, cats with transected spinal cords and cats with transected spinal cords whose heart rates were restored to control values by artificial pacing. The lethal dose of ouabain was higher in cats with transected spinal cords and not paced than it was in the control group. However, the lethal dose of ouabain in spinal-sectioned cats with ventricular pacing was no different from that in controls. However, in both groups of spinal-sectioned cats, death was associated with higher ventricular and serum levels of ouabain than in controls. The ventricular ouabain content of paced animals with transected spinal cords was higher than that of controls and lower than that of unpaced spinal cats. Thus, restoration of heart rate to control levels in spinal animals appeared to accelerate myocardial ouabain uptake. The lower myocardial ouabain content in the spinal-sectioned animals which were paced suggests that pacing sensitizes the heart to cardiotoxicity. Spinal section itself appears to decrease the sensitivity to ouabain partly through a decrease in cardiac rate and partly through a loss of neurogenic influence.

Restraint and housing of ratites.

Large animal practitioners are called upon to assist producers to prevent and control disease and to manage flocks. The concerns that exist in traditional livestock and poultry management are also applicable to ratites. Adequate ventilation, shelter, and space allocation are the foundations of flock health. Practitioners need to know how to handle ratites in order to perform a through physical examination and collect diagnostic samples.

Fludrocortisone is effective in the management of tacrolimus-induced hyperkalemia in liver transplant recipients.

Tacrolimus is the cornerstone of immunosuppression following liver transplantation (OLT). However, this agent may cause hyperkalemia by multiple mechanisms affecting potassium in the distal tubule. The purpose of this study was to evaluate the impact of fludrocortisone for the management of tacrolimus-induced hyperkalemia. Hospitalized adult OLT recipients who received fludrocortisone for tacrolimus-induced hyperkalemia were retrospectively identified. Change in serum potassium within 14 days of initiation was the primary endpoint. Secondary endpoints included serum sodium, blood urea nitrogen, serum creatinine, and tacrolimus concentrations up to 14 days after fludrocortisone initiation. Nine patients were evaluated. Outcomes were analyzed with separate repeated-measures analyses of variance. Mean daily fludrocortisone dose was 0.14 ± 0.08 mg. Serum potassium decreased significantly within the 14-day study period (P < .001). Mean potassium decreased from 5.7 ± 1 to 4.3 ± 0.5 mmol/L within 48 hours of fludrocortisone initiation (P = .002). Sodium concentrations were statistically higher (P = .024), while serum creatinine was not significantly different by day 14. Mean tacrolimus concentration at fludrocortisone initiation was 10.2 ± 5.2 and remained stable to 14 days (10.4 ± 4.7 ng/mL; P = .9). This is the first study in OLT recipients demonstrating fludrocortisone significantly decreases serum potassium in patients with stable tacrolimus concentrations. Larger prospective studies are needed to confirm these results.

Effects of carbamazepine on muscle spindle discharges.

Spinal and alpha-chloralose anesthetized cats were prepared for single unit recording from fibers originating in deefferented spindles of the triceps surae muscles. Carbamazepine (CBZ), 200 and 300 mg/kg, suspended in 1% methylcellulose in saline was administered i.p. and plasma concentrations were determined by gas liquid chromatography. Stretch induced by a 500 g weight drop was used to evaluate spontaneous, static stretch, and poststretch spindle activity, while stretch induced by stimulation of the antagonist muscle group was used to evaluate a phasic stretch response. Preparations were monitored from 15 minutes before to 90 minutes after drug administration. CBZ produced a concentration-dependent depression of most aspects of spindle activity at concentrations ranging from approximately 9 to 45 microgram/ml. Activity during the poststretch period exhibited the greatest sensitivity to CBZ depression, spontaneous and static stretch activity exhibited intermediate sensitivity and phasic responses were relatively insensitive. No difference between Ia and II sensory endings were observed. Spindle depression was evident at concentrations which had no effect on axonal conduction velocity. The possible influence of this peripheral activity of CBZ is discussed with regard to neurotoxicity and use in the treatment of various neuropathological states.