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Prostaglandins are known to lower activation threshold to thermal, mechanical, and chemical stimulation in small-diameter sensory neurons. Although the mechanism of prostaglandin action is unknown, agents known to elevate intracellular calcium produce a sensitization that is similar to that produced by prostaglandins. Consistent with the idea of prostaglandin-induced elevations in calcium, prostaglandins might also stimulate the release of neurotransmitter from sensory neurons. We therefore examined whether prostaglandin E2 (PGE2) could enhance the release of the putative sensory transmitter substance P (SP) from isolated neurons of the avian dorsal root ganglion grown in culture. Utilizing the whole-cell patch-clamp recording technique, we also examined whether PGE2 could alter calcium currents in these cells. Exposure of sensory neurons to PGE2 produced a dose-dependent increase in the release of SP. One micromolar PGE2 increased release approximately twofold above basal release, whereas 5 and 10 microM PGE2 increased release by about fourfold. The release evoked by these higher concentrations of PGE2 was similar in magnitude to the release induced by 50 mM KCl. Neither arachidonic acid (10 microM), prostaglandin F2 alpha (10 microM), nor the lipoxygenase product leukotriene B4 (1 microM) significantly altered SP release. The addition of 1 microM PGE2 increased the peak calcium currents by 1.8-fold and 1.4-fold for neurons held at potentials of -60 and -90 mV, respectively. The action of PGE2 was rapid with facilitation occurring within 2 min. As with release studies, arachidonic acid, prostaglandin F2 alpha, and leukotriene B4 had no significant effect on the amplitude of the calcium current. These results suggest that PGE2 can stimulate the release of SP through the activation or facilitation of an inward calcium current. The capacity of PGE2 to facilitate the calcium current in these sensory neurons may be one mechanism to account for the ability of prostaglandins to sensitize sensory neurons to physical or chemical stimuli.

Effects of clonidine and tizanidine, which have antinociceptive and alpha 2-agonistic actions, were studied on the release of substance P from slices of spinal cord from the rat. Veratridine-evoked depolarization induced a 2-3-fold increase in the release of substance P from the slices of spinal cord. Exposure of the cord tissue to 10 microM clonidine and tizanidine significantly reduced the release of substance P. The inhibitory effects of clonidine and tizanidine were attenuated by pre-exposure of the tissue to 10 microM piperoxane, which has alpha 2-antagonistic activity and the inhibitory effect of clonidine was attenuated by 10 microM yohimbine. Moreover, the inhibitory effects of clonidine and tizanidine were also blocked by a small dose of prazosin, an antagonist for alpha 1- and alpha 2B-receptors. None of the antagonists had any effect on release of substance P, when given alone. These results suggest that alpha 2B-adrenoceptors are involved in the inhibitory effects of clonidine and tizanidine on the release of substance P.

We studied the effect of a bayesian pharmacokinetic dosing program on the outcome of aminoglycoside therapy in patients with clinical infections. Patients were randomized to a control (dosing based on physician choice; n = 75) or experimental group (dosing based on the bayesian program; n = 72). Both groups used serum aminoglycoside concentration data when making dosing decisions. Improved response rates were seen in the experimental (60%; 42/68) compared with the control group (48%; 36/68). A higher, but not statistically significant, incidence of toxicity was found in the control (7/75; 9.7%) versus the experimental group (4/72; 5.1%). Mean length of total hospital stay was significantly longer for patients in the control group (20.3 days) compared with the experimental group (16.0 days) (p = 0.028). The variables from multivariate analysis with a significant impact on length of stay were patient group and length of aminoglycoside therapy. On the basis of a reduced length of stay, a potential cost savings of $1311 per patient can be achieved.

Adenosine agonists produce antinociception when injected directly onto the spinal cord of rats and mice. One mechanism to account for this effect could be inhibition of neurotransmitter release from nociceptive sensory neurons. Consequently, we studied whether these agents could inhibit the potassium stimulated release of one such transmitter, substance P, from rat spinal cord slices. A 2 cm section of lumbar spinal cord was dissected from male Sprague-Dawley rats, chopped into 0.5 x 0.5 mm sections and perfused at 37 degrees C with a modified Krebs bicarbonate buffer containing either 3.5 mM, 30 mM, or 50 mM KCl in the presence and absence of various adenosine analogs. Perfusates, collected every 2 min, were assayed for substance P by radioimmunoassay. Exposure of tissue to 50 mM KCl produced an approximate three-fold increase in the release of substance P over basal release. This increase in release was calcium dependent. Perfusion of spinal cord tissues with either adenosine (10(-3) M). N6-cyclohexyladenosine (10(-5) M or 5 x 10(-5) M), 5'-N-ethylcarboxamide adenosine (10(-5) M) or L-N6-phenylisopropyladenosine (10(-5) M) did not significantly alter basal or potassium-stimulated release of SP when compared to controls. In contrast to the adenosine agonists, exposure of the spinal cord tissue to 10(-5) M morphine significantly reduced the potassium-stimulated release of substance P. Pretreatment of the slices with 10(-5) M theophylline or 8-phenyl-theophylline did not significantly attenuate the inhibition of substance P release produced by morphine. Theophylline alone (10(-5) M) had no significant effect on either basal or potassium-stimulated release of SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence supports the idea that somatostatin (SO) is a neurotransmitter or neuromodulator of primary afferent neurons involved in nociception. Since gamma-aminobutyric acid (GABA), norepinephrine, and morphine alter nociception at the level of the spinal cord, we examined whether these agents could alter the potassium-stimulated release of somatostatin from rat spinal cord slices. Male Sprague-Dawley rats were decapitated and a 2 cm segment of the lumbar spinal cord removed and chopped into 0.5 x 0.5 mm pieces and perfused at 37 degrees C in individual perfusion chambers with a modified Krebs-bicarbonate buffer at a flow rate of 0.5 ml/min. Perfusates were collected at 2 min intervals and assayed for SO using radioimmunoassay. Exposure of spinal cord tissue to 50 mM KCl resulted in a 3-fold increase in release of SO from a basal level of approximately 0.2 to 0.6 pg/mg tissue/min. This evoked release was calcium dependent. Pre-exposure of tissue to GABA at 10(-4) and 10(-5) M significantly inhibited the potassium-stimulated release of SO, but did not alter basal release. The GABA receptor antagonist, bicuculline methiodide, at 10(-5) but not 10(-6) M attenuated the GABA-induced inhibition of somatostatin release. Bicuculline methiodide alone did not significantly alter either basal or stimulated release. Neither baclofen (10(-5) M, 5 x 10(-5) M), norepinephrine (10(-5) M), nor morphine (10(-5) M) had any significant effect on basal or stimulated release of SO from spinal cord tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied whether morphine, norepinephrine (NE), 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) inhibit the potassium-stimulated release of substance P (SP) from rat spinal cord slices. Male Sprague-Dawley rats were decapitated and a 2-cm segment of lumbosacral spinal cord was removed, chopped into 0.5 X 0.5 mm pieces, weighed, placed in a perfusion chamber and perfused at 37 degrees C with a modified Krebs bicarbonate buffer. Perfusate was collected, lyophilized, then assayed for SP using radioimmunoassay. Exposure of spinal cord tissue to 50 mM KCl for 8 min produced a calcium-dependent increase in the release of SP from a basal level of approximately 0.1 pg/mg tissue/min to 0.3 pg/mg tissue/min. Morphine and NE at concentrations of 10(-4) and 10(-5) M did not alter basal release but caused a significant reduction in the potassium-stimulated release of SP. Naloxone (10(-5) M) and phentolamine (10(-5) M) did not affect SP release but attenuated the effects of morphine and NE, respectively. Naloxone did not antagonize the inhibition of release produced by NE nor did phentolamine block the effect of morphine, suggesting that the actions of the agonists are independent. In contrast, 5-HT and GABA at concentrations of 10(-4) M and 10(-5) M did not significantly alter the basal or potassium-stimulated release of SP. These results demonstrate a differential regulation of SP release in the spinal cord and support the hypothesis that morphine and NE may modify nociception, in part, by inhibiting the release of SP in the spinal cord.

Lorazepam, a dichloro-3-hydroxy-1,4-benzodiazepine, has been shown to be a potent anticonvulsant in animal models of epilsepsy and has minimal depressant effects on respiration and circulation in humans. The effects of this compound were studied in status epilepticus. Twenty-five patients were given intravenous lorazepam during status epilepticus of varying cause. Four or 8 mg of the drug controlled status in 22 of the 25 patients. Although single seizures recurred in 5 of the 22 patients, none experienced recurrence of status during a prolonged follow-up period. Transient respiratory arrest occurred in 1 patient, but no other significant complications were observed. Studies of plasma drug levels suggest that most patients attain good seizure control at concentrations between 30 and 100 ng per milliliter. Clinical observations indicate that repetitive injections are not required for continuing control of seizures in patients whose seizures are initially controlled. Lorazepam appears to be an effective and safe drug for treatment of status epilepticus, with a duration of control longer than that achieved with diazepam.

The purpose of this study was to determine if the use of drug profiles could improve drug utilization in an ambulatory care setting. Four clinics were provided drug profiles on each patient for a 6- to 9-month period. Evaluation of drug utilization and physician response to using the profiles was performed. The data indicated that, after the profiles were introduced, there was a reduction in the total number of medications and duplications in a majority of patients studied. In addition, physician time spent in reviewing the drug history was significantly reduced. Overall, the physicians who were surveyed felt that the profile helped them and improved patient care. These data support the conclusions that the integration of drug profiles within an ambulatory care setting can improve patient care and help the hospital with large outpatient workloads to realize significant savings.

Morphine HCl (10 micrograms/0.5 microliter) was injected into the right striatum, the caudal aqueduct and the region of the nucleus raphe magnus of the rat. Turnover of 5-hydroxytryptamine (5-HT) in the brain was assessed by fluorimetric estimation of 5-hydroxyindol-3-ylacetic acid following the administration of probenecid. Injection into the right striatum (a region containing 5-HT terminals) increased 5-HT turnover in the right, but not in the left striatum or in the anterior medulla. The pain threshold was unaltered. Injection into the aqueduct accelerated 5-HT turnover in the anterior medulla, but the striata and spinal cord showed no such change. Analgesia was pronounced. Injection of morphine into the region of the nucleus raphe magnus analgesia and increased 5-HT turnover in the posterior medulla and the spinal cord. The action on the cord must have been the result of the stimulation of cells in the raphe. The effects of the local injections of morphine on 5-HT turnover were antagonized by systemic naloxone (1-2 mg/kg) in all the regions studied. When morphine was administered subcutaneously three times a day for five days, tolerance developed to the analgesic effect of morphine (7mg/kg). However, tolerance to its acceleration of 5-HT turnover was only seen in the spinal cord, not in striatum or anterior and posterior medulla. When morphine was withdrawn, its effects on analgesia and 5-HT turnover in the spinal cord recovered simultaneously. The results emphasize the likely part played by the descending serotoninergic pathway in the analgesic effect of morphine.

A filtration technique for the gentle lysis of erythrocytes has been developed using cellulose triacetate membranes. When cell suspensions are filtered under nitrogen pressure, lysis occurs at the surface of the filter in such a way that the cell ghosts are retained on the filter. The contents of the cell are extruded through the pores of the filter without mixing with the cell suspension. Cell ghosts and intact erythrocytes have been collected on membranes and examined by electron microscopy. These preparations have the advantage of being free of the structural artifacts that result from centrifugation. In addition, the filter facilitates preparation for electron microscopy by providing a support for the sample during fixation and then dissolving during the dehydration of the sample.

The literature reviewed herein clearly demonstrates the poor correlation between drug dosing and the ability to achieve a specific serum drug concentration and between drug dosing and clinical response, especially for drugs with a narrow therapeutic index. There is, however, a better correlation between serum drug concentration and observed clinical response. Thus, clinicians use serum drug concentrations to more accurately dose drugs. Numerous dosing methods have been developed in an attempt to improve the relationship between dosing, serum drug concentration, and response. The major hypothesis is that if dosing methods can be developed that will accurately predict serum drug concentrations, these methods would be useful in improving clinical care. Several dosing methods have been developed including use of 'standard' doses, population-based predictive algorithms and nomograms, pharmacokinetic equations, and Bayesian feedback. Some of these methods are accurate and useful, whereas others are not. This review evaluates the commonly used dosing methods (some of which utilise serum drug concentration feedback for dosage estimation) for 5 drugs: gentamicin, digoxin, phenytoin, theophylline, and lignocaine (lidocaine). These drugs were selected since they exhibit a representative cross section of pharmacokinetic parameters and since they exhibit a representative cross section of pharmacokinetic parameters and since they have narrow therapeutic ranges. An individualised method and a Bayesian method, both using serum drug concentration feedback, appear most accurate and precise in dosing to achieve desired serum drug concentrations and, hence, response. Our bias from personal experience with this method and from published use by others is that the Bayesian method is more flexible in that any number of serum drug concentrations may be used to determine dose, instead of the 3 or more required for the individualised method. Although use of these methods would appear to be cost-effective in timely provision of health care by reduction of toxicity and hospital stay, only sparse data have been generated to support this conclusion. Thus, further examination of the cost-effectiveness of drug dosing methods is necessary to establish their place in routine patient care.

Evidence has accumulated over the past several years indicating that environmental factors can have a substantial influence on cardiovascular dynamics. It has been hypothesized by many investigators that through these influence environmental stressors may be important to the etiology and maintenance of cardiovascular diseases. Since the nervous system is intimately involved in the regulation of cardiovascular function it may be assumed that environmental influences on cardiovascular dynamics are to a large extent mediated by the nervous system. This assumption is supported by the literature reviewed which indicates that there are many nervous system nuclei and neurotransmitter systems involved in the regulation of cardiovascular dynamics which are also involved in an organisms adjustment to environmental stressors. The conclusion is reached that further multidisciplinary research will reveal underlying neurophysiological and neuropharmacological mechanisms responsible for stress induced cardiovascular disease and lead to new methods of treatment.

We assessed the accuracy of a Bayesian method in providing dosing regimens to achieve desired serum aminoglycoside concentrations. This method calculates individual kinetics based on serum drug concentration data. Performance was analyzed by determining accuracy, bias, correlations of observed to desired serum drug concentrations, and the ability to achieve a target serum drug concentration. We also compared results from the Bayesian method with those resulting from the use of the predictive algorithm portion of the computer program and with routine physician dosing. The Bayesian method resulted in a high correlation coefficient (r = 0.913) between observed and predicted serum concentrations. Analysis of peak aminoglycoside concentrations indicated that the Bayesian method was more accurate and less biased than the predictive algorithm portion of the program or routine physician dosing. A similar trend occurred for trough concentrations. Finally, there were no statistically significant differences between the predicted and observed peak (6.4 +/- 1.5 and 5.9 +/- micrograms/ml) and trough (1.2 +/- 0.9 and 1.4 +/- 0.8 micrograms/ml) serum aminoglycoside concentrations with the Bayesian dosing method. There were significant differences for peak concentrations with the predictive algorithm portion of the program and for peak and trough concentrations with physician dosing. These data demonstrate the accuracy of the Bayesian dosing method in attaining desired peak and trough serum aminoglycoside concentrations.

1 Pretreatment doses of barbitone, pentobarbitone, ethanol, and phenytoin (diphenylhydantoin) in non-tolerant rats produced increases in operant responding at low doses and at higher doses resulted in decreases in responding.2 Daily barbitone injections (100 mg/kg, i.p.) resulted in the development of functional tolerance to both the stimulant and depressant effects of barbitone on responding.3 Barbitone tolerance development did not result in any change in the brain or plasma pharmacokinetics of barbitone.4 Barbitone-tolerant rats were cross-tolerant to the behavioural effects of pentobarbitone, ethanol, and phenytoin. The dose-effect curves for all of these drugs were shifted to the right in tolerant rats, compared to non-tolerant rats.5 Comparison of the brain and plasma levels of these drugs in non-tolerant and tolerant rats provided a means of separating functional cross-tolerance from dispositional cross-tolerance. Barbitone-tolerant rats appeared to be functionally cross-tolerant to ethanol in that there was no change in the brain and blood ethanol levels at times when the degree of behavioural impairment was substantially reduced. In contrast to ethanol, cross-tolerance to phenytoin appeared to be due to a decrease in the brain and plasma levels (dispositional tolerance). Cross-tolerance to pentobarbitone appeared to be comprised of both functional and dispositional cross-tolerance.6 The usefulness of a multidisciplinary approach in the analysis of sedative hypnotic tolerance and cross-tolerance is discussed. It is concluded that without the concurrent determination of both brain and plasma drug levels it would not be possible to distinguish between functional and dispositional tolerance.

We studied whether antinociception produced by injection of morphine into the nucleus raphe magnus (NRM) or superfusion onto the spinal cord involved serotonergic neurons that descend from brainstem to spinal cord. Involvement of 5-hydroxytryptamine (5-HT)-containing neurons was determined by correlating morphine-induced analgesia with an increase in turnover of 5-HT and by determining if depletion of cord 5-HT with the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) could attenuate the antinociceptive effects of morphine. When injected directly into the NRM, 10 micrograms of morphine produced profound analgesia as measured by the paw-pressure technique, and significantly increased the turnover of 5-HT in both posterior medulla and spinal cord. Depletion of cord 5-HT to less than 10% of control concentrations attenuated the antinociceptive effect of morphine injected into the NRM. When various concentrations of morphine (1, 10 or 50 micrograms) were injected directly into the spinal subarachnoid space, a dose-dependent analgesia was observed. No change in 5-HT turnover in spinal cord was observed with any dose of morphine superfused onto the cord. In addition, depletion of cord 5-HT with 5,7-DHT did not alter the analgesic response to either 1 or 10 micrograms of intrathecal morphine. These results suggest that although 5-HT-containing neurons descending from brainstem into spinal cord are involved with analgesia produced by morphine injection into the NRM, they are not involved in the analgesia induced by applying morphine directly to the cord.

The purpose of this study is to evaluate the performance of a vancomycin dosing program in predicting dosages necessary to achieve desired serum vancomycin concentrations in a relatively large patient population. With the completion of initial performance evaluation, revised pharmacokinetic parameter estimates derived in the initial evaluation are used to reevaluate program performance. The program uses population estimates of vancomycin's volume of distribution (Vd) and clearance (Cl) to initially predict dosing, then individualizes those estimates by a Bayesian algorithm (iterations) which uses dosing and the resulting serum vancomycin concentration data. Use of the Bayesian forecaster with one iteration significantly increases the calculated Cl value as compared with population estimates; two and three iterations significantly increase both Vd and Cl when compared with population estimates. Absolute values of the predicted minus observed peak serum vancomycin concentrations (accuracy) are 17.7 +/- 14.0, 6.1 +/- 3.6, and 3.4 +/- 2.1 mg/L for dosing using population estimates, Bayesian with one iteration, and Bayesian with two iterations, respectively. Similarly, accuracy of predictions for trough concentrations is 13.8 +/- 12.4, 3.5 +/- 3.2, and 3.2 +/- 2.6 mg/L for each method, respectively. Bias of dosing predictions in achieving desired peak and trough serum vancomycin concentrations is also significantly reduced by using the Bayesian algorithm. Use of the mean Vd and Cl values from three iterations as the starting parameters in a new group of 12 patients significantly improves program performance when compared with use of initial population parameters. Time of sampling for peak serum concentrations has no effect on program performance. In patients with impaired renal function, use of population estimates resulted in less accurate dosing prediction, but this less accurate performance was not observed with use of the Bayesian forecaster. These data demonstrate the accuracy and lack of bias in individualized dosing predictions using the Bayesian dosing method and the ability of revised pharmacokinetic parameter estimates to improve performance.

We studied whether antinociception produced by injection of morphine into the nucleus reticularis paragigantocellularis (NRPG) or by superfusion onto the spinal cord involved norepinephrine (NE)-containing neurons that descend from brainstem into the spinal cord. Spinal cord NE concentrations were depleted with the neurotoxin, 6-hydroxydopamine, and antinociception was measured following morphine injection into NRPG or onto spinal cord. Depletion of cord NE by approximately 90% did not attenuate the antinociceptive effect of either 2 or 10 micrograms of morphine injected intrathecally. In contrast, the depletion did significantly attenuate the antinociceptive effect of 2.5 micrograms morphine injected bilaterally into the NRPG. These results suggest that NE-containing neurons descending from brainstem nuclei into the spinal cord are not important in the analgesia produced by injecting morphine directly onto the spinal cord but may be involved with analgesia produced by morphine injection into the NRPG.

The derived pharmacokinetic variable estimates from a Bayesian aminoglycoside dosing program were compared with those from the Sawchuk-Zaske method to determine which variable estimates were the most accurate in fitting the test dose and in predicting subsequent peak and trough serum concentrations. Data on 17 patients with moderately impaired but stable renal function were analyzed. All patients received gentamicin sulfate for treatment of their infections. To determine the individualized variables using the Bayesian program, demographic data, dosing history, and one (midpoint), two (peak and trough), or four serum drug concentrations were entered into the program. The Sawchuk-Zaske method used three serum concentrations determined following a first dose or four concentrations before and after a subsequent dose to derive individualized pharmacokinetic variables. The estimates of pharmacokinetic variables determined using the Bayesian method with one, two, or four serum concentrations did not differ significantly from those obtained using all the available serum concentrations with the Sawchuk-Zaske method. Although the actual numeric differences of prediction, absolute, and squared errors for fitting the test dose were minimal, significant differences were seen. All methods were similar in predicting serum concentrations from continued dosing. For the prediction error from continued dosing, a slight but significant difference was observed with the Bayesian method using one serum concentration when compared with the other methods. The Bayesian method using one, two, or four serum gentamicin concentrations individualized pharmacokinetic variables as well as the Sawchuk-Zaske method.