Pain: neuroanatomy, chemical mediators, and clinical implications.

Most pain information begins at simple, naked nerve endings called nociceptors that form a functional pain unit with nearby tissue capillaries and mast cells. Tissue injury causes these nerve terminals to depolarize, an event that is propagated along the entire afferent fiber eventuating in sensory impulses reaching the spinal cord. This firing of primary afferent fibers at the site of tissue injury causes axonal release of vesicles containing neuropeptides such as substance P, which acts in an autocrine and paracrine manner to sensitize the nociceptor and increase its rate of firing. Cellular damage and inflammation increase concentrations of other chemical mediators such as histamine, bradykinin, and prostaglandins in the area surrounding functional pain units. These additional mediators act synergistically to augment the transmission of nociceptive impulses along sensory afferent fibers. Primary fibers travel from the periphery to the dorsal horn where they synapse on secondary neurons and interneurons. When activated, interneurons exert inhibitory influences on further pain signal trafficking. Efferent supraspinal influences, in turn, determine the activity of interneurons by releasing a variety of neurotransmitter substances, thus resulting in a high degree of modulation of nociception within the dorsal horn. Events occurring in the periphery and in the dorsal horn can cause a dissociation of pain perception from the presence or degree of actual tissue injury. These phenomena involve many chemical mediators and receptor systems, and can increase pain experience qualitatively, quantitatively, temporally, and spatially. The complexity and plasticity of the nociceptive system can make clinical management of pain difficult. Undestanding the structure and chemical signals associated with this system can improve the use of existing analgesics and provide targets for development of newer and more specific pain-fighting drugs.

A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Rizatriptan Multiple Attack Study Group.

OBJECTIVE: To examine the safety and efficacy of rizatriptan 10 mg PO in the treatment of multiple migraine attacks. BACKGROUND: Rizatriptan is a potent and rapidly absorbed 5-HT1B/1D receptor agonist. Efficacy and general safety have been examined in controlled trials treating single migraine attacks. In the current placebo-controlled study, we report constancy of safety and efficacy of rizatriptan for patients treating four discrete migraine attacks. METHODS: Patients with moderate or severe migraine (n = 473) were randomized to one of five sequence groups, in which each patient was to treat four migraine attacks. Patients in four groups received rizatriptan 10 mg for three of four attacks and placebo for the remaining attack. Patients in the fifth group received rizatriptan 10 mg for four attacks. Headache severity, functional disability, and migraine symptoms were measured immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours postdose. RESULTS: After the first attack, response rates were 77% for rizatriptan and 37% for placebo (p < 0.001). Similar efficacy of rizatriptan, ranging from a 75 to 80% response, was observed in each of the subsequent attacks with no evidence of tolerance to therapeutic effects. Most patients (93%) responded to rizatriptan 10 mg during the first or second attack. Adverse experiences were generally mild and transient, the most common being dizziness and somnolence. Incidence of adverse experiences per attack decreased after the first attack. CONCLUSIONS: Rizatriptan 10 mg PO is efficacious and generally well tolerated in acute migraine. Its efficacy is maintained throughout the treatment of multiple, discrete migraine attacks.

The dental scientist model.

A case has been presented for strengthening the science-base of the future dentist. Such a development is essential and inevitable and we must plan the changes in the dental education continuum that will facilitate it. Transfer of advanced clinical training to mandatory post-doctoral education will control the economic impact of the change and improve the education of the dentist tomorrow.

Uranium-series dated authigenic carbonates and acheulian sites in southern egypt.

Field investigations in southern Egypt have yielded Acheulian artifacts in situ in authigenic carbonate deposits (CaCO(3)-cemented alluvium) along the edges of nowaggraded paleovalleys (Wadi Arid and Wadi Safsaf). Uranium-series dating of 25 carbonate samples from various localities as far apart as 70 kilometers indicates that widespread carbonate deposition occurred about 45, 141 and 212 ka (thousand years ago). Most of the carbonate appears to have been precipitated from groundwater, which suggests that these three episodes of deposition may be related to late Pleistocene humid climates that facilitated human settlement in this now hyperarid region. Carbonate cements from sediments containing Acheulian artifacts provide a minimum age of 212 ka for early occupation of the paleovalleys.

The effects of exclusion of epithelium from healing periodontal pockets.

Epithelium was excluded experimentally from artificially induced periodontal pockets by cutting off the crowns of vital teeth and covering the roots with mucoperiosteal flaps. This procedure was carried out on 58 teeth in eight rhesus monkeys and specimens recovered at from five to 36 weeks postoperatively. Thirty-eight (66%) of the teeth remained completely covered by soft tissue for the duration of the experiment. Up to 4.4 mm (mean = 0.9 mm) of new attachment with cementum and attached collagen fibers was found on both the sides of the roots and the cut ends, but root resorption and downgrowth of epithelium over root surfaces were about equally common. Thus, even when epithelium is excluded from healing periodontal pockets, reattachment with new cementum and attached collagen fibers is not consistently achieved, even after periods of 36 weeks. Root resorption and ankylosis are major complications. Although most new attachment appears to result from cells originating in the periodontal ligament, it can also arise from cells from the gingival connective tissue.

Neuromyopathy in venous insufficiency.

Since July, 1985, the authors have studied 23 patients with history and physical findings of venous insufficiency syndrome (VIS) confirmed by venous pressure, muscle biopsy, ascending and descending venography, electromyography, and nerve conduction velocity studies. Clinically, swelling appears to be the most important symptom, along with high venous pressure, particularly ambulatory venous pressure, correlated with venography findings. Muscle atrophy was present in 18 cases. Electromyography and nerve conduction velocity studies yielded abnormal findings in 20 of 23 cases. The authors suggest that nerve conduction velocity and EMG studies could perhaps be used as noninvasive tests for diagnosis and follow-up of cases with VIS.

Lipid-soluble and water-soluble beta-blockers. Comparison of the central nervous system depressant effect.

The sedative effects of a relatively lipid-soluble and a water-soluble beta-blocker were compared in 20 male hypertensives, 30 to 60 years old. In a blinded, randomized, crossover study, critical flash fusion frequency and computerized Stroop Word Test were used to assess psychomotor function parameters during a drug-free control day and then following 14 days of either metoprolol, 150 mg daily, or atenolol, 100 mg daily, treatment. Both drugs caused subtle but significant reductions in both parameters of sedation (critical flash fusion frequency and computerized Stroop Word Testing). Sedation was significantly related to serum concentrations of both drugs. The maximum drug-induced change was 17.2% +/- 9% for metoprolol and 19.6% +/- 3% for atenolol. The duration of effect was six hours after atenolol and two hours after metoprolol. Blood pressure control for all patients was similar during both treatment phases. These results demonstrate that relative lipid solubility does not reliably predict the neurologic effects of beta-blockers. The intensity of drug-induced sedation was similar, but the water-soluble agent produced a longer duration of sedative activity.

Accumulation and washout kinetics of valproic acid and its active metabolites.

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250-mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady-state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono-desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half-life of each metabolite was longer than the elimination half-life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.

Attenuation of response to mental stress in patients with essential tremor treated with metoprolol.

The response to mental stress in patients with benign essential tremor is an exaggeration of the resting tremor. We have studied the ability of metoprolol tartrate to attenuate specifically the tremorgenic response to mental stress in five patients with essential tremor who were each studied on four occasions. Treatment regimens consisted of 0-, 25-, 50-, and 75-mg doses of metoprolol tartrate, given twice daily for seven- to ten-day periods. Tremor was measured while patients were resting comfortably and then again following mental stress over eight-hour study periods. During the baseline study period, the investigational mental stress consistently exaggerated tremor in each patient. Metoprolol treatment reduced both the resting tremor and tremor following mental activity, but the drug-induced change in the response to mental stress was more pronounced than the drug-induced reduction in resting tremor. The ability of metoprolol to blunt the response to mental stress was associated with serum concentrations of the drug. The time courses of metoprolol serum concentrations were similar to the time course of metoprolol's ability to blunt the response to mental stress. Metoprolol possesses the ability to blunt the tremorgenic response to mental stress in patients with essential tremor, but the duration of this effect lasts less than seven hours after administration of a dose.

Dental caries and staining after twenty-eight months of rinsing with stannous fluoride or sodium fluoride.

The aim of this study was to compare the effects of daily mouthrinsing with aqueous solutions of 0.05% NaF or 0.1% SnF2 on dental caries and tooth staining. The study population consisted of 437 children, aged from 12 to 15 years at baseline, residing in a non-fluoridated community. By stratified random sampling, the subjects were divided into two groups, one group rinsing daily under supervision for 28 months with the NaF solution and the other with the SnF2 solution. The SnF2 group exhibited four to five times as much extrinsic stain as did the NaF group, although the stains were quite mild and not explicitly distinguishable between groups. There were no statistically significant differences between the two groups in terms of total DMFS. However, the increment of pit and fissure caries was 0.9 surfaces fewer for the SnF2 group (p = 0.04), while the increment of smooth surface caries was 0.6 surfaces fewer for the NaF group (p = 0.04). These data suggest that there may be a difference in mechanism of action between SnF2 and NaF rinses.

The relationship between serum concentrations and central nervous system actions of metoprolol.

The relationship between serum levels of metoprolol, hydroxymetoprolol and changes in psychomotor function as measured by standard reaction time and flash fusion frequency was studied. Blinded subjects were given placebo or 150 mg dose of metoprolol and crossed over on the next study day. Flash fusion frequency, reaction time, and serial blood levels of metoprolol and hydroxymetoprolol were collected. Oral dosing of metoprolol produced no significant changes in reaction time. However, significant decreases in flash fusion frequency were observed from 2 to 6 hours after the dose. Changes in flash fusion frequency were related to levels of metoprolol. Flash fusion frequency changes lagged behind the time course of metoprolol concentrations. The nadir of variance in the metoprolol plus hydroxymetoprolol concentration-effect relationship occurred when potency of hydroxymetoprolol was assumed to be 0.3 of metoprolol. These data suggest that the central nervous system actions of metoprolol are related to metoprolol serum levels and occur at low metoprolol concentrations. However, CNS effects of metoprolol do not intensify at high concentrations. Further CNS activity of hydroxymetoprolol may explain the lag seen in the relationship between concentration and CNS effect.

Metoprolol and alpha-hydroxymetoprolol concentrations and reduction in essential tremor.

The relationship between reductions in essential tremor and concentrations of metoprolol and alpha-hydroxymetoprolol was examined in five patients with essential tremor after treatment with 0, 25, 50, and 75 mg metoprolol twice daily for 7 to 10 days. Serum concentrations of metoprolol and alpha-hydroxymetoprolol were measured simultaneous to serial accelerometry measurements of tremor over 8-hr periods. There was a relationship between degree of tremor reduction and steady-state metoprolol concentration. Time course of the drug and metabolite concentration correlated better with the time course of effect than with the time course of metoprolol concentration alone. Data suggest that the alpha-hydroxymetabolite of metoprolol may contribute to the reduction in essential tremor.

Effect of daily rinsing with stannous fluoride on plaque and gingivitis: final report.

Two groups of children, ages 12 to 15, rinsed daily for 28 mo with aqueous fluoride solutions, one group using 0.05% sodium fluoride (NaF) and the other group using 0.1% stannous fluoride (SnF2). The SnF2 group had less plaque accumulation after four mo, but no difference was apparent at 16 and 28 mo. Gingivitis was less severe in the SnF2 group throughout the study, although the difference did not reach statistical significance. The 0.1% SnF2 solution, used daily as a mouthrinse, inhibits plaque formation, although this inhibitory effect is not apparent after 16 mo of rinsing.

High-performance liquid chromatographic determination of metoprolol and alpha-hydroxymetoprolol concentrations in human serum, urine, and cerebrospinal fluid.

A sensitive and simplified high-performance liquid chromatographic procedure was developed for the simultaneous quantification of metoprolol and alpha-hydroxymetoprolol in human serum, as well as cerebrospinal fluid and urine. Following protein precipitation with trichloroacetic acid, the sample was alkalinized with 1 M NaOH and extracted with dichloromethane. The mobile phase consisted of acetonitrile-water (50:50) containing 0.005 M 1-heptanesulfonic acid in 0.001% acetic acid. Using pronetalol as an internal standard, compounds were quantitated using fluorescence detection at 230 nm with a 300-nm emission filter and 0.02 AUFS. Extraction recovery is approximately 80% for both compounds. The lower limits of detection are 5 ng/mL and 4 ng/mL for metoprolol and alpha-hydroxymetoprolol, respectively.