Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators--identification of a novel pharmacophore.

The naturally occurring acylated phloroglucinol derivative hyperforin was recently identified as the first specific canonical transient receptor potential-6 (TRPC6) activator. Hyperforin is the major antidepressant component of St. John's wort, which mediates its antidepressant-like properties via TRPC6 channel activation. However, its pharmacophore moiety for activating TRPC6 channels is unknown. We hypothesized that the phloroglucinol moiety could be the essential pharmacophore of hyperforin and that its activity profile could be due to structural similarities with diacylglycerol (DAG), an endogenous nonselective activator of TRPC3, TRPC6, and TRPC7. Accordingly, a few 2-acyl and 2,4-diacylphloroglucinols were tested for their hyperforin-like activity profiles. We used a battery of experimental models to investigate all functional aspects of TRPC6 activation, including ion channel recordings, Ca(2+) imaging, neurite outgrowth, and inhibition of synaptosomal uptake. Phloroglucinol itself was inactive in all of our assays, which was also the case for 2-acylphloroglucinols. For TRPC6 activation, the presence of two symmetrically acyl-substitutions with appropriate alkyl chains in the phloroglucinol moiety seems to be an essential prerequisite. Potencies of these compounds in all assays were comparable with that of hyperforin for activating the TRPC6 channel. Finally, using structure-based modeling techniques, we suggest a binding mode for hyperforin to TRPC6. Based on this modeling approach, we propose that DAG is able to activate TRPC3, TRPC6, and TRPC7 because of higher flexibility within the chemical structure of DAG compared with the rather rigid structures of hyperforin and the 2,4-diacylphloroglucinol derivatives.

Historical biogeography and speciation in the Creole wrasses (Labridae, Clepticus).

We tested whether vicariance or dispersal was the likely source of speciation in the genus Clepticus by evaluating the evolutionary timing of the effect of the mid-Atlantic barrier, which separates C. brasiliensis and C. africanus, and the Amazon barrier, which separates C. parrae and C brasiliensis. Genetic data from three mitochondrial genes and one nuclear gene were used. Mitochondrial genes separated Clepticus into three well supported clades corresponding to the three recognized allopatric morpho-species. All analyses provided consistent support for an initial separation (~9.68 to 1.86 mya; 4.84% sequence divergence) of the Caribbean and South Atlantic lineages, followed by a much more recent divergence (~ 0.60 to 0.12 mya; 0.3% sequence divergence) of the Brazilian and African sister morpho-species. Both these phylogenetic events occurred well after the formation of the two barriers that currently separate those three allopatric populations. The planktonic larval duration of these species (35-49 days) and coastal pelagic habits may have facilitated dispersal by this genus across those dispersal barriers after they formed.

Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression.

The efficacy of nefazodone in prevention of relapse of depression was evaluated in a 36-week double-blind, placebo-substitution, continuation treatment trial. After 16 weeks of acute, single-blind treatment with nefazodone, 131 patients responding to treatment and in stable remission were randomized in a 36-week double-blind trial to either nefazodone (n = 65) or placebo (n = 66). Patients were defined as having relapsed if they had a total score > or = 18 on the 17-item Hamilton Depression Scale on two consecutive visits or if they discontinued treatment for lack of efficacy. Relapse rates were significantly lower for patients randomized to continued nefazodone treatment than for patients switched to placebo. Kaplan-Meier estimates of relapse rates 9 months (36 weeks) after the end of acute treatment were 1.8% for nefazodone versus 18.3% for placebo (P = 0.009) by the Hamilton Depression Scale and 17.3% versus 32.8% (P = 0.028) by discontinuation for lack of efficacy. The mean modal dose of nefazodone was 412 mg/day at study endpoint. These results demonstrate the clinical effectiveness of up to 1 year's treatment (16 weeks acute and 36 weeks continuation) with nefazodone in depressed patients. Long-term efficacy of nefazodone was accompanied by a good safety profile without any weight gain and with minimal symptoms of withdrawal upon abrupt discontinuation of treatment.

A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients.

We report the results of a double-blind study comparing the efficacy and safety of low-dose (10-50 mg) and high-dose (20-100 mg) ranges of gepirone-extended release (ER) and placebo in 145 outpatients with major depressive disorder. At multiple time points and endpoint (Week 6), statistically significant reductions in Hamilton Rating Scale for Depression (HAM-D) scores were recorded for high-dose gepirone-ER compared to placebo. Analysis of the 17-item HAM-D and 28-item HAM-D scores indicated a relatively early onset of antidepressant efficacy with statistically significant results at treatment Weeks 1, 2, 4, and 6. A rapid response was evident in the high-dose group, beginning at Week 1 (p < .05). The most frequently reported adverse experiences were headache, nausea, dizziness, and insomnia. The results indicate that gepirone-ER is clearly superior to placebo in terms of antidepressant efficacy. When used at higher doses, gepirone-ER appears to be efficacious, safe, and well-tolerated in depressed out-patients.

Comparison of the effects on pupil size and accommodation of three regimens of topical dapiprazole.

BACKGROUND: Patients who have their pupils dilated for an eye examination traditionally have to wait several hours before their pupils return to normal size and their blurred vision (caused by paralysis of accommodation) resolves. Earlier studies with dapiprazole have demonstrated an accelerated reversal of dilatation. METHODS: Three regimens of dapiprazole were studied to determine the effects on pupil diameter and accommodation after mydriasis produced by 2.5% phenylephrine and 0.5% tropicamide. Test regimens included one drop and 1 + 1 drop regimens, compared with a 2 + 2 drop reference regimen. Dapiprazole was administered in one eye and placebo in the other. Mean change from baseline was analysed for pupil diameter and accommodation at various time points after drug administration. Also, for the same variables, 90% confidence intervals for the areas under the curve (AUC) were computed. RESULTS: Both test regimens were equivalent to the reference regimen on the basis of mean change from baseline for pupil diameter and accommodation at individual time points, and for the mean AUC. Most signs and symptoms (injection, stinging, burning, lid oedema, and ptosis) were less frequent in the test regimen treated eyes. There was no significant interaction between regimen and eye colour. CONCLUSION: This study indicates that a lower dosage (for example, one drop) is also efficacious and has the added benefit of fewer side effects.

A fixed-dose study of adinazolam-SR tablets in generalized anxiety disorder.

1. This four-week, randomized, double-blind, multicenter study compared the efficacy and safety of adinazolam-SR, at three dosage levels, with placebo. Forty (40) patients were randomized at our site: 10 to adinazolam 30 mg/day, 10 to 60 mg/day, 10 to 90 mg/day, and 10 to placebo. All patients were moderately anxious with Hamilton Anxiety Scale (HAM-A) scores of > or = 21 at baseline. 2. The data were analyzed by pooling the three adinazolam groups and comparing them with the placebo group using t-tests. HAM-A scores decreased significantly more in the pooled adinazolam-SR treatment group than in the placebo group at both Week one (p < .02) and at Week two (p < .01), as well as at endpoint (p < .03). 3. At endpoint the adinazolam-treated group included 8 "responders" (> or = 50% reduction on the baseline HAM-A score) while none of the placebo patients were responders (p < .05). Dose-response effects were evaluated and relationships were not statistically significant. 4. The results indicate that adinazolam-SR was clearly superior to placebo for the treatment of patients suffering from Generalized Anxiety Disorder.

Are selective serotonin reuptake inhibitors well tolerated in somatizing depressives?

This retrospective evaluation included 89 patients who participated in two independent clinical investigations of the antidepressant medications paroxetine and fluoxetine. Baseline gastrointestinal (GI) somatic symptoms, as indicated by the baseline scores on the Hamilton Rating Scale for Depression (HAM-D) items 11, 12, and 16, the Symptom Checklist (SCL) items 19 and 40, and the Covi Anxiety Scale somatic anxiety item were analyzed for their discriminative ability in predicting which patients would subsequently develop adverse GI side effects on medication. Subjects with baseline complaints of nausea or upset stomach (SCL #40), GI somatic symptoms (HAM-D #11 and #12, Covi somatic anxiety), or weight loss (HAM-D #16) were not statistically more likely to develop GI side effects on paroxetine or fluoxetine. Only a baseline complaint of appetite loss (SCL #19) was associated with subsequent GI side effects on paroxetine to a statistically significant degree (p < .05).

Predictors of placebo response: a retrospective analysis.

This retrospective evaluation involved 197 patients from independent clinical investigations of four antidepressant medications. Six variables were analyzed for their discriminative utility in predicting placebo response rates: gender; marital status; age; education; duration of illness; and severity of depressive symptomatology, as measured by Hamilton Rating Scale for Depression (HAM-D or HDRS) scores. Men were slightly more responsive to placebo than were women (29.8%, n = 94 vs. 24.3%, n = 103). Married patients demonstrated the highest probability of a positive placebo response (38.15%, n = 76), as compared with widowed/separated/divorced (21.9%, n = 73) or single (16.7%, n = 48) patients. A trend toward an increased probability of placebo response was detected for patients aged 60 and above (35.7%, n = 14). Educational level achieved and duration of illness were not predictive. Severity of illness proved most noteworthy, with the placebo response rate higher in the more mild patients (40.8%, n = 27 vs. 23.4%, n = 77).

Massive strychnine intoxication: serial blood levels in a fatal case.

A fatal case of strychnine intoxication is reported. The patient expired despite early aggressive management and prevention of metabolic complications. Serial blood levels are reported. In contrast to a previous report describing first order elimination kinetics, our data suggest that strychnine follows Michaelis-Menton elimination kinetics. The case illustrates the rapid, dramatic course of severe strychnine ingestions. A review of the toxicokinetics, mechanism of action and treatment of strychnine intoxication follows.

Analysis of base station morphine orders: assessment of supervising physician consistency.

Paramedic contact with a base station should gemerate consistent recommendations reflecting a consensus of base station physician care. In our urban EMS system, paramedics must contact a single base station to provide morphine sulfate (MS) for a patient with chest pain. We performed a retrospective cohort analysis of all prehospital MS requests for chest pain to determine the consistency of the circumstances for which the paramedic team was refused MS. These MS requests represented 123 of the 1,715 (7%) on-line physician consultations during the 6-month study. Only 15 of the 123 (12%) MS requests were refused. Neither the mean patient age, sex distribution, or presenting vital signs correlated with MS refusal. A maximum estimate of transport time to the hospital of less than or equal to 5 minutes was noted for 7 of 15 (47%) medication refusals compared to only 11 of 96 (11%) approvals with documented estimated transport times (P less than or equal to 0.005). A simultaneous request for nitroglycerin (NTG) was noted for 6 of the 15 (40%) medication refusals and 15 of the 108 (14%) approvals (P less than 0.05). We found refusal of MS administration to be uncommon. Supervising physicians tended to refuse MS when the transport time was short and when NTG was requested for concomitant administration. We also noted physician inconsistencies in refusal scenarios. These findings can guide physician consensus development to avoid sending mixed messages to paramedics.

Functional airway obstruction presenting as stridor: a case report and literature review.

We report the case of a young man who presented to 3 emergency departments with apparent upper airway obstruction and was intubated each time before being diagnosed with paradoxical vocal cord motion. His previous discharge diagnoses were laryngeal edema secondary to anaphylaxis, even though he had no other objective findings of IgE-mediated disease. Flexible fiberoptic laryngoscopy demonstrated tight apposition of the vocal cords during inspiration while symptomatic, but normal movement when asymptomatic. Psychiatric evaluation revealed severe posttraumatic stress disorder. Of the approximately 41 reported cases of functional airway obstruction in the medical literature, only two have been adult males and none have been associated with posttraumatic stress disorder. The current literature is reviewed, and an approach to evaluation and management of such patients is provided.

Evaluation of a sick child day care program: lack of detected increased risk of subsequent infections.

A day care center for the short term care of mildly ill children opened in Minneapolis in October, 1985. We conducted a prospective study to evaluate the risk for study participants of acquiring subsequent infections as a result of possible exposure to other infectious agents while at the center. Between June, 1986, and August, 1987, we determined the rates of subsequent infections for 118 children attending the day care center (center-based children) and compared them with rates of subsequent infections for children participating in a home-based sick child care program (home-based children). Of 105 center-based children potentially exposed to respiratory illness while at the center, 24 (23%) developed subsequent respiratory illness compared with 17 (16%) of the matched home-based children (odds ratio, 1.5; 95% confidence interval, 0.7, 3.1). Of 17 center-based children potentially exposed to gastrointestinal illness, 1 (6%) developed subsequent gastrointestinal illness compared with one (6%) of the matched home-based children (odds ratio, 1.0; 95% confidence interval, 0.06, 16.0). Of 12 pairs of children, where the center-based child was potentially exposed to chickenpox while at the center and both were susceptible to chickenpox, 1 center-based child (8%) developed chickenpox compared with 2 home-based children (17%) (odds ratio, 0.5; 95% confidence interval, 0.04, 5.5). We were not able to demonstrate that children who attended the sick child day care center were at significantly increased risk of developing subsequent infections when compared with a matched group of children who did not attend the center.

Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: a prospective study.

The development of acute dystonic reactions was monitored in 202 acute psychiatric patients during initial hospitalization and treatment with various neuroleptic drugs in a prospective study. Data were analyzed to determine the effect of anticholinergic prophylaxis, age, sex, and type and dosage of neuroleptic on the incidence of dystonic reactions. Nearly 90% of dystonic reactions occurred by the third day of treatment. The overall trend favored the prophylactic use of antiparkinsonian drugs with all neuroleptics, and the effect of this prophylaxis with haloperidol was statistically significant. Because anticholinergic prophylaxis was used more often when larger dosages of neuroleptics were prescribed, an added effect in the observed trend for fewer dystonic reactions is suggested.

Hair analysis for detection of phencyclidine in newly admitted psychiatric patients.

The authors implemented a new procedure for analyzing phencyclidine (PCP) content in hair. They compare the results of analyses of hair with results of analyses of blood and urine in 47 patients newly hospitalized with acute psychiatric illness. Hair analysis identified 11 patients who had used PCP, and blood and urine analyses did not identify any among the sample population. In three patients, the results of hair analysis aided in establishing a diagnosis of PCP intoxication. The authors discuss interpretations of their findings and psychiatric applications of this new technique.

The surgery of pulmonary artery "sling".

Two consecutive infants with pulmonary artery sling underwent successful surgical repair utilizing a median sternotomy for surgical exposure and adjunctive aortopexy. Bronchoscopy demonstrated severe tracheomalacia in both patients which was corrected under direct bronchoscopic control. Median sternotomy (rather than recommended left thoracotomy) provided perfect exposure of the pulmonary artery at its bifurcation thus permitting easy reconstruction of pulmonary artery. Aortopexy eliminated postoperative respiratory symptoms. Both patients are well.

Thymectomy for myasthenia gravis: a changing perspective.

A review of 28 patients with nonthymomatous myasthenia gravis who underwent thymectomy at the University of Colorado Health Sciences Center, Denver, from 1967 to 1979 shows significant stepwise changes in management and results. Comparison among three periods--period 1 (1967 to 1971), when thymectomy competed with prednisone,which were not given in the perioperative period (seven patients); period 2 (1974 to 1976), when thymectomy was followed by six months of prednisone therapy (ten patients); and period 3 (1977 to 1979), when prednisone was also given to prepare the patients for thymectomy (11 patients)--demonstrated a decreasing need for tracheostomy and respiratory support (86% v 10% v 0%), shorter stay in the intensive care unit (21 v 3 v 1 day), and shorter hospitalization (36 v 13 v 4 days). Remission or marked amelioration of symptoms occurred in 56% of group 1 and 100% of both groups 2 and 3. Earlier application of thymectomy and its performance through a short upper transverse sternotomy incision also contributed to the improved results.

Fractures of the hip in children: a review of forty cases.

In a series of children's hip fracture seen over a 27-year-period, there were 39 patients (40 fractures) with a mean age of 8.9 years followed for an average 7 years. After an initial period of traction, 50% of the fractures were treated in a spica cast, 40% by internal fixation, and 10% by bed rest. Overall, there were 65% good results, 25% fair and 10% poor. All nondisplaced fractures were found to have a good result, while only one-half of displaced fractures were considered a good result. The complications were premature epiphyseal closure 23%, avascular necrosis 17%, coxa vara 12.5%, and nonunion 7.5%. Intertrochanteric fractures should be treated in traction followed by a spica cast. All other displaced fractures should be reduced and internally fixed. The hip joint capsule is opened in those transepiphyseal and transcervical fractures for which closed reduction has been unsuccessful. Spica casts are used to protect the fixation until roentgenograms show healing. Nondisplaced fractures may be treated non-operatively but must be watched closely for varus angulation. Threaded pins or lag screws are the devices of choice except in transepiphyseal fractures where smooth pins can be used to cross the physis. Nail-plates should be avoided.