Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (delta max) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, delta max for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Effect of oral ondansetron on total cholecystokinin plasma levels following CCK-4 panic challenge procedure in healthy men.

OBJECTIVE: To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men. METHODS: Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo. RESULTS: Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment. CONCLUSION: Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.

High-resolution liquid chromatographic method using ultraviolet detection for determination of ondansetron in human plasma.

This paper describes a simple technique for extraction and a sensitive high-performance liquid chromatographic method for separation and quantitation of ondansetron in human plasma. The procedure involved liquid-liquid extraction of ondansetron from plasma, reversed-phase HPLC separation and ultraviolet detection at 305 nm. The internal standard method was applied for quantitation. The recovery of ondansetron was >85%. Linearity was good throughout the concentration range anticipated in human plasma from investigations in panic disorder (0.5-15 ng/ml, r2 ranging from 0.9953 to 0.9988). This method was applied to the determination of plasma concentrations of ondansetron in humans.

Lack of presystemic metabolism of nifedipine in the rabbit.

In humans, oral bioavailability of nifedipine has been reported to be around 60%, although the organ(s) contributing to its first-pass metabolism have not been determined. The aim of this study was to determine in vivo, in anesthetized and conscious rabbits the role of the intestine, liver, and lungs in the first-pass metabolism of nifedipine. To assess the extraction of nifedipine by the intestine, liver, and lungs, nifedipine was administered before and after each organ, and serial blood samples were withdrawn from an artery. In conscious rabbits, the systemic clearance of nifedipine injected into a lateral vein of an ear was 14.6 +/- 1.6 ml/min per kg, a value that was slightly decreased by anesthesia. In anesthetized rabbits, compared to the clearance estimated when nifedipine was administered into the thoracic aorta, the administration of nifedipine into a jugular vein, into the portal vein, or into the portal vein, or into the duodenum did not increase the value of the systemic clearance. In conscious rabbits, the clearance of nifedipine estimated when the drug was administered into the duodenum, the peritoneum, the portal vein, or into the jugular vein was identical to the clearance calculated when the drug was injected into the thoracic aorta. In vitro, nifedipine was metabolized in liver and intestinal epithelial cells homogenates but not in lungs or kidneys. We concluded that in the rabbit, oral nifedipine is not subjected to a first-pass metabolism, even though the intestine and the liver may contribute to nifedipine systemic clearance.

Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine.

In this double-blind, randomized, crossover, placebo-controlled study, the effect of multiple oral doses of acetaminophen on lamotrigine disposition was examined in healthy volunteers. Eight volunteers received two single 300 mg oral doses of lamotrigine, administered 20 days apart. Acetaminophen (2.7 gm/day) or placebo was taken for 24 hours before and continued for 10 days after each lamotrigine dose. Area under the plasma concentration-time curve for lamotrigine [AUC(O-infinity)] and lamotrigine half-life were statistically decreased by 20% (229.0 +/- 62.5 micrograms.hr/ml versus 191.2 +/- 42.1 micrograms.hr/ml, p less than 0.01) and 15% (35.7 +/- 9.3 hours versus 30.2 +/- 7.3 hours, p less than 0.01), respectively, when concurrently administered with acetaminophen. There was no significant difference in the peak plasma concentration or the time to reach peak plasma concentration. The percentage of the dose of lamotrigine recovered in the urine (total) was significantly higher during the acetaminophen treatment (65.9% +/- 12.3% versus 72.5% +/- 5.7%, p = 0.048). Acetaminophen seems to facilitate lamotrigine removal through a yet to be determined mechanism(s).

Bilateral and extensive xanthelasma palpebrarum in a young man.

A 25-year-old white man had been aware since childhood of yellow discolorations of the medial aspects of his upper lids. The skin changes progressively spread to involve all four eyelids, the inferior skin of the brow, and the lateral and medial canthal skin. The clinical diagnosis was extensive bilateral xanthelasmas . The patient had no manifest abnormality of lipid metabolism, although his father and grandfather had both developed xanthelasmas early in childhood. A snip biopsy of upper lid skin was performed and studied by both light and electron microscopy. The light microscopic appearance confirmed the diagnosis of xanthelasma, in that the upper dermis contained mono- and multinucleated foamy xanthoma cells beset with myriad cytoplasmic vacuoles. Cells displaced outwardly into the interstitium evidenced degradation phenomena within the vacuoles, consisting of lamellar bodies or fingerprint-like inclusions, presumably the result of fusion of lysosomes with the lipidic inclusions. Scattered non- lipidized mononuclear histiocytes with abundant profiles of smooth-surfaced endoplasmic reticulum possibly represented a reserve population of monocytes for conversion into xanthoma cells.

Combined clinical and computed tomographic diagnosis of orbital glioma and meningioma.

The clinical information on 22 patients with orbital optic nerve gliomas and 47 patients with meningiomas was correlated with computed tomographic findings obtained in both axial and coronal studies. Most of the gliomas occurred in children, although 7 patients presented after 20 years of age. Among the patients with meningiomas, the majority were women in early middle age, although two tumors occurred in children less than 20 years of age. Low grades of proptosis (median, 2 mm for both tumors), frequent significant visual field obscurations with eye movements, and opto-ciliary shunt vessels pointed toward the diagnosis of an optic nerve tumor. Patients with gliomas generally manifested massively swollen fusiform optic nerves with clear-cut margins due to circumscription by an intact dura. Kinks and bucklings of the optic nerve as well as infarctive cysts distinguished the glioma CT-scan patterns from the meningiomas. Distinctive axial CT-scan features of the meningiomas not shared by the gliomas were narrowly and diffusely enlarged nerves with polar expansions either at the orbital apex or immediately behind the globe; calcification; irregular excrescent margins signifying extradural invasion into the orbital soft tissues; a negative optic nerve shadow running down the center of the lesion; and bone erosion near the orbital apex. Coronal studies often revealed irregular margins signifying transgression of the dura. A diffusely and narrowly enlarged optic nerve shadow with regular margins (intrasheath lesions) was the one morphologically overlapping pattern displayed by 11 meningiomas and three gliomas. In these cases there tended to be more profound visual loss in the gliomas compared with the meningiomas, as well as the more frequent presence of opto-ciliary vessels in the meningiomas. Arteriography may be helpful in this particular category by demonstrating a tumor blush for the meningiomas, whereas this finding is typically absent with optic nerve gliomas. Meningiomas may be very closely simulated by dural or intraneural inflammations.

Fluorescein angiographic patterns of iris melanocytic tumors.

Iris fluorescein angiography was performed on 23 patients with primary iris melanocytic tumors. Four angiographic patterns were identified, the first three of which were considered to be usually indicative of a benign lesion, based on clinical duration and follow-up, biopsy specimens, and stable patterns on repeated angiography. (1) Eleven moderately to heavily pigmented placoid lesions were angiographically silent, in that they failed to display either a tumor-associated vasculature or diffuse leakage. (2) Seven generally nonpigmented lesions demonstrated a quasi-geometric filigree vascular network, approximating the caliber of the normal radial vasculature. These tumor-associated vessels fluoresced early and in synchrony with the appearance of dye in the radial vasculature from which they probably were derived, but they diffusely and confluently leaked fluorescein in the late phases of the angiogram. (3) Three brown or variably pigmented lesions manifested a mixed angiographic pattern, combining features of groups 1 and 2. (4) The final angiographic pattern was comprised of two pathologically proved mixed spindle-epithelioid cell melanomas, each of which in part or in toto showed diffuse and eventually confluent fluorescence emanating from ill-defined vascular foci. One of these two lesions additionally exhibited a large area that was perfused late by irregular leashes of vessels. The ability to distinguish benign from malignant melanocytic lesions of the iris can be greatly enhanced by iris fluorescein angiography.