Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

Radiation dosimetry of iodine-123 HEAT, an alpha-1 receptor imaging agent

Biologic distribution data in the rat were obtained for the alpha-1 adrenoceptor imaging agent (+/-) 2-[beta-(iodo-4-hydroxyphenyl)ethylaminomethyl]tetralone (HEAT) labeled with [125I]. The major excretory routes were through the liver (67%) and the kidney (33%). Internal radiation absorbed dose estimates to nine source organs, total body, the GI tract, gonads, and red bone marrow were calculated for the human using the physical decay data for [123I]. The critical organ was found to be the lower large intestine, receiving 1.1 rad per mCi of [123I]HEAT administered. The total-body dose was found to be 58 mrad per mCi.     

The extracellular matrix of stratum corneum: role of lipids in normal and pathological function

The mammalian stratum corneum, formerly treated as a homogeneous film, is now more properly viewed as a two-compartment system. The cornified cell is protein-enriched and lipid-depleted, lying embedded in an expanded extracellular matrix of highly nonpolar lipids. Because of its strategic location between the cornified layer, this lipid matrix is responsible for many phenomena related to the permeability barrier, as well as cohesion and desquamation. Thus, manipulation of this compartment could lead to enhanced drug delivery and improved lubrication, as well.     

Melatonin Receptors on Ovine Pars Tuberalis: Characterization and Autoradiographicai Localization

The functional significance of the pars tuberalis (PT) of the mammalian adenohypophysis has remained an enigma (1, 2). One view of its function is that it acts as an auxiliary gland to support the endocrine role of the pars distalis (PD) (2), as it has been shown to contain immunocytochemically identifiable thyrotrophs and gonadotrophs (1). Many of the cells of the PT are, however, ultrastructurally unique suggesting an independent function for this tissue. Our recent demonstration that the PT of the rat is a major binding site for the ligand iodomelatonin lends further support to this idea (3). We have utilized the highly specific ligand [¹²⁵l]melatonin, and have demonstrated that it binds exclusively, with very high affinity, to the PT but not the PD of the adult sheep adenohypophysis. These findings support the conclusion that the PT has a distinct role in relation to melatonin action and seasonal reproduction.     

Pharmacology of the internal anal sphincter and its relevance to faecal incontinence

1 The internal anal sphincter (IAS) has a spontaneous tone and is the main contributor to the maintenance of faecal continence. The spontaneous resting tone exhibited by the sphincter can be modified by neurotransmitters from the autonomic and enteric nervous systems. 2 In this review, the influence of the sympathetic and parasympathetic nervous systems on IAS tone are discussed and the putative roles of nitric oxide, carbon monoxide, vasoactive intestinal peptide and adenosine triphosphate in non‐adrenergic non‐cholinergic transmission are considered. 3 Faecal incontinence is a common condition that places a heavy financial burden on the health service and severely affects patients’ quality of life. Resting anal pressure is reduced in patients with faecal incontinence and agents that increase sphincter tone tend to relieve symptoms. The results of clinical studies of the use of phenylephrine to treat faecal incontinence are reviewed. 4 It is concluded that the IAS is a potential target for drug development for the treatment of faecal incontinence.     

Histopathological characterisation of effects of the mouse Pax6 missense mutation on eye development

Mutations in PAX6/Pax6 lead to a variety of ocular anomalies in humans and mice. The aim of the study was to characterise the ocular abnormalities caused by the missense Pax6^Leca4 mutation and compare them to published observations on Pax6 alleles that are functionally equivalent to Pax6⁻ null alleles (such as Pax6^Sey and Pax6^Sey-Neu) and human inherited eye diseases. Ocular features of homozygous Pax6^Leca4/Leca4 and heterozygous Pax6^Leca4/+ embryos at E12.5-E18.5, heterozygous Pax6^Leca4/+ young mice at P18 and heterozygous Pax6^Leca4/+ adults at 12 weeks were analysed histologically with their wild-type Pax6^+/+ littermates. Homozygous Pax6^Leca4/Leca4 fetuses died perinatally with no eyes although an optic cup rudiment with pigmented cells developed. Pax6^Leca4/+ mice were microphthalmic and a range of other severe ocular phenotypes affected both the anterior and the posterior segments. In contrast to Pax6^+/−, the Pax6^Leca4/+ eyes had no goblet cells in the corneal epithelium, the iris was not hypoplastic and there was no lens-corneal epithelial plug. However, microphthalmia was more severe, corneal vascularisation occurred earlier (during fetal stages), pigmented cells were present in the vitreous and corneal stroma and the ciliary body was malformed or abnormal. These results show that, although Pax6^Leca4/+ lacked some eye abnormalities commonly seen in Pax6^Sey/+ and Pax6^Sey-Neu/+ eyes, in most respects their eyes were more severely affected. These differences probably reflect both differences between the Pax6^Leca4 and the Pax6^Sey-Neu mutations and differences in modifier gene expression in different genetic backgrounds. The presence of pigmented cells in the cornea is a novel observation. Some Pax6^Leca4/+ ocular abnormalities were similar to those present in human Peters' anomaly and persistent hyperplastic primary vitreous (PHPV) so Pax6^Leca4/+ mice provide a useful model for some inherited eye diseases.     

化疗药物对轴型皮瓣血运影响的组织学观察

目的探讨抗癌药物动脉灌注后对局部轴型皮瓣血运影响的组织学评价。方法在猪腹部的腹壁上动脉插管灌注抗癌药物,10d后在猪腹部形成以腹壁上血管为蒂的岛状皮瓣,通过对灌注区域轴型血管供养的岛状皮瓣的成活率、光镜、透射电镜及血管铸型透明标本的组织学观察,显示其血管结构及构筑的变化。结果抗癌药物用于局部动脉灌注后,使局部轴型血管支配的血管网有损伤的表现,岛状皮瓣远端的血运显著降低。结论抗癌药物经动脉灌注后可影响局部轴型皮瓣的血运,使皮瓣血供的安全范围缩小,为提高相关修复手术的成功率提供可靠的科学依据。