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2.
Hong Kong Med J ; 21(5): 401-6, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26234688

ABSTRACT

OBJECTIVE: To identify specific angiographic factors associated with haemorrhagic presentation of brain arteriovenous malformation in Chinese paediatric patients. DESIGN: Retrospective cross-sectional observational study. SETTING: Four locoregional tertiary neurosurgical centres in Hong Kong: Queen Elizabeth Hospital, Tuen Mun Hospital, Kwong Wah Hospital, and Pamela Youde Nethersole Eastern Hospital. PATIENTS: Patients aged 18 years or younger who underwent pretreatment digital subtraction angiography for brain arteriovenous malformation between 1 January 2005 and 31 July 2013 were included. Patients were divided into haemorrhagic and non-haemorrhagic groups based on the initial presentation. Pretreatment digital subtraction angiographies were independently reviewed by two experienced neuroradiologists. MAIN OUTCOME MEASURES: The following parameters were evaluated for their association with haemorrhagic presentation by univariate and multivariate analyses: nidus location, nidus size, nidus morphology (diffuse or compact); origin and number of arterial feeders; venous drainage; number of draining veins; presence of aneurysms, venous varices, and venous stenosis. RESULTS: A total of 67 children and adolescents (28 male, 39 female) with a mean age of 12 years were included. Of them, 52 (78%) presented with haemorrhage. Arteriovenous malformation size (P=0.004) and morphology (P=0.05) were found to be associated with haemorrhagic presentation by univariate analysis. Small arteriovenous malformation nidus size and diffuse nidal morphology were identified as independent risk factors for haemorrhage by multivariate analysis. CONCLUSION: Smaller arteriovenous malformation size and diffuse nidal morphology are angiographic factors independently associated with haemorrhagic presentation. Bleeding risk is important in determining the therapeutic approach (aggressive vs conservative) and timeframe, particularly in paediatric patients.


Subject(s)
Cerebral Angiography , Cerebral Hemorrhage/etiology , Intracranial Arteriovenous Malformations/complications , Intracranial Arteriovenous Malformations/diagnostic imaging , Adolescent , Angiography, Digital Subtraction , Cerebral Hemorrhage/diagnostic imaging , Child , Child, Preschool , Female , Hong Kong , Humans , Male , Retrospective Studies , Risk Factors
3.
Hong Kong Med J ; 20(5): 437-43, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25045883

ABSTRACT

Vesicoureteric reflux is an important association of paediatric urinary tract infection. Fluoroscopic micturating cystourethrography and radionuclide cystography have been employed for detecting and grading vesicoureteric reflux. However, both modalities involve ionising radiation, which can pose significant radiation risk to growing children. They also have a lower detection rate due to intermittent fluoroscopic technique in micturating cystourethrography, and lower spatial resolution in radionuclide cystography. Therefore, newer radiation-free ultrasound-based contrast-enhanced voiding urosonography has been developed in Europe for 15 years. This article aimed to summarise the current literature and discuss the first local pilot study in our institution on detection of vesicoureteric reflux by contrast-enhanced voiding urosonography. Contrast-enhanced voiding urosonography is a valid alternative to micturating cystourethrography in assessing vesicoureteric reflux, based on its superior diagnostic performance, reliability, safety, feasibility, and radiation safety for children. Therefore, it should be incorporated in the guideline for investigating paediatric urinary tract infection.


Subject(s)
Urination , Vesico-Ureteral Reflux/diagnostic imaging , Child , Child, Preschool , Diagnostic Techniques, Urological , Female , Humans , Infant , Infant, Newborn , Male , Sensitivity and Specificity , Ultrasonography
4.
Eur J Pediatr ; 173(8): 1095-101, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24659313

ABSTRACT

Vesicoureteric reflux has been associated with paediatric urinary tract infection. Fluoroscopic micturating cystourethrography (MCU) has been the gold standard of diagnostic test for decades; however, it has been criticized owing to its lower detection rate and radiation dose to children. Therefore, new radiation-free reflux imaging modalities have been developed, in which ultrasound-based contrast-enhanced voiding urosonography (ceVUS) is a good example. However, ultrasonography has been considered as an operator-dependent examination. Therefore, our study aimed to examine the inter-observer agreement of this sonographic technique, which has not been evaluated before. Moreover, the second-generation ultrasound contrast SonoVue has been recently marketed, and the data on its efficacy on intravesical use in ceVUS is relatively scarce. Thus, we also aimed to investigate the diagnostic performance and safety profile of SonoVue-enhanced VUS in the diagnosis of vesicoureteric reflux. Our prospective comparative study compared the diagnostic performance of ceVUS with MCU in young children presenting with first episode of urinary tract infection. We performed sequential ceVUS and MCU examinations in 31 patients (62 pelvi-ureter units). Perfect inter-observer agreement (Cohen's kappa statistics = 1.0, p < 0.001) was achieved in ceVUS, suggesting its good reliability in reflux detection and grading. Using MCU as reference, ceVUS had 100 % sensitivity and 84 % specificity and carried higher reflux detection rate than MCU (p < 0.001). There was no complication encountered. Conclusion: Voiding urosonography is a reliable, sensitive, safe and radiation-free modality in the investigation of vesicoureteric reflux in children. It should be incorporated in the diagnostic algorithm in paediatric urinary tract infection.


Subject(s)
Urinary Tract/diagnostic imaging , Urography/methods , Vesico-Ureteral Reflux/diagnostic imaging , Child, Preschool , Contrast Media , Cross-Sectional Studies , Female , Fluoroscopy , Humans , Infant , Male , Observer Variation , Prospective Studies , Ultrasonography , Urination
5.
Radiother Oncol ; 104(3): 317-23, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22551564

ABSTRACT

BACKGROUND AND PURPOSE: Significant tumor shrinkage and weight loss may occur during Intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aims to evaluate the dosimetric effect of volumetric changes on target volumes and organs at risk (OARs) during IMRT, using reassessment of computed tomography (CT) and magnetic resonance imaging (MRI). MATERIAL AND METHODS: Nineteen loco-regionally advanced NPC patients treated with IMRT were recruited prospectively. Repeat planning CT and MRI were acquired at 30 and 50 Gy intervals. Recontouring of target volumes and OARs was based on the fused CT-MRI images. Hybrid plans with recontouring were generated. The assessment of volumetric and dosimetric changes was performed by comparing the hybrid plans with the original plan. RESULTS: There was volume reduction of target volumes and parotid glands over the course of IMRT. Relative to the original plan, the hybrid plans demonstrated significantly higher dose to most of target volumes with greater dose inhomogeneity, higher maximum doses to the spinal cord and brainstem, and higher median doses to the parotid glands. CONCLUSIONS: Replanning with repeat CT and MRI scans at 30 Gy is essential to keep a satisfactory dose to the target volumes and avoid overdosing the OARs.


Subject(s)
Nasopharyngeal Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated , Adult , Aged , Carcinoma , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/pathology , Prospective Studies , Radiotherapy Dosage , Radiotherapy, Intensity-Modulated/adverse effects , Tomography, X-Ray Computed , Tumor Burden , Weight Loss
7.
Hong Kong Med J ; 14(6): 492-4, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19060351

ABSTRACT

A persistent sciatic artery is a rare embryological anomaly. We report a case of a persistent sciatic artery with aneurysm formation and thrombosis in a patient with rheumatoid arthritis/systemic lupus erythematosus overlap syndrome and Raynaud's phenomenon. The diagnosis and complete, accurate evaluation of the arterial anatomy of the lower limb were achieved using computed tomographic angiography.


Subject(s)
Aneurysm/etiology , Femoral Artery/abnormalities , Lower Extremity/blood supply , Thrombosis/etiology , Female , Humans , Middle Aged
9.
Can J Neurol Sci ; 33(1): 95-100, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16583730

ABSTRACT

Magnetic resonance imaging (MRI) of the brain is the most important paraclinical diagnostic test in multiple sclerosis (MS). The appearance of MRI in Asians with MS is not well defined. We retrospectively surveyed the first brain and spinal cord MRI in patients diagnosed to have MS, according to Poser's criteria in seven regions throughout Asia to define the MRI changes among Asians with MS. There were 101 patients with first brain, and 86 with first spinal cord MRI, 66 of whom had both. The brain MRI showed a mean of 17 lesions per patient in T2 weighted images, mostly asymptomatic. Almost all the lesions were in the white matter, particularly in the juxtacortical, deep and periventricular white matter. A third of the lesions were greater than 5 mm, 14% enhanced with gadolinium. There were more supratentorial than infratentorial lesions at a ratio of 7.5: 1. Ninety five percent of the spinal cord lesions were in cervical and thoracic regions, 34% enhanced with gadolinium. The lesions extended over a mean of 3.6 +/- 3.3 vertebral bodies in length. Fifty (50%) of the brain and 54 (63%) of the spinal MRI patients had the optic-spinal form of MS. The MRI of the optic-spinal and classical groups of patients were similar in appearance and distribution, except that the optic-spinal MS patients have fewer brain but longer and more severe spinal cord lesions. In conclusion, the brain and spinal cord MRI of Asian patients with MS was similar to that of the West, although, in this study, Asian MS patients had larger spinal cord lesions.


Subject(s)
Brain/pathology , Magnetic Resonance Imaging , Multiple Sclerosis/pathology , Spinal Cord/pathology , Adult , Asian People , Female , Humans , Male , Retrospective Studies
10.
Hong Kong Med J ; 10(1): 38-43, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14967854

ABSTRACT

OBJECTIVES: To study the spectrum of diseases that can be detected by magnetic resonance imaging in patients suspected to have vestibular schwannoma (acoustic neuroma) presenting with sensorineural or mixed hearing loss, and to assess the extent of the problem of hearing loss in a screened population. DESIGN: Retrospective study. SETTING: Diagnostic radiology and imaging department of a regional hospital, Hong Kong. PATIENTS: A total of 1821 consecutive patients from September 1999 to February 2001 with sensorineural or mixed hearing loss were referred by otolaryngologists for magnetic resonance imaging of the internal auditory canal. MAIN OUTCOME MEASURES: Vestibular schwannoma; other cerebellopontine angle masses and other diseases that could account for the patients' hearing loss. RESULTS: In all, 132 (7%) patients had positive findings that could explain their hearing loss. Fifty-four (41%) of the 132 patients had vestibular schwannoma; 39 (30%) had inflammation of the middle ear and mastoids; 17 (13%) had ischaemic foci in the brainstem; 10 (8%) had other cerebellopontine angle masses or tumours; four (3%) had inner ear dysplasia; seven (5%) had vascular loop compression; and one (1%) had chronic cryptococcal meningitis. The overall incidence of vestibular schwannoma detected in this screened population was about 3%. CONCLUSIONS: This study indicates that magnetic resonance imaging is an effective tool to screen for vestibular schwannoma in patients with sensorineural or mixed hearing loss. It can also be used to assess a considerable number of different pathological conditions in patients with audiovestibular disorders.


Subject(s)
Hearing Loss/etiology , Magnetic Resonance Imaging , Mass Screening/methods , Neuroma, Acoustic/diagnosis , Brain Ischemia/diagnosis , Cerebellopontine Angle/pathology , Ear, Inner/abnormalities , Ear, Inner/pathology , Hong Kong , Humans , Mastoiditis/diagnosis , Meningitis, Cryptococcal/diagnosis , Nerve Compression Syndromes/diagnosis , Otitis Media/diagnosis , Retrospective Studies , Vertebral Artery/pathology
11.
Interv Neuroradiol ; 8(3): 265-72, 2002 Sep 30.
Article in English | MEDLINE | ID: mdl-20594484

ABSTRACT

SUMMARY: Patients with dural arteriovenous fistula (DAVF) are at higher risk of developing neurological deficits when there is retrograde leptomeningeal venous drainage. Our aim is to demonstrate the presence of dilated deep medullary veins in the brain on magnetic resonance imaging (MR) in this group of patients, and to assess their clinical significance. Nine patients with angiographically proven DAVF associated with leptomeningeal venous drainage who had MR before treatment were studied.MR was performed in at least two orthogonal planes before and after gadolinium administration. The dural fistula was located at the cavernous sinus in five patients, at the transverse-sigmoid sinus in three and at the tentorium in one. Dilated deep medullary veins were noted in six patients. Of these, four showed parenchymal abnormalities which included intracerebral haematoma, venous infarction, brain oedema and T2 hyperintensity in brainstem. Venous varix was present in one patient. No neurological complication or parenchymal change was observed in the three patients without dilated deep medullary veins. Therefore, in patients with intracranial DAVF associated with leptomeningeal venous recruitment, the MR finding of dilated deep medullary veins suggests a more severe degree of venous hypertension and congestion in the brain. This subgroup of patients has a much higher chance of neurological complications and warrants urgent intervention.

12.
Acta Neurochir (Wien) ; 143(4): 351-5; discussion 355-6, 2001.
Article in English | MEDLINE | ID: mdl-11437288

ABSTRACT

Haemorrhage from rupture of petrous ICA aneurysm can be life threatening and emergency treatment is required. We report 2 cases of radiation-induced petrous internal carotid artery (ICA) aneurysm presenting with acute haemorrhage (epistaxis and otorrhagia) after radiotherapy (RT) for nasopharyngeal carcinoma (NPC). Both patients had a history of RT treatment for NPC. The first patient, a 54-year-old man, presented with sudden severe epistaxis and haemorrhagic shock. The second patient, a 35-year-old man, presented with episodes of severe otorrhagia. The first patient was immediately resuscitated. Obliteration of the aneurysm was performed by endovascular occlusion of the ICA with Guglielmi detachable coils and fibered platinum coils. For the second patient, the aneurysm was treated by deploying a self-expandable stent across the aneurysm neck. In an emergency situation, ruptured petrous ICA aneurysm can be treated with endovascular occlusion of the ICA with microcoils if there is a good collateral blood flow. Alternatively, the aneurysm can be treated by deployment of a stent, which can induce stasis and eventual thrombosis of the aneurysm.


Subject(s)
Carotid Artery Diseases/etiology , Carotid Artery Diseases/therapy , Carotid Artery, Internal/radiation effects , Carotid Artery, Internal/surgery , Embolization, Therapeutic , Intracranial Aneurysm/etiology , Intracranial Aneurysm/therapy , Intracranial Hemorrhages/etiology , Intracranial Hemorrhages/therapy , Nasopharyngeal Neoplasms/radiotherapy , Acute Disease , Adult , Carotid Artery Diseases/diagnostic imaging , Carotid Artery, Internal/diagnostic imaging , Humans , Intracranial Aneurysm/diagnostic imaging , Intracranial Hemorrhages/diagnostic imaging , Male , Middle Aged , Radiography
14.
J Exp Mar Biol Ecol ; 256(2): 185-198, 2001 Jan 31.
Article in English | MEDLINE | ID: mdl-11164862

ABSTRACT

DMSP-consuming bacteria (DCB) were recovered from the body and fecal pellets of the copepod Acartia tonsa (Dana). The most probable number of DCB associated with starved A. tonsa was 9.2x10(2) cells copepod(-1). The abundance of DCB recovered from the copepod body increased to 1.6-2.8x10(4) after the copepod fed on DMSP-containing alga. DCB abundance associated with fecal pellets averaged 1.2x10(4) cells pellet(-1). In enrichment cultures, the DCB grew with a doubling time of 1.1-2.9 days, and consumed DMSP at a rate of 4.5-7.5 fmol cell(-1) day(-1). The apparent DMSP-to-DMS conversion efficiency was 25-41% for DCB from copepod body, and 99% for DCB from fecal pellets. Our study demonstrated that copepods and their fecal pellets may harbour dense populations of DCB, and that the copepod-bacteria coupling represents a novel mechanism for DMSP consumption in the water column.

15.
J Chromatogr A ; 883(1-2): 137-42, 2000 Jun 23.
Article in English | MEDLINE | ID: mdl-10910208

ABSTRACT

An insoluble beta-cyclodextrin polymer cross-linked with identified epichiorohydrin has been prepared; its structure was identified by means of infrared and 13C NMR spectra. Three capillary columns have been coated with the polymer treated by ultrasonication by three coating methods. Chromatographic characteristics such as column efficiency, thermal stability and polarity, have been studied, and two kinds of disubstituted benzene isomers and eight pairs of enantiomers have been separated on the three capillary columns. The results show that the beta-cyclodextrin polymer is suitable for use as a capillary gas chromatographic stationary phase, and that the column, prepared by loading beta-cyclodextrin polymer stationary phase with 50% methyl-50% phenylsilicone (OV-17), shows good chromatographic properties in separating enantiomers and positional isomers.


Subject(s)
Chromatography, Gas/methods , Cyclodextrins/chemistry , beta-Cyclodextrins , Isomerism , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , Stereoisomerism
16.
Se Pu ; 18(4): 343-5, 2000 Jul.
Article in Chinese | MEDLINE | ID: mdl-12541514

ABSTRACT

An insoluble beta-cyclodextrin polymer cross-linked with epichlorohydrin was prepared. beta-Cyclodextrin polymer (0.26 g) was treated for 0.5 h by a ultrasonator in the mixed solvent (10 mL) of isopropyl ether, methylene dichloride and benzene with a volume ratio 2:1:2, and a 26 g/L colloidal stationary liquid was prepared. It was coated on a fused silica capillary by superdynamic coating method. The capillary column was of high column efficiency of above 3,000/m with good thermal stability and moderate polarity. Enantiomers of xylene, dichlorobenzene, alpha-pinene, beta-pinene, ethyl lactate, alpha-phenyl ethanol, 1, 2-propanediol, alpha-lonone, methyl alpha-chloropropionate and gamma-valerolactone were separated on the capillary column. The experimental results showed that beta-cyclodextrin polymer treated by a ultrasonator is a capillary chromatographic stationary phase with good performance and high selectivity.


Subject(s)
Chromatography, Gas/instrumentation , Cyclodextrins , Siloxanes , beta-Cyclodextrins , Polymers , Propylene Glycol/isolation & purification , Stereoisomerism , Ultrasonics , Xylenes/chemistry , Xylenes/isolation & purification
17.
Chin Med J (Engl) ; 113(3): 254-6, 2000 Mar.
Article in English | MEDLINE | ID: mdl-11775258

ABSTRACT

OBJECTIVE: To detect for hippocampal sclerosis presurgically in a group of patients with refractory temporal lobe epilepsy. METHODS: Eighty-four consecutive patients with refractory temporal lobe epilepsy were subjected to brain MRI of hippocampal volumetry. A ratio of smaller to larger hippocampal volume was determined and unilateral hippocampal atrophy (HA) was diagnosed if the ratio is less than 0.91. RESULTS: Unilateral HA was diagnosed in 42 patients (50%) and bilateral HA in 1 patient. Other MRI abnormalities were detected in 18 patients with or without coexisting HA. CONCLUSIONS: Hippocampal sclerosis can be detected presurgically in many patients by brain MRI. Additional abnormalities not detected by brain CT can also be demonstrated.


Subject(s)
Epilepsy, Temporal Lobe/pathology , Hippocampus/pathology , Adult , Atrophy , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Sclerosis
18.
Eur J Pharmacol ; 286(2): 185-91, 1995 Nov 14.
Article in English | MEDLINE | ID: mdl-8605955

ABSTRACT

Several novel cholecystokinin (CCK) receptor ligands with differing degrees of receptor selectivity were characterised in both in vitro and in vivo models. In radioligand binding assays, the dipeptoid PD 135666 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino],-[R-(+*,S*)]) selectively inhibited [125I]Bolton Hunter CCK-8 binding to CCKB receptors in mouse cerebral cortex (CCKB IC50 = 0.1 nM) but was weaker as an inhibitor of CCKA receptor binding in the rat pancreas (IC50 = 26 nM). In contrast, its enantiomer PD 140548 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7] dec-2-yloxy)carbonyl]amino]propyl] amino],-[S-(R*,S*)) displayed the reverse selectivity (CCKA IC50 = 2.8 nM, CCKB IC50 = 260 nM). PD 142898 ([benzenebutanic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2- methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-,[1S-[1 alpha[S*(R*)],2 beta ]]) possessed nanomolar affinity for both receptor subtypes (CCKB IC50 = 4.2 nM, CCKA IC50 = 3.8 nM) whereas its corresponding enantiomer PD 142896 ([benzenebutanic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2- methylcyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-, [1R-[1 alpha[S*(R*)],2 beta]]) displayed 147-fold selectivity for the CCKA receptor (CCKA IC50 = 7.9 nM, CCKB IC50 = 1160 nM). The pyrazolidinone PD 141479 (trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4- (trifluoromethyl)phenyl]-1-pyrazolidinecarboxamide) was found to interact selectively with the CCKB receptor (CCKB IC50 = 36 nM, CCKA IC50 = 1100 nM). PD 140548, PD 142896, PD 135666 and PD 142898 antagonised the CCKA receptor-mediated contraction of guinea pig gall bladder with respective pA2 values of 7.2, 7.4, 6.6 and 8.5. In the rat elevated X-maze, PD 135666 and PD 141479, together with the mixed CCKA/B receptor antagonist PD 142898 produced anxiolytic effects with respective minimum effective doses (MEDs) of 0.01, 0.001 and 0.01 mg/kg s.c. Furthermore, the selective CCKB receptor antagonist CI-988 (0.01-1 mg/kg) and PD 142898 (0.001-0.1 mg/kg), dose dependently induced behavioural changes suggestive of anxiolysis in the marmoset human threat test with respective MED values of < 0.01 and < 0.001 mg/kg s.c. In contrast, compounds with the CCKA selective profile were either inactive in the two behavioural models or showed activity only at doses of 1 mg/kg and above. These data suggest that the anxiolytic effects of CCK receptor antagonists parallel their affinity for the CCKB rather than the CCKA receptor.


Subject(s)
Anti-Anxiety Agents/pharmacology , Receptors, Cholecystokinin/antagonists & inhibitors , Animals , Callithrix , Gallbladder/drug effects , Gallbladder/physiology , Guinea Pigs , Humans , In Vitro Techniques , Male , Maze Learning/drug effects , Mice , Peptoids , Rats , Receptors, Cholecystokinin/physiology
19.
Singapore Dent J ; 20(1): 24-6, 1995 Jul.
Article in English | MEDLINE | ID: mdl-9582686

ABSTRACT

The limitations on advertising set by current regulations are examined and the possible consequences of relaxing these regulation discussed. The opinions of the dental profession on this issue, as determined through a questionnaire survey of members of the Singapore Dental Association (SDA), are included. Finally, some recommendations are made with respect to modifying current advertising laws.


Subject(s)
Advertising , Dentistry , Advertising/economics , Attitude of Health Personnel , Costs and Cost Analysis , Data Collection , Dentists/statistics & numerical data , Health Education, Dental , Humans , Singapore , Societies, Dental
20.
Br J Pharmacol ; 110(1): 385-91, 1993 Sep.
Article in English | MEDLINE | ID: mdl-7693284

ABSTRACT

1. We investigated the effects of the non-peptide NK1 receptor antagonist, CP-96,345, its inactive enantiomer CP-96,344, and the racemic mixture (+/-)-CP-96,345, on the binding of [3H]-nimodipine and [3H]-diltiazem to L-type calcium channels in rat cerebral cortex membranes. In isolated peripheral tissues containing tachykinin receptors, the effects of (+/-)-CP-96,345 have been compared with those of diltiazem. 2. In guinea-pig trachea, (+/-)-CP-96,345 produced antagonism of responses to the selective NK1 agonists [Sar9, Met(O2)11]SP and substance P-methyl ester that was apparently competitive in nature (pKB 7.0-7.5), while in guinea-pig ileum the antagonism was not surmountable. 3. The reduction of maximum responses by (+/-)-CP-96,345 in the guinea-pig ileum was not selective; it was obtained with muscarinic agonists and other agents, and was also observed in the portal vein of the rat where NK1 receptors are not present. 4. The tissue-specific reduction of maximum responses by (+/-)-CP-96,345 in ileum was reproduced by diltiazem. 5. (+/-)-CP-96,345 produced a concentration-dependent enhancement of [3H]-nimodipine binding to rat cerebral cortex membranes with a maximal stimulation of 186 +/- 29% above control (EC50 83.2 nM). Scatchard analysis revealed that (+/-)-CP-96,345 increased the affinity of [3H]-nimodipine for its binding sites without affecting Bmax (control: KD = 0.32 nM; with 100 nM (+/-)-CP-96,345: KD = 0.074 nM). 6. CP-96,345, CP-96,344, and the racemate all inhibited [3H]-diltiazem binding in rat cerebral cortex membranes with Ki values of 22.5 nM, 34.5 nM and 29.9 nM respectively; a similar value was obtained for diltiazem itself (33.6 nM). In comparison, CP-96,345 and ( +/- )-CP-96,345 inhibited the binding of[125I]-Bolton-Hunter-conjugated substance P in this tissue with Ki values of 59.6 nM and 82.0 nM respectively, while CP-96,344 had no measurable affinity (IC50> 10 microM).7. Substance P and a range of ligands selective for NK1, NK2, or NK3 receptors had no significant effect at 10 microM on either [3H]-diltiazem or [3H]-nimodipine binding.8. The results indicate that in addition to possessing affinity for the NK1 receptor, the non-peptide antagonist, CP-96,345, displays high affinity for [3H]-diltiazem binding sites on L-type calcium channels.The functional effect that may be observed in integrated models will be a consequence of either property, or be a composite effect of NK1 receptor antagonism and L-channel blockade.


Subject(s)
Biphenyl Compounds/pharmacology , Calcium Channels/drug effects , Neurokinin-1 Receptor Antagonists , Animals , Calcium Channels/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Diltiazem/pharmacokinetics , Diltiazem/pharmacology , Guinea Pigs , In Vitro Techniques , Male , Membranes/drug effects , Membranes/metabolism , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Nimodipine/pharmacokinetics , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stereoisomerism , Substance P/metabolism , Succinimides/metabolism , Trachea/drug effects , Trachea/metabolism
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