Effects of dilazep on cytoplasmic calcium ion concentrations and arachidonic acid metabolism in activated human platelets

The effects of dilazep (tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanol bis(3,4,5-trimethoxybenzoate)-di-hydrochloride monohydrate, Comelian), a coronary and cerebral vasodilator and an antiplatelet drug, on the cytoplasmic Ca2+ concentration ([Ca2+]i) and arachidonic acid (AA) metabolism in activated human platelets were investigated. [Ca2+]i (free calcium ion concentration) of aequorin-loaded platelets was estimated by using the platelet ionized calcium aggregometer. AA metabolism was studied by the determination of AA metabolites, hydroxyheptadecatrienoic acid and 12-hydroxyeicosatetraenoic acid, using reversed-phase high performance liquid chromatography. When platelets were preincubated with dilazep (0-0.5 mmol/l), the drug inhibited both platelet aggregation and [Ca2+]i elevation induced by thrombin, AA and collagen in a concentration dependent manner, while only aggregation was inhibited after stimulation with the Ca ionophore A23187 (calcimycin). Both influx and release of Ca2+ into platelet cytoplasm induced by thrombin or AA were inhibited by dilazep, while neither of them was affected when induced by A23187. Oral ingestion of dilazep as a 100-mg capsule significantly depressed the [Ca2+]i elevation induced by thrombin, AA and collagen after 3 h. Dilazep inhibited endogenous AA metabolism by platelets induced by thrombin, although it enhanced exogenous one. Thus, dilazep inhibited platelet aggregation induced by any agonists including A23187, while [Ca2+]i elevation was inhibited by the drug only when the receptor-mediated agonist was used. Furthermore, it is suggested that dilazep inhibited AA liberation from platelet membrane phospholipids, leading to reduced production of all endogenous AA metabolites after platelet activation although metabolites of exogenous AA could be increased.     

The prognostic significance of cell cycle markers in esophageal cancer after neoadjuvant chemotherapy

Proliferating cell nuclear antigen (PCNA), p27 and cyclin A were analyzed by immunohistochemistry in 89 patients (untreated control n = 40, neoadjuvant chemotherapy n = 49) with esophageal cancer invading the submucosal lesion. The mitotic index (MI) was calculated as the percentage of mitotic cells. In control subjects, the mean PCNA, p27, cyclin A and MI were, respectively, 60.4%, 18.0%, 19.9% and 1.7%; in the chemotherapy group, these values were 46.8%, 15.1%, 18.0% and 1.2% respectively. Neoadjuvant chemotherapy decreased PCNA and the MI significantly. As prognostic indicators, PCNA and the MI were significant in control subjects and p27 and cyclin A were significant in the chemotherapy group. Using multivariate analysis, p27 was a prognostic factor in both groups and cyclin A was prognostic only in the chemotherapy group. Although PCNA and the MI were useful growth and prognostic markers in untreated control subjects, their significance was lost after neoadjuvant chemotherapy. p27 and cyclin A were determined to be significant markers in the neoadjuvant chemotherapy group, especially p27, which was independent in both groups.     

A case of brachial plexus neuropathy who presented with acute paralysis of the hand after sleep]

We report a 46-year-old woman who presented with acute paresis of the right hand and arm. She was well until when she noted a paresis and dysesthesia in her right hand in the morning. Neurological examination revealed weakness in the muscles which were supplied by lower cervical segments, with increased deep tendon reflexes in the right arm. Allen's test and Wright's test were positive. The nerve conduction studies disclosed a reduced CMAPs more severely by right median than ulnar nerve stimulation. The frequency and amplitude of the F waves was also reduced. Needle electromyogram showed a mild neurogenic pattern in the right hand muscles. Digital subtraction angiography revealed a tapering of the subclavian artery when the right arm was abducted. She underwent decompression surgery. A remarkable improvement of the symptoms was observed after surgery. Our patient suggests that brachial plexus neuropathy should be considered in the acute paresis of the hand after sleep, and that surgical procedure would lead to a successful outcome.     

Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study

A multi-institutional study comparing the antimanic effect of carbamazepine (CBZ) and lithium carbonate (Li) was performed using a double-blind group comparison design in a series of 105 patients with bipolar disorders. CBZ and Li were given for four weeks using a fixed-flexible method at an equipotent dose ratio of 1:1, starting from an initial dosage of 400 mg with a maximum dosage of 1200 mg. The final global improvement rate, based on the number of cases showing moderate to marked amelioration of manic symptoms, was 62% in the CBZ group and 59% in the Li group, with no significant difference being found between the two groups. Incidence of cutaneous side-effects was significantly higher in the CBZ group. The mean daily dosage and serum level of CBZ in the fourth week were 674 +/- 239 mg and 7.3 +/- 2.4 micrograms/ml respectively; these were within the therapeutic range. The daily dose and serum level of Li, however, were 710 +/- 239 mg and 0.46 +/- 0.22 mEq/l, and the Li level seemed to be too low to compare its therapeutic effect with that of CBZ. Prior to the present study, approximately 80% of the patients in both groups had been receiving antipsychotic medication, equivalent to 8.0 mg of haloperidol on average, without favorable response. This medication was maintained unchanged during treatment. While the shortcomings of the present study limit the interpretation of the data, it may be suggested that the usefulness of CBZ as a drug for the treatment of manic states is comparable to that of Li.     

Dephosphorylation of specific proteins in HL-60 cells by 1 alpha, 25-dihydroxyvitamin D3: possible involvement of cAMP-dependent protein kinase.

Changes of phosphoprotein patterns in HL-60 cells were studied during short exposures to 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3]. One hundred nanometers 1,25(OH)2D3 dephosphorylated at least three proteins in 6 h: phosphoproteins with molecular weights of 82 kD (pp82), 33 kD (pp33), and 31 kD (pp31). Phosphorylation of pp33 and pp31 was also suppressed by 1 mM dbcAMP, and dephosphorylation of the two protein by 1,25(OH)2D3 was inhibited by 8 microM H-8, an inhibitor of cAMP-dependent protein kinase (PKA). Furthermore, 8 microM H-8 inhibited dephosphorylation of the two proteins when it was added with 1,25(OH)2D3. On the other hand, 10 nM TPA gave no significant change to these two phosphoproteins. These results suggest the possibility that PKA is involved in the early stages of 1,25(OH)2D3-induced HL-60 cell differentiation through specific protein dephosphorylation.     

Clinical efficacy of rizatriptan for patients with migraine: efficacy of drug therapy for migraine accompanied by tension headache–like symptoms, focusing on neck stiffness

According to an epidemiological study in Japan, there are as many as 22 million patients with tension headache and 8.4 million with migraine. Furthermore, patients suffering from both types of headache concurrently are estimated to account for more than 50% of headache patients. We studied the efficacy of drug therapy for migraine accompanied by tension headache–like symptoms, focusing principally on neck stiffness. We evaluated the efficacy of rizatriptan by comparison of findings before and after therapy in 34 migraine patients, consisting of 16 without neck stiffness (migraine without neck factor: WONF) and 18 with it (migraine with neck factor: WNF), who received treatment at our neurology/internal medicine department from 1 March 2004 to 31 May 2005. In the study, all the patients were asked to keep a record of their migraine status. The severity of migraine was classified by physicians according to the International Headache Society diagnostic criteria, based on which drug efficacy was evaluated. We selected rizatriptan for migraine treatment in our study based on Dr. Ferrari’s report. In the efficacy study of rizatriptan, in the group of 34 migraine patients, the pain relief rate (79.4%) and pain–free rate (41.2%) at two hours after treatment were as high as those reported in the meta–analysis performed by Ferrari et al., indicating high efficacy of rizatriptan. In the efficacy comparison between the WONF and WNF groups, the painfree rates were 56.3% and 27.8%, and cumulative pain relief rates were 100% and 61.1%, respectively, with better results in the WONF group. A test result was also significantly better (p=0.0076) in the WONF group. Rizatriptan was proved effective in treating migraine patients accompanied by tension headachelike symptoms. Comparison of efficacy rates between patient groups with and without tension headache–like symptoms showed that the pain relief rate in the group without neck stiffness was higher.     

Epidemiology of headache

We discuss here the epidemiology of chronic headache. Headache is a widespread and costly public health problem. Few people do not experience headache: in men, the lifetime prevalence for headache of any kind is 93 %, and for women it is up to 99%. Approximately 8.4 million people in Japan suffer from migraine, and 22 million have tension-type headache. Despite the painful, costly, and disabling impact of headache, many patients with headache do not seek medical advice. It is important to recognize the incidence of various kinds of chronic headache, and to diagnose and treat them correctly. In this article, we review the incidence, precipitating factors, regional prevalence, and age dependence of the incidence of each type of chronic headache.     

Release of endogenous noradrenaline from the vascularly perfused rat stomach in vitro: modulation by pre- and postsynaptic adrenoceptors.

We developed an experimental in vitro model to detect a very small amount of endogenous noradrenaline (NA) released from the rat gastric sympathetic nerve terminals. The stomach was perfused via celiac artery with modified Krebs-Ringer solution containing 10 mM pargyline and 0.1% bovine serum albumin at a constant flow of 4 ml/min. The right greater splanchnic (SPL) nerve (preganglionic nerve of the gastric sympathetic nerve) was stimulated electrically with square-wave pulses of 2 msec duration and supramaximal intensity (5 mA) for 1 min. The rat stomach contained about 750 ng of NA and spontaneous overflow was about 0.05% of tissue content per 2 min. The NA overflow induced by SPL nerve stimulation at 5 Hz was abolished by tetrodotoxin (3 x 10(-7) M) and by Ca(++)-free medium containing 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Hexamethonium (5 x 10(-4) M) significantly decreased the NA overflow induced by SPL nerve stimulation at 5 Hz. Yohimbine (10(-7) and 10(-6) M) and prazosin (10(-7) and 10(-6) M) dose-dependently enhanced the NA overflow induced by SPL nerve stimulation at 5 Hz. Clonidine (10(-7) and 10(-6) M) and methoxamine (10(-5) M) significantly decreased the NA overflow induced by SPL nerve stimulation at 1 Hz and this methoxamine-induced inhibition was abolished by 8-(p-sulfophenyl)-theophylline (5 x 10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum acid phosphatase can be a useful tumour marker for giant cell tumour of bone

Introduction

The purpose of this study was to elucidate the clinical significance of acid phosphatase in giant cell tumour of bone.

Patients and methods

Serum acid phosphatase levels were measured in 32 patients with this tumour both preoperatively and postoperatively.

Results

Serum acid phosphatase value before surgery was high in 15 patients, whereas it was within normal limits in 17 patients. The serum acid phosphatase values of all the 15 patients with high preoperative serum level fell within normal limits postoperatively. In the remaining 17 patients in whom preoperative serum acid phosphatase values were within normal limits, postoperative serum acid phosphatase levels were lower than that of preoperative ones in all the patients. In addition, there was a statistically significant positive correlation between the tumour volume and the preoperative serum acid phosphatase level.

Conclusion

It is concluded that serum acid phosphatase is a useful tumour marker for giant cell tumour of bone.