Tolerance to the anticonvulsant effects of lamotrigine on amygdala kindled seizures: cross-tolerance to carbamazepine but not valproate or diazepam

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.     

地西泮亚微乳注射液处方及制备工艺的研究

目的：确定地西泮亚微乳注射液的制备处方及工艺。方法：采用二级高压均质法制备地西泮亚微乳注射液，分别考察了高压均质条件，油相组成，乳化剂及稳定剂用量，pH调节，灭菌过程对制剂稳定性的影响。结果：采用15％油相（MCT与LCT等比例混合），1．2％豆磷脂，0．06％油酸钠，2．5％甘油，均质前调节至pH8．0，以20℃，80MPa压力均质6-10次，所制备的地西泮亚微乳注射液在4-25℃下12个月内理化性质没有明显变化。结论：本品具有良好的物理化学稳定性。     

Njurskador vid behandling med litium och neuroleptika

Urinary concentrating ability was estimated in 69 patients on longterm lithium therapy. Thirty-nine of the patients were treated with neuroleptic drugs as well. For comparison 30 patients on neuroleptic therapy only and 30 healthy objects were also examined. Almost all of the lithium-treated patients had a concentrating ability of < 800 mOsm/kg during lithium therapy. Still two months after withdrawal of lithium only 17 patients reached > 800 mOsm/kg. The total dose of lithium and peaks of high serum lithium levels seem to be correlated to a low concentrating ability. Patients treated with neuroleptic drugs plus lithium had a lower concentrating ability than patients treated with lithium only. Patients treated with neuroleptic drugs only had a lower concentrating ability than healthy persons. Kidney biopsies were performed in 14 cases (9 with lithium and 5 with the combination lithium and neuroleptic drugs). Lithium-treated patients hade rather discrete changes, mainly in the form of slight medullary fibrosis. Biopsies from patients treated with lithium plus neuroleptic drugs showed more severe lesions, with hyalinization of glomeruli and interstitial focal fibrosis.     

Diazepam treatment blocks the elevation of hippocampal activity and the accelerated proliferation of hippocampal neural stem cells after focal cerebral ischemia in mice

Hippocampal neurogenesis is accelerated during the elevation of hippocampal neural activities under both physiological and pathophysiological conditions. One of these conditions, middle cerebral artery occlusion (MCAO), induces both the hyperactivities of hippocampal network and the elevation of neural stem cell (NSC) proliferation. However, the causal relationship between the elevated activity and the elevation of NSC proliferation is still unclear. In this study, to block the elevation of hippocampal activity after MCAO in mice, we utilized a typical γ‐aminobutyric acid type A (GABA_A) receptor active modulator, diazepam. With MCAO mice treated with diazepam, we observed complete disappearance of the elevation of hippocampal activity. Additionally, the diazepam treatment blocked the elevation of NSC proliferation after MCAO. From this result, it is speculated that the increased NSC proliferation is blocked by the suppression of elevated neural activity. However, diazepam might have effects other than the suppression of hippocampal activity, so we performed additional experiment and found that diazepam did not affect the number of bromodeoxyuridine‐positive cells under the normal condition, whereas the GABA agonist pentobarbital stimulated NSC/neural progenitor cell proliferation and differentiation. Next, we evaluated the expression of the diazepam‐binding inhibitor (DBI) protein and found that the cells expressed DBI in soma and on the surface of cell membrane. From these observations, we can propose that diazepam blocks the elevation of hippocampal activity and also NSC proliferation after MCAO. © 2013 Wiley Periodicals, Inc.     

Propofol infusion for sedation in outpatient oral surgery

An infusion of propofol was compared with intravenous boluses of diazepam as sedation for minor oral surgery under local anaesthesia in 12 healthy patients who had elective bilateral surgical extraction of lower third molars; the patients served as their own controls. Plasma catecholamine, vasopressin and cortisol concentrations were determined from repeated blood samples. The total administered dose of propofol was 3.93 (SD 1.34) mg/kg and of diazepam 0.28 (SD 0.07) mg/kg. No cardiovascular depression or airway problems occurred. Other side effects were also rare but some discomfort on injection was frequent with propofol. Recovery times were faster after propofol than after diazepam as assessed by the Maddox wing and visual analogue scales. Propofol also provided better amnesia compared to diazepam at the time of the extraction of the teeth. Eight of the 12 patients subjectively preferred propofol sedation. There was no hormonal stress response in either group.     

可乐定对两种苯二氮受体激动剂程控操作效应的影响

Ⅰ,Ⅱ型苯二氮受体激动剂安定和可乐定均可剂量依赖性抑制大鼠程控操作。可乐定可协同安定的抑制。育亨宾可拮抗之。Ⅰ型苯二氮受体激动剂GL218,872对大鼠程控操作无显著影响。增加其剂量至10mg/kg,使程控操作速率最大降低32%。可乐定可显著加强该剂量的抑制作用,对其余小剂量组无显著影响。结果提示,苯二氮激活Ⅱ型受体对去甲肾上腺素系统功能抑制,可能是其镇静作用机理之一。     

安定对人工流产手术扩宫效果的观察─—附208例分析

本文通过安定10mg宫颈注射对108例人工流产孕妇进行观察，结果用药后宫颈口扩张有显著性意义（P＜0．01），且不影响于它收缩，不增加出血量（P＞0．05），人工流产综合征发生率明显减少（P＜0．01），提示安定宫颈注射可起到扩宫，减少人工流产综合征发生的作用。     

静注安定亚微乳的制备及其特征

应用泊洛沙姆108与精制豆磷脂为乳化剂,制成静注安定亚微乳剂。用单纯形优化法来优化处方中乳化剂的用量(最优化值分别为4%和0.3%)。粗乳经两步高压乳匀机处理后,得很细的单分散乳剂。乳剂用透射电子显微镜检查,粒径均小于364nm。亚微乳不溶血,毒性低,小鼠 LD_(50)是市售安定注射液的2.5倍。药时曲线与市售安定注射液相似。     

Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor

1. The responses of the electrically-driven right ventricle strip of the guinea-pig heart to diazepam were recorded in the absence and in the presence of different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors.
2. Diazepam, at concentrations ranging from 1 μM to 100 μM, was devoid of effect on the contractile force in this preparation.
3. Conversely, diazepam (5 μM–100 μM) produced a consistent positive inotropic response in the presence of a concentration (1 μM), that was without effect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram.
4. This effect of diazepam was not γ-aminobutyric acid (GABA)-dependent, since it was neither mimicked nor potentiated by GABA, and was not affected by either a high concentration (5 μM) of the antagonists of the benzodiazepine/GABA/channel chloride receptor complex, picrotoxin, flumazenil and β-carboline-3-carboxylic acid methyl ester (βCCMe), or by the inverse agonists, β-carboline-3-carboxylic acid N-methylamide (βCCMa) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM, 0.1 μM). Furthermore, a specific antagonist of the peripheral benzodiazepine receptors, PK 11195 (5 μM), did not influence the effect of diazepam.
5. Biochemical studies with isolated PDEs, confirmed that diazepam selectively inhibits type 4 PDE from guinea-pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non-competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP specific PDE absent from cardiac muscle, with a potency close to that shown for PDE 4.
6. Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high affinity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea-pig eosinophils, where only type 4 PDE is present.
7. The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally-related benzodiazepines, that also displaced [³H]-rolipram from its high affinity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site.
8. The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this effect seems neither to be mediated by the benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.

     

安定治疗异烟肼急性中毒的实验研究

对异烟肼(INH)急性中毒的小白鼠,腹腔注射安定(DZ)25mg/Kg有明显的保护作用。在1～3倍LD_(50)INH中毒时,DZ使所有动物免于死亡;对6倍LD_(50)INH中毒者,DZ虽未能降低死亡率,但能明显延长动物的存活时间。本文还就作用原理加以讨论。