Chlorphentermine uptake by rabbit lung slices

Slices of rabbit lung tissue (～ 150 mg; 0.5 mm) were incubated in 5 ml of Krebs-Ringer phosphate buffer, in the presence of 0.25 mM [¹⁴C] chlorphentermine (CP) with shaking at 37°C and under an atmosphere of an O₂/CO₂ mixture (95 : 5). Incubation medium (M) and tissue (T)_were analyzed for radioactivity. Uptake of CP reached a plateau after 30 min at a T/M ratio of 20. Upon varying the concentration of [¹⁴C] CP from 0.125 mM to 2 mM, the concentration-response curve was seen to saturate and the T/M ratio decreased with increasing concentration. Substituting LiCl for NaCl or increasing the K⁺ content in the medium decreased CP uptake. Incubation of slices with Na⁺-pump inhibitors, harmaline and iodoacetate, significantly decreased CP uptake. Chloroamphetamine, desimipramine, imipramine, morphine, chlorpromazine, dieldrin, methadone, amphetamine (each at 1 mM) and incubation at 10°C inhibited CP uptake. Imipramine and amphetamine were both effective in displacing previously accumulated CP from the tissue slices. Efflux of CP from the lung slices was biphasic and was not affected by removal of Na⁺ from the medium. Binding of CP to lung homogenate was unaffected by substituting LiCl for NaCl or by the presence of 1 mM iodoacetate. However, 1 mM harmaline or 1 mM imipramine decreased CP binding. These studies offer evidence for a partially Na⁺-dependent, active uptake process for pulmonary sequestration of CP compatible with earlier findings obtained with perfused intact lung preparations.     

Relationship between regional distribution of imipramine and its effect on learned helplessness in the rat

The regional distribution of imipramine and its major metabolite, desipramine, was determined in relation to drug effects in a “learned helplessness” paradigm. This model for depression has been shown to parallel the antidepressant action of imipramine in humans. Although 4 days of drug administration were required for a significant number of animals to show drug effects, some animals were responsive to a single dose of imipramine. Beginning with the first day. the desipramine levels in the hippocampi of animals in which imipramine prevented learned helplessness were significantly higher than in those animals which did not respond to imipramine. No such relationship was found for the other regions studied. The data suggest that the delay in onset of the effects of imipramine is related to the rate of hippocampal transport of its demethylatecl metabolite.     

Platelet H-imipramine binding: A state-dependent marker in depression

1. Reduced density of ³H-imipramine binding sites (B_max) to platelets has been reported in depressed patients during an episode of illness. In the present study we assessed the usefullness of decreased B_max of platelet ³H-imipramine binding as an indicator of the depressed state. We also investigated the effect of long-term treatment with imipramine on platelet ³H-imipramine binding.

2. A comparison of platelet ³H-imipramine binding in 10 drug-free depressed patients and 8 normal volunteers revealed significantly lower mean Bmax values in depressed patients, whereas the affinity (K_d) of ³H-imipramine binding was identical in both groups.

3. A longitudinal study of platelet ³H-imipramine binding in 10 depressed patients during and after imipramine treatment (125–200 mg/day) revealed consistently low B_max values despite clinically meaningful improvement. However, B_max values increased significantly following complete remission and remained elevated even after imipramine had been discontinued for 4 weeks.

4. These findings suggest that decrease in the sensity of platelet ³H-imipramine binding sites in depressed patients is not likely to be a direct drug effect and that normalization of this variable may follow clinical remission.     

A double blind comparison of lofepramine,imipramine and placebo in patients with primary depression

The results of a double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group. In particular, for severe and/or moderate occurrences of dry mouth, the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 (8 lofepramine vs 21 imipramine patients).     

Medical management of neurogenic bladder with oral therapy

This is a review of the most current literature on medical management of the neurogenic bladder (NGB) to treat detrusor overactivity (DO), improve bladder compliance and treat urinary incontinence. The use of antimuscarinics, alpha blockers, tricyclic antidepressants, desmopressin and mirabegron will be discussed along with combination therapy to improve efficacy. These medical therapies will be the focus of this review with surgical therapy and botulinum toxin injections being the subject of other articles in this series.     

丙咪嗪中毒患者应用血液灌流的疗效分析

目的观察血液灌流(HP)对丙咪嗪中毒患者的疗效。方法35例丙咪嗪中毒患者分为两组。对照组予以常规治疗,治疗组在常规治疗的基础上予以HP一次。绘制两组的SAPS评分的平均得分随治疗时间的变化曲线,判定HP的疗效。结果两组病例的SAPS评分的平均得分随治疗时间的变化情况大致相同,血液灌流治疗对它们的变化趋势无明显影响。结论血液灌流对丙咪嗪中毒患者无明显疗效。     

Long-Term Antidepressant Treatment Inhibits Neuropathic Pain-Induced CREB and PLCγ-1 Phosphorylation in the Mouse Spinal Cord Dorsal Horn

The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate–responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal–regulated kinase (ERK_1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury–induced CREB and PLCγ-1 phosphorylation but had no effect on ERK_1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway.     

N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: Behavioral and biochemical analyses in rats

The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N-acetylcysteine (NAC) – a putative precursor of the most important tissue antioxidant glutathione – in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50–100 mg/kg, ip) or IMI (10 mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity — TAC and the superoxide dismutase activity — SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity.     

Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment

Preclinical data indicate the antidepressant activity of zinc and the involvement of the brain-derived neurotrophic factor (BDNF) in this mechanism. The present study investigates the effect of chronic (16 days) combined treatment with zinc (15 mg/kg zinc hydroaspartate) and imipramine (5 mg/kg) in chronic unpredictable stress (CUS) on the BDNF mRNA level in the rat brain. Moreover, serum zinc concentrations were also assessed. CUS induced a significant reduction in the BDNF mRNA level in the hippocampus by 21% but had no effect in the frontal cortex. Repeated treatment with zinc induced a significant increase in the BDNF mRNA level in the hippocampus in the unstressed animals by 12% and as in the chronically stressed animals by 14%, compared to the appropriate controls. Imipramine treatment did not affect this factor. However, combined treatment of zinc and imipramine induced a 12% elevation of the BDNF mRNA level in the stressed but not in the unstressed rats. CUS induced a 19% reduction in the serum zinc concentration, whereas combined treatment of zinc and imipramine reduced this concentration by 24% in the unstressed and increased it (by 20%) in the stressed animals. These results indicate that: 1) CUS induces a reduction in the BDNF gene expression with a concomitant diminution of serum zinc concentration and 2) the CUS-induced reduction in the BDNF gene expression is antagonized by chronic treatment with zinc.