The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics.

Clomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 µM to 59.64 µM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes.

Comparative effect of administration and discontinuation of sildenafil and/or clomipramine on the hepatic, cardiac and testicular tissues of male rats.

In this study, we examined the adverse consequences of prolonged treatment with sildenafil and/or clomipramine (CLO) on the hepatic, cardiac and testicular tissues of rats. Additionally, we investigated the potential effects of treatment discontinuation. To this end, 60 adult male rats were randomly assigned into six groups and were orally treated with 4.5 mg sildenafil /kg BW (SLD) and 9 mg/ kg BW (SHD), 2.25 mg CLO/kg BW (CLO), 4.5 mg sildenafil/kg BW + 2.25 mg CLO/kg BW (SLD-CLO) and 9 mg sildenafil/kg BW + 2.25 mg CLO/kg BW (SHD-CLO) while the control rats received 0.5 ml distilled water for 8 weeks. Then, five rats from each group were sacrificed and the other five rats were left untreated for another four weeks to recover from the drug treatment. Long-term administration of sildenafil and/or CLO led to oxidative stress, inflammation and structural changes in the liver, heart and testis, reduction in sperm count and motility, an increase in abnormalities, and a reduction in serum testosterone, FSH and LH levels. All tested parameters returned to the normal state following the four-week discontinuation of sildenafil. Additionally, all the alterations caused by long-term administration of CLO, SLD-CLO and SHD-CLO were significantly improved during the recovery period.

Early postnatal treatment with clomipramine induces female sexual behavior and estrous cycle impairment.

Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems.

Drugs targeting intermediate filaments can improve neurosupportive properties of astrocytes.

In response to central nervous system (CNS) injury, astrocytes upregulate intermediate filament (nanofilament) proteins GFAP and vimentin. Whereas the intermediate filament upregulation in astrocytes is important for neuroprotection in the acute phase of injury, in some contexts it might inhibit some of the regenerative processes later on. Thus, timely modulation of the astrocyte intermediate filaments was proposed as a strategy to promote brain repair. We used clomipramine, epoxomicin and withaferin A, drugs reported to decrease the expression of GFAP, and assessed their effect on neurosupportive properties and resilience of astrocytes to oxygen and glucose deprivation (OGD). Clomipramine decreased protein levels of GFAP, as well as vimentin and nestin, and did not affect astrocyte resilience to oxidative stress. Withaferin A sensitized astrocytes to OGD. Both clomipramine and epoxomicin promoted the attachment and survival of neurons co-cultured with astrocytes under standard culture conditions. Moreover, epoxomicin increased neurosupportive properties of astrocytes after OGD. Our data point to clomipramine and epoxomicin as potential candidates for astrocyte modulation to improve outcome after CNS injury.

Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations.

Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1-100µM. At therapeutic concentrations (0.1µM) no significant cytotoxicity was observed after 4, 24, or 48h. At high therapeutic to overdose concentrations (1-100µM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1µM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5µM) and clomipramine (5.5µM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants.

Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish.

Cardiovascular toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause cardiovascular toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed cardiovascular toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-cardiovascular toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and cardiovascular toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of cardiovascular toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo cardiovascular toxicity screening. The procedures we developed in this report for assessing cardiovascular toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection.

The role of clomipramine in potentiating the teratogenic effects of caffeine in pregnant rats: a histopathological study.

Since little is known about the teratogenic effects of clomipramine used concurrently with caffeine during the organogenesis period, the aim of this study was to test the teratogenic effects of a coadministration of caffeine and clomipramine on rat fetuses. We divided 42 pregnant rats into seven groups, randomly. The first group (control) received 0.5 mL of normal saline. Clomipramine was injected at 40 mg/kg and 80 mg/kg to the second and third groups, respectively. The fourth and fifth groups received caffeine in doses of 60 mg/kg and 120 mg/kg, respectively. The sixth group received a combination of 40 mg/kg clomipramine and 60 mg/kg caffeine, and the seventh group was given clomipramine and caffeine at 80 mg/kg and 120 mg/kg, respectively. The fetuses were removed on the 17th day of pregnancy and studied in terms of microscopic and macroscopic morphological features. Fetuses of rats receiving high doses of caffeine or combinations of caffeine and clomipramine showed a significant rate of cleft palate development, open eyelids, mortality, torsion anomalies, shrinkage of skin, and subcutaneous haemorrhage (P ≤ 0.001). This study concludes that caffeine in high doses or the simultaneous administration of caffeine and clomipramine leads to teratogenicity.

Comparison of intravenous lipid emulsion, bicarbonate, and tailored liposomes in rabbit clomipramine toxicity.

OBJECTIVES: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity. METHODS: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). RESULTS: Thirty-minute MAP was greatest in ILE-treated animals: 61 mm Hg ILE (interquartile range [IQR] = 49 to 64 mm Hg), 43 mm Hg LIP (IQR = 36.5 to 49 mm Hg), and 10 mm Hg BIC (IQR = 10 to 44 mm Hg; all p = 0.02). Two of the five BIC-treated animals survived to 30 minutes, compared with all five of the ILE-treated animals and all five of the LIP-treated animals (p = 0.044). CONCLUSIONS: Both ILE and LIPs improved hemodynamic recovery compared with bicarbonate in clomipramine-induced cardiotoxicity in rabbits. Greater 30-minute MAP was observed in the ILE group.

Phospholipase D-mTOR signaling is compromised in a rat model of depression.

Depression is associated with structural and neurochemical changes in limbic structures, including the hippocampus, that control emotion and mood. Structural abnormalities such as decrease in hippocampal cell proliferation, neurogenesis and hippocampal volume, and loss of neurons and glial cells have been widely reported in physical and psychosocial stress paradigms and animal model of depression, but corresponding neurochemical changes are largely unknown. Using neonatal clomipramine (CL)-treated rats as a model to elucidate the association of phospholipase D (PLD) and mammalian target of rapamycin (mTOR) signaling with depressive pathology, we found that the hippocampus of CL-treated rats showed significantly down-regulation of PLD1 expression and attenuation of PLD activity which leads to the less formation of phosphatidic acid (PA), an activator of mTOR, and free choline, a potential biomarker for depression. With lower PA levels which could affect mTOR signaling, we further observed that the phosphorylation of p70S6 kinase, one of the downstream effectors of mTOR, was also significantly decreased in the hippocampus of CL-treated rats compared to the controls. Down-regulation of PLD1 expression, PLD activity and p70S6 phosphorylation was also found in the hypothalamus and frontal cortex with CL-treated rats. Our results indicate that PLD-mTOR signaling is associated with depressive disorder.

Evaluation of animal models of obsessive-compulsive disorder: correlation with phasic dopamine neuron activity.

Obsessive compulsive disorder (OCD) is a psychiatric condition defined by intrusive thoughts (obsessions) associated with compensatory and repetitive behaviour (compulsions). However, advancement in our understanding of this disorder has been hampered by the absence of effective animal models and correspondingly analysis of the physiological changes that may be present in these models. To address this, we have evaluated two current rodent models of OCD; repeated injection of dopamine D2 agonist quinpirole and repeated adolescent injection of the tricyclic agent clomipramine in combination with a behavioural paradigm designed to produce compulsive lever pressing. These results were then compared with their relative impact on the state of activity of the mesolimbic dopaminergic system using extracellular recoding of spontaneously active dopamine neurons in the ventral tegmental area (VTA). The clomipramine model failed to exacerbate compulsive lever pressing and VTA dopamine neurons in clomipramine-treated rats had mildly diminished bursting activity. In contrast, quinpirole-treated animals showed significant increases in compulsive lever pressing, which was concurrent with a substantial diminution of bursting activity of VTA dopamine neurons. Therefore, VTA dopamine activity correlated with the behavioural response in these models. Taken together, these data support the view that compulsive behaviours likely reflect, at least in part, a disruption of the dopaminergic system, more specifically by a decrease in baseline phasic dopamine signalling mediated by burst firing of dopamine neurons.

Administration of clomipramine to neonatal mice alters stress response behavior and serotonergic gene expressions in adult mice.

Early life exposure to antidepressants frequently occurs when pregnant mothers take the medication during late pregnancy. Previous studies in animal models have shown that early exposure to certain antidepressants can alter some behaviors in adulthood. We examined whether the administration of clomipramine, a serotonin reuptake inhibitor, to neonatal mice could result in depression-related behavioral alterations in adult mice. In addition, in an attempt to uncover the mechanism underlying these behavioral changes, we examined the expression of candidate genes in different areas of the brain. Here we show that mice chronically injected with clomipramine specifically during early postnatal development demonstrated depression-like behavior as well as altered stress responses in adulthood. An analysis of the expression of serotonergic genes after exposure to social defeat stress revealed small but significant changes in the expression of 5-HT1A receptor gene (Htr1a) and 5-HTT gene (Slc6a4) in the mice treated with clomipramine compared with the mice injected with saline. We concluded that antidepressant exposure in early days of life could alter stress-related behavior in adulthood and that the behavioral alterations are accompanied by altered serotonergic gene expressions.

Inter-tissue networks between the basal forebrain, hippocampus, and prefrontal cortex in a model for depression caused by disturbed sleep.

Disturbances in sleep are encountered in the majority of patients with depressive disorder. To elucidate the molecular mechanisms behind this relationship, we examined gene expression changes in a rodent model for disturbed sleep and depression. The animals were treated with daily injections of clomipramine to affect their sleep during early infancy. This early interference with sleep is known to induce depression-like behavior in adult animals. After 2 weeks of treatment, the change in gene expression was examined using the Affymetrix Rat 230.2 chip. We studied the gene expression in the basal forebrain, hippocampus, and frontal cortex and combined the results to reveal the otherwise indissectible networks between and around the tissues. The major disrupted pathways between the three brain areas were related to synaptic transmission, regulation of translation, and ubiquitinylation. The involved pathways were within the cellular components of the axons, growth cones, melanosomes, and pigment granules. A network analysis allowing for additional interactors, in the form of chemicals or gene products, revealed a disturbed communicational network between the different brain areas. This disturbed network is centered around serotonin, Mn(II), and Rhoa. The findings elucidate inter-tissue pathways and networks in the brain that are involved in sleep and mood regulation. The findings are of uttermost interest, some are quite predictable and obvious, but some are novel or have only been proposed by rare theoretical speculations (such as the melanosome and Mn(II) involvement). Equally important as the findings are the methods described in this article. In this study, we present two novel simple ways to perform system biological analysis based on gene expression array data. We used two already existing tools in a new way, and by careful planning of the input data, managed to extrapolate intricate hidden inter-tissue networks to build a molecular picture of disease.

Sleep-related epilepsy in a Long-Evans hooded rat model of depression.

INTRODUCTION: Neonatal treatment with clomipramine (CLI) has been shown to have reliable behavioral and biological changes that mimic major symptomatic and biochemical changes found in depression. This paper further explores a common feature of depression, the comorbidity of seizure activity and depressive behaviors in this mode. METHODS: Rat pups were neonatally treated with 40 mg/kg/day of CLI from postnatal day 8 through 21. In adulthood, they were instrumented with electroencephalographic (EEG) and electromyographic (EMG) electrodes for 24 h of polysomnogram (PSG) recordings. PSG data were analyzed for: (1) sleep-wake cycle; (2) spectral power; and (3) epileptiform activity, including NREM-to-REM transition (NRT) bursts. RESULTS: Neonatal treatment with CLI reliably produces enhanced levels of REM (p < 0.01) and reduced sexual activity (p < 0.05). Theta power was enhanced during NREM sleep in the CLI group (p = 0.02). CLI-treated animals experienced increased frequency at the NRT (p < 0.01), as well as additional epileptiform activity of continuous (CTS; p < 0.05) and petite-continuous (P-CTS; p < 0.01) types, across the sleep-wake cycle. There is a strong temporal correlation with increased REM sleep duration, increased frequency of NRT bursts, and increased theta power during NREM sleep in CLI-treated animals. DISCUSSION: Neonatal CLI-treated animals experienced significantly more epileptiform activity as a whole, in addition to comorbid features of depression in adulthood. Neonatal exposure to CLI will not only produce depressive phenotype but may also enhance risk for epilepsy in some individuals. This warrants further investigation into currently acceptable medicinal use in humans.

Reactividad glial tras el tratamiemto con antipsicóticos. Estudio experimental en ratas e implicaciones para la psiquiatría / Glial reactivity after antipsychotic treatment. An experimental study in rats and its implications for psychiatry

Introducción. La importancia de las células gliales en la función del sistema nervioso y en su patología ha sido objeto de múltiples estudios en los últimos años. Concretamente se debate su papel en la acción de los antipsicóticos. Nuestro estudio analiza la reactividad glial en ratas tratadas con antipsicóticos. Metodología. En un primer estudio ultraestructural del núcleo arcuato del hipotálamo, los animales fueron tratados con clorpromacina durante 40 días, sacrificándose al final del tratamiento y tras 20 días de descanso. En otra serie de estudios, con el microscopio de luz y con técnicas inmunohistoquímicas valoramos la reacción a la proteína glial fibrilar ácida (GFAP) en seis regiones del sistema nervioso central de ratas tratadas con antipsicóticos típicos y atípicos. Resultados. Con el microscopio electrónico, las ratas tratadas mostraron una reducción significativa de las sinapsis axosomáticas sobre las neuronas del núcleo arcuato del hipotálamo, así como un incremento de la presencia glial evidenciable por la mayor cantidad de laminillas de astrocitos. Las modificaciones mencionadas son reversibles, tendiendo a normalizarse en los animales sacrificados a los 20 días de finalizado el tratamiento. En el estudio inmunohistoquímico la reacción astrocitaria fue muy importante en el territorio del núcleo accumbens con todos los antipsicóticos, moderada en la corteza cingular, aunque sólo con los atípicos, y discreta en el resto de las regiones. Conclusiones. Nuestros resultados confirman que las células gliales son diana de los antipsicóticos, lo que ha de contribuir a entender mejor la acción de estos fármacos y el papel de las células gliales en el normal funcionamiento del sistema nervioso y en la enfermedad mental (AU)

Introduction. The importance of the glial cells in the function of the nervous system and in its pathology has been the object of multiple studies in the last years. Specifically, their role in the action of the antipsychoticsis debated. Our study has analyzed glial reactivity in rats treated with antipsychotics. Methodology. In a first ultrastructural study of the arcuate nucleus of the hypothalamus, the animals were treated with chlorpromazine for 40 days, and were sacrificed at the end of the treatment, after 20 days of rest without treatment. In another series of studies, with the light microscope and immunohistochemistry we evaluated the immunoreactivity of the glial fibrillary acidic protein (GFAP) in six regions of the central nervous system ofrats treated with typical and atypical antipsychotics. Results. With the electron microscope, the animals treated with chlorpromazine showed a significant reduction of the axosomatic synapses on the neurons of the hypothalamic arcuate nucleus and an increase of glial presence, as noted by the greater amount of astrocyte processes. The mentioned modifications were reversible, tending to normalize in a group of animals sacrificed 20 days after completion of the treatment. In the immunohistochemical study, the glial reaction was important in the territory of the nucleus accumbens with all the antipsychotics, moderate in the cingulate cortex, although only with atypical antipsychotics, and scarcely significant in the rest of the regions. Conclusions. Our results confirm that the glial cells are targets of the antipsychotic action, and this will allow us to better understand the action of these drugs and the role of the glial cells in the normal function of the nervous system and in the mental disease (AU)

The role of methylene blue in serotonin syndrome: a systematic review.

BACKGROUND: A recent series of case reports has demonstrated a significant, previously unrecognized drug interaction between serotonin reuptake inhibitors (SRIs) and methylene blue (MB). OBJECTIVE: The authors review the case reports and clinical audits relevant to this interaction and consider the diagnosis of serotonin syndrome in these cases. METHOD: Articles were obtained from a systematic search of MEDLINE and PsychInfo databases, and from the bibliographies of relevant articles. Studies were considered relevant if the patient received MB and developed an acute confusional state, neuropsychiatric complications, or autonomic instability. RESULTS: The review identified nine case reports and two retrospective reviews; 26 patients developed an acute confusional state after MB infusion; 24 of these patients were taking an SRI, and 1 was taking clomipramine. Serotonin syndrome was a possible diagnosis in all 25 of these patients. CONCLUSION: SRIs can interact with MB, causing a serious adverse reaction consistent with serotonin syndrome.

Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity.

STUDY OBJECTIVE: Previous investigators have demonstrated amelioration of lipid-soluble drug toxidromes with infusion of lipid emulsions. Clomipramine is a lipid-soluble tricyclic antidepressant with significant cardiovascular depressant activity in human overdose. We compare resuscitation with Intralipid versus sodium bicarbonate in a rabbit model of clomipramine toxicity. METHODS: Thirty sedated and mechanically ventilated New Zealand White rabbits were infused with clomipramine at 320 mg/kg per hour. At target mean arterial pressure of 50% initial mean arterial pressure, animals were rescued with 0.9% NaCl 12 mL/kg, 8.4% sodium bicarbonate 3 mL/kg, or 20% Intralipid 12 mL/kg. Pulse rate, mean arterial pressure, and QRS duration were sampled at 2.5-minute intervals to 15 minutes. In the second phase of the experiment, 8 sedated and mechanically ventilated rabbits were infused with clomipramine at 240 mg/kg per hour to a mean arterial pressure of 25 mm Hg. Animals received either 2 mL/kg 8.4% sodium bicarbonate or 8 mL/kg 20% Intralipid as rescue therapy. External cardiac compression and intravenous adrenaline were administered in the event of cardiovascular collapse. RESULTS: Mean difference in mean arterial pressure between Intralipid- and saline solution-treated groups was 21.1 mm Hg (95% confidence interval [CI] 13.5 to 28.7 mm Hg) and 19.5 mm Hg (95% CI 10.5 to 28.9 mm Hg) at 5 and 15 minutes, respectively. Mean difference in mean arterial pressure between Intralipid- and bicarbonate-treated groups was 19.4 mm Hg (95% CI 18.8 to 27.0 mm Hg) and 11.5 mm Hg (95% CI 2.5 to 20.5 mm Hg) at 5 and 15 minutes. The rate of change in mean arterial pressure was greatest in the Intralipid-treated group at 3 minutes (6.2 mm Hg/min [95% CI 3.8 to 8.6 mm Hg/min] Intralipid versus -0.25 mm Hg/min [95% CI -1.9 to 1.4 mm Hg/min] saline solution) and 5 minutes (4.4 mm Hg/min [95% CI 3.0 to 5.9 mm Hg/min] Intralipid versus 0.06 mm Hg/min [95% CI -0.9 to 1.1 mm Hg/min] saline solution). In the second phase of the experiment spontaneous circulation was maintained in all Intralipid-treated rabbits (n=4). All animals in the bicarbonate-treated group developed pulseless electrical activity and proved refractory to resuscitation at 10 minutes (n=4, P=.023). CONCLUSION: In this rabbit model, Intralipid infusion resulted in more rapid and complete reversal of clomipramine-induced hypotension compared with sodium bicarbonate. Additionally, Intralipid infusion prevented cardiovascular collapse in a model of severe clomipramine toxicity.

Intrahepatic flow disturbance: possibility of a hidden cause of drug toxicity.

The liver has an intricate microvascular system that allows homogenous perfusion throughout the organ. However, the regulatory mechanisms of intrahepatic circulation are still unclear, and the effects of drugs on this system have rarely been reported. Oxethazaine, a topical anesthetic, was incidentally found to induce a consistent increase in portal pressure in the isolated perfused rat liver, which led us to characterize this phenomenon. For this, a vital staining method was developed to detect microcirculatory alterations in the isolated liver. Using this method, not only vasoconstrictors like endothelin-1, but the drugs oxethazaine and clomipramine, a tricyclic antidepressant, were found to induce flow redistribution to the deeper and hilar portions of the liver with minimal perfusion at the periphery, which was due to a short-circuit flow at the center owing to the constriction of the intrahepatic portal vein branches. Hepatic nerve stimulation also produced a similar flow disturbance. Since the portal pressure increases by these compounds were inhibited by the Rho-kinase inhibitors Y27632 and HA1077, portal vein branches may employ a Rho-kinase-dependent pathway for sustained contraction. However, oxethazaine, clomipramine, and endothelin-1 may activate this pathway differently. The intrahepatic flow disturbance could play a hidden role in drug toxicity of certain drugs.

Chronic treatment with clomipramine and desipramine induces deficit in long-term visuo-spatial memory of rats.

Although the effects of antidepressants in brain neurochemistry have been extensively studied, there are scarce and inconsistent data on the effect of these drugs in learning and memory. The authors studied the effect of daily administration of a single dose of either clomipramine or desipramine, two monoamine-reuptake-inhibitors with preferential serotonergic and noradrenergic profiles, respectively, during 15 days, on the visuo-spatial memory of adults rats measured through their performance in an eight-arm radial maze. Rats receiving 10 mg/kg i.p. daily of clomipramine or desipramine, 30 min before testing, committed a significantly greater number of errors than saline-treated control rats throughout the duration of the test (5 sessions, 15 days), excepting for session one (after 3 days of testing) where there were no differences between the 3 groups of rats. Results indicated that both serotonergic and noradrenergic antidepressants could impair long-term visuo-spatial memory in the rat, whereas inducing no changes in working memory, effects that are likely related to changes in brain monoamine metabolism induced by the antidepressant drugs.

Does oxidative stress contribute in tricyclic antidepressants-induced cardiotoxicity?

Different members of tricyclic antidepressants (TCAs) were found to induce free radical and oxidative stress in vitro. Accordingly, in the present study we tried to explore the possible role of oxidative stress in TCAs-induced cardiotoxicity. Rats were given a single injection of clomipramine (45 mg/kg). The cardiotoxicity was assessed by measuring ECG parameters (heart rate and QRS widening) and serum lactate dehydrogenase activity. The oxidative stress was assessed by measuring the myocardial reduced glutathione and lipid peroxides levels as well as different antioxidant enzyme activities after 24h of drug injection. In addition, we specifically investigated whether clomipramine could induce hydroxyl radical generation in vitro. The study revealed that clomipramine-induced a significant increase in lipid peroxides level (133%) and a significant decrease in glutathione level (84%) as well as a significant decrease in the activity of glutathione peroxidase and superoxide dismutase by 64% and 73%, respectively, as compared with the control group. In addition, clomipramine at concentrations 10 microM, 25 microM, 50 microM and 100 microM increased hydroxyl radical generation by 148%, 204%, 268% and 391%, respectively. Addition of hydroxyl radical scavenger or iron chelator significantly counteracted the effect of clomipramine. In conclusion, the present study demonstrates that free radical generation and oxidative stress play a role in clomipramine-induced cardiotoxicity. In addition, clomipramine can induce hydroxyl radical in vitro.