piperidines and Pheochromocytoma

In this prospective case-series study, a balanced anesthetic scheme of sevoflurane in nitrous oxide supplemented with remifentanil and sustained neuromuscular block was applied in nine patients scheduled for laparoscopic adrenalectomy for pheochromocytoma. Laparoscopic adrenalectomy to treat pheochromocytoma results in marked catecholamine release during pneumoperitoneum and tumor manipulation. Remifentanil infusion was adjusted to maintain systolic arterial pressure between 120-170 mmHg. Increased infusion rate of remifentanil was used (up to 3 microg/kg/min) to prevent and treat marked hemodynamic changes from catecholamine release during tumor manipulation. Hpotension after tumor removal was treated with additional colloids fluids and decreasing the remifentanil infusion rate by 25-50%.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Catecholamines; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Hypotension; Laparoscopy; Male; Methyl Ethers; Middle Aged; Neuromuscular Blockade; Nitrous Oxide; Pheochromocytoma; Piperidines; Postoperative Nausea and Vomiting; Prospective Studies; Remifentanil; Sevoflurane; Treatment Outcome

Topics: Adrenal Gland Neoplasms; Adult; Dexmedetomidine; Drug Therapy, Combination; Humans; Laparoscopy; Male; Methyl Ethers; Perioperative Care; Pheochromocytoma; Piperidines; Remifentanil; Sevoflurane

We describe three consecutive cases of successful anesthetic management for pheochromocytoma resection under balanced anesthesia with sevoflurane inhalation and extremely high-dose remifentanil infusion. This case series aimed to examine whether the aggressive dosing of remifentanil, exerting both depressor and bradycardic actions with short durations, is applicable for hemodynamic control during pheochromocytoma resection. The remifentanil infusion rate was set to maintain the systolic arterial pressure below 150 mmHg and heart rate below 100 beats x min(-1). In 2 of 3 cases, intraoperative hemodynamics were controlled by titrated remifentanil infusion with up to 2 and 3 microg x kg(-1) min(-1) in each case, without additional vasoactive agents. In another case, since adequate antihypertensive control was ineffective despite incremental remifentanil infusion to a maximum of 5 microg x kg(-1) x min(-1) supplemented with repeated boluses of 200 microg remifentanil, a total of 2.4 mg of nicardipine as a depressor was needed. Ephedrine 12 mg was employed following tumor removal. This anesthetic regimen thus allowed minimal or no concomitant use of depressors during tumor manipulation and vasopressors following tumor removal. In conclusion, the liberal use of remifentanil for the anesthetic management of pheochromocytoma resection appears to be simple, safe and effective.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Anesthetics, Inhalation; Anesthetics, Intravenous; Female; Humans; Infusions, Intra-Arterial; Methyl Ethers; Middle Aged; Pheochromocytoma; Piperidines; Remifentanil; Sevoflurane

Balanced anesthesia under bispectral index monitoring was administered to a child undergoing a pheochromocytoma resection. By titration of anesthesia depth, the stress response during resection could be avoided as well as postresection hypotension, without resort to additional pharmacological manipulation.

Topics: Adrenal Gland Neoplasms; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Catecholamines; Child; Electroencephalography; Heart Rate; Humans; Male; Methyl Ethers; Monitoring, Intraoperative; Pheochromocytoma; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Renin; Sevoflurane

A 12-year-old boy with bilateral adrenal pheochromocytoma pretreated with furosemide, nifedipine, prazosin, and propranolol underwent surgical removal of the tumors. General anesthesia with desflurane, remifentanil infusion and thoracic epidural analgesia was performed. To control the blood pressure (BP), remifentanil up to 1 microg.kg(-1).min(-1) infusion rate, sodium nitroprusside, and esmolol infusions were administered successfully. Following the ligation of the adrenal veins, hemodynamic parameters were stable and neither inotropic support nor corticosteroid replacement was required. We concluded that remifentanil-based anesthesia combined with low-dose desflurane and thoracic epidural analgesia may reduce the need for vasoactive drugs in the anesthesia management of pheochromocytoma. This combination may not prevent the hemodynamic fluctuations during tumor manipulation, but appears to facilitate a rapid and stable postoperative recovery.

Topics: Adrenal Gland Neoplasms; Adrenergic beta-Antagonists; Anesthesia, Epidural; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Antihypertensive Agents; Blood Pressure; Child; Desflurane; Humans; Isoflurane; Male; Nitroprusside; Pheochromocytoma; Piperidines; Propanolamines; Remifentanil

The present report monitors the hemodynamic fluctuations in a 63 year-old female patient undergoing laparoscopic resection of right adrenal pheochromocytoma during remifentanil-based anesthesia. Anesthesia was induced with lidocaine 1 mg x kg(-1), propofol 3.5 mg x kg(-1), and cisatracurium 0.2 mg(-1) x kg(-1) and a remifentanil infusion was started at a rate of 1 ug.kg (-1) x min(-1). Anesthesia was then maintained with remifentanil infusion (0.5 microg(-1) x kg(-1) x min), sevoflurane 1-2% (end-tidal) in a mixture of air/oxygen (3:1), and a continuous infusion of cisatracurium. There were no significant changes of BP and HR following tracheal intubation or surgical incision. However, creation of pneumoperitoneum as well as tumor manipulation resulted in a dramatic increase of systolic BP and pulmonary artery pressure, associated with a decrease in cardiac output. These hemodynamic changes were unresponsive to an increase in the remifentanil infusion rate up to 1.5 ug.kg(-1) x min(-1), but were controlled by increasing the concentration of sevoflurane up to 6%, and by a nitroglycerin (NTG) infusion. Ten min after removal of the tumor, and despite discontinuation of the NTG infusion as well as a reduction in the remifentanil infusion and sevoflurane concentration, the BP decreased down to 64/43 mmHg. In conclusion, the present report shows in a patient undergoing laparoscopic resection of adrenal pheochromocytoma that remifentanil does not prevent the severe hypertensive episodes associated with intraperitoneal carbon dioxide insufflation or tumor manipulation. However, it can be titrated to prevent the hemodynamic reflex response to tracheal intubation and surgical stimulation.

Topics: Adrenal Gland Neoplasms; Anesthetics, Intravenous; Female; Hemodynamics; Humans; Laparoscopy; Middle Aged; Pheochromocytoma; Piperidines; Remifentanil

Topics: Adult; Anesthetics, Inhalation; Anesthetics, Intravenous; Atracurium; Cardiopulmonary Bypass; Catheterization, Central Venous; Desflurane; Dose-Response Relationship, Drug; Heart Neoplasms; Hemodynamics; Humans; Intubation, Intratracheal; Isoflurane; Male; Midazolam; Neuromuscular Blocking Agents; Norepinephrine; Pheochromocytoma; Piperidines; Propofol; Remifentanil; Vasoconstrictor Agents

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Catecholamines; Female; Humans; Intraoperative Complications; Laparoscopy; Male; Multiple Endocrine Neoplasia Type 2a; Pheochromocytoma; Piperidines; Propofol; Remifentanil

Topics: Adrenal Gland Neoplasms; Adult; Anesthetics, Intravenous; Female; Humans; Hypertension; Intraoperative Complications; Male; Pheochromocytoma; Piperidines; Remifentanil

The use of remifentanil has been recommended because of its ability to minimise the hypertensive response to tracheal intubation and surgical stimulation in various types of surgery. We describe the use of remifentanil in the anaesthetic management of three cases of open adrenalectomy, two for removal of a phaeochromocytoma and one for removal of an adrenal cortical tumour. Although the use of remifentanil was associated with no adverse events in the patient undergoing resection of the adrenal cortical tumour, its administration was associated with significant hypotension and bradycardia in the two phaeochromocytoma patients, who had both been given alpha- and beta-adrenergic receptor blocking drugs before surgery. It did not prevent the increases in blood pressure or plasma catecholamine levels associated with tumour manipulation in these patients. Remifentanil should therefore be used with caution in patients receiving alpha- and beta-adrenergic receptor blocking drugs. The use of potent vasodilators may still be necessary during tumour manipulation even if remifentanil is being infused.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Anesthetics, Intravenous; Epinephrine; Female; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Pheochromocytoma; Piperidines; Remifentanil

Halofuginone has recently been shown to inhibit tumor progression of various types of cancers. The antitumoral effect was associated with decreased tumor angiogenesis rather than a direct cytostatic effect on the tumor cells. The antiangiogenic action of the drug could be related to its inhibition of collagen type I synthesis, inhibition of matrix metalloproteinases (MMPs), or via both mechanisms because both collagen synthesis and MMP activity have been shown to be involved in angiogenesis. Vascular endothelial growth factor (VEGF), in addition to its effect on endothelial cell proliferation, has been shown to be a potent inducer of MMP expression. Because von Hippel-Lindau (VHL)-associated tumors express high levels of VEGF, it was of interest to ascertain the potential usefulness of halofuginone for treatment of these tumors. Pheochromocytoma tissue fragments obtained at surgery from a VHL type 2a patient were propagated s.c. in male BALB/c nu/nu (nude) mice. For experiments, 2-3-mm tumor fragments were transplanted secondarily s.c. to nude mice. Two treatment groups received halofuginone in standard lab chow at 3 and 5 ppm; control animals received regular chow. All groups were followed for 6 weeks after transplantation. A marked and significant diminution of tumor size and weight was observed in the drug-treated animals (>90% reduction of mean tumor volume for both the 3 and 5 ppm groups). In vivo magnetic resonance imaging analysis of tumors in halofuginone-treated animals showed a significant reduction of vascular functionality. Immunohistochemical studies revealed decreased collagen type I levels and vascular density in treated tumors and gelatinase assays of tumor extracts revealed a reduction of MMP-2 and MMP-9 activity in halofuginone-treated cells. Taken together, our data indicate that therapy directed at blocking MMP activity (presumably related to excessive VEGF expression in VHL) and reduction of type I collagen deposition curtails angiogenesis and thereby presumably tumor growth in this model system.

Topics: Animals; Antineoplastic Agents; Cell Division; Collagen; Collagen Type I; Disease Progression; Electrophoresis, Polyacrylamide Gel; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Pheochromocytoma; Piperidines; Protein Synthesis Inhibitors; Quinazolines; Quinazolinones; Rats; Temperature; Time Factors; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

The laparoscopic adrenalectomy approach to phaeochromocytoma surgery offers the opportunity to use new short-acting drugs to facilitate rapid recovery.. We report on 2 cases who underwent laparoscopic resection of phaeochromocytoma. The first was a 40-year-old lady who had been started on phenoxybenzamine 20 mg bd, but developed a recurrence of bronchial asthma after starting atenolol which was subsequently stopped. The second was a 51-year-old lady with neurofibromatosis who was taking phenoxybenzamine 20 mg bd and propanolol 20 mg tds.. The intraoperative management was facilitated by the stress suppressive effects of remifentanil infusion combined with nitroprusside as a vasodilator, and desflurane as an anaesthetic.. Both patients were extubated at the end of surgery and made uneventful recovery.. Remifentanil possesses several useful properties, which deserve serious consideration in phaeochromocytoma surgery, particularly in the instance where beta-blockade is contraindicated. In combination with other titratable short-acting agents, it potentially facilitates rapid recovery especially following the laparoscopic approach to adrenalectomy.

Topics: Adrenal Gland Neoplasms; Adult; Analgesics, Opioid; Female; Humans; Laparoscopy; Middle Aged; Nitroprusside; Pheochromocytoma; Piperidines; Remifentanil; Vasodilator Agents

Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effects of sub-chronic donepezil administration on nAChRs in rats and rat pheochromocytoma PC-12 cells. Male Sprague Dawley rats were administered donepezil (0.7 and 2.4 micromoles/kg), nicotine (2.5 micromoles/kg) or saline subcutaneously twice daily for 14 days, PC-12 cells were incubated with 10(-6) to 10(-4) M donepezil for 72 hours and nAChR levels were determined by receptor binding assay using the nAChR ligands [3H]-epibatidine (EPI) for non-alpha 7 nAChRs and [3H]-methyllyconitine (MLA) for alpha 7 nAChRs. Chronic donepezil administration at 1.4 micromoles/kg/day and 4.8 micromoles/ kg/day significantly increased [3H]-epibatidine binding in the cortex to 126 +/- 1.3% and 127 +/- 3.2% of the saline control animals, respectively. [3H]-MLA binding in the cortex increased to 114 +/- 4.4% and 124 +/- 2.8% of the control group for the high and low dose groups, respectively. Hippocampal [3H]-EPI binding in the low dose and high dose groups significantly increased to 135 +/- 3.6% and 125 +/- 4.6% of the controls, respectively while there were no changes in the level of [3H]-MLA binding. In striatal homogenates, neither [3H]-EPI nor [3H]-MLA binding were significantly effected at either dose of donepezil. In PC-12 cells, [3H]-EPI binding was increased at the non-physiological 10(-4)M concentration only. There was no effect of donepezil on [3H]-MLA binding at any concentration examined. These results indicate that donepezil increases cortical alpha 7 and non-alpha 7 nAChRs, hippocampal non-alpha 7 nAChRs but does not influence striatal nAChR levels. Furthermore, the lack of an effect on the alpha 7-nAChRs in PC-12 cells suggests that the increase in cortical alpha 7 nAChRs may be an indirect effect of increased acetylcholine levels in vivo.

Topics: Aconitine; Animals; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Hippocampus; In Vitro Techniques; Indans; Male; Nicotinic Agonists; Nicotinic Antagonists; Pheochromocytoma; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic

The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease.

Topics: Adrenal Gland Neoplasms; Amyloid beta-Peptides; Animals; Cell Survival; Cholinesterase Inhibitors; Donepezil; Indans; Mecamylamine; Neurons; Neuroprotective Agents; Neurotoxins; Nicotinic Antagonists; PC12 Cells; Peptide Fragments; Pheochromocytoma; Piperidines; Rats; Tacrine; Tubocurarine

Chimeras between the human vesicular acetylcholine transporter (hVAChT) and the neuronal isoform of the human vesicular monoamine transporter (hVMAT2) have been constructed and stably expressed in a rat pheochromocytoma cell line (PC12) in an effort to identify cholinergic-specific domains of VAChT. Examination of the transport properties of a chimera in which the N-terminal portion (up to putative transmembrane domain II and including the lumenal glycosylated loop) of hVAChT was replaced with hVMAT2 sequences (2/V@NheI) revealed that its apparent affinity for acetylcholine (ACh) was reduced approximately seven-fold compared to wild-type. However, the affinity of this chimera for vesamicol did not significantly differ from hVAChT. Similarly, the 2/V@NheI chimera retained its preferential targeting to the small synaptic-like vesicles found in PC12 cells in agreement with our recently reported observations that the synaptic vesicle targeting domain resides in the cytoplasmic tail of VAChT.

Topics: Acetylcholine; Adrenal Gland Neoplasms; Animals; Binding Sites; Biological Transport; Carrier Proteins; Humans; Kinetics; Membrane Glycoproteins; Membrane Transport Proteins; Neuromuscular Depolarizing Agents; Neuropeptides; PC12 Cells; Pheochromocytoma; Piperidines; Rats; Recombinant Fusion Proteins; Synaptic Vesicles; Transfection; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins; Vesicular Transport Proteins

The characteristics of ATP-dependent transport of acetylcholine (ACh) in homogenates of pheochromocytoma (PC-12) cells stably transfected with the human vesicular acetylcholine transporter (VAChT) cDNA are described. The human VAChT protein was abundantly expressed in this line and appeared as a diffuse band with a molecular mass of approximately 75 kDa on Western blots. Vesicular [3H]ACh accumulation increased approximately 20 times over levels attained by the endogenous rat VAChT, expressed at low levels in control PC-12 cells. The transport of [3H]ACh by human VAChT was dependent upon the addition of exogenous ATP at 37 degrees C. Uptake was abolished by low temperature (4 degrees C), the proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (2.5 microM) and bafilomycin A1 (1 microM), a specific inhibitor of the vesicular H+-ATPase. The kinetics of [3H]ACh uptake by human VAChT were saturable, exhibiting an apparent Km of 0.97 +/- 0.1 mM and Vmax of 0.58 +/- 0.04 nmol/min/mg. Maximal steady-state levels of vesicular [3H]ACh accumulation were directly proportional to the concentration of substrate present in the medium with saturation occurring at approximately 4 mM. Uptake was stereospecifically inhibited by L-vesamicol with an IC50 of 14.7 +/- 1.5 nM. The apparent affinity (Kd) of [3H]vesamicol for human VAChT was 4.1 +/- 0.5 nM, and the Bmax was 8.9 +/- 0.6 pmol/mg. The turnover (Vmax/Bmax) of the human VAChT was approximately 65/min. This expression system should prove useful for the structure/function analysis of VAChT.

Topics: Acetylcholine; Adrenal Gland Neoplasms; Animals; Biological Transport, Active; Carrier Proteins; Cytosol; Humans; Kinetics; Membrane Transport Proteins; Neuromuscular Depolarizing Agents; PC12 Cells; Pheochromocytoma; Piperidines; Rats; Recombinant Proteins; Substrate Specificity; Tetrabenazine; Transfection; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

Phencyclidine binds with high affinity to both PCP and sigma receptors. We investigated whether the clonal cell line PC12 expressed either of these receptors, and found that these cells contain a haloperidol-sensitive (+)-[3H]3-PPP binding site with a KD of 56 nM, but no PCP binding sites. The (+)3-PPP binding sites in PC12 cells displayed a reversed stereoselectivity for the benzomorphan opiates compared to CNS sigma receptors. Neither nerve growth factor nor sodium butyrate treatment affected the expression of either (+)-3-PPP or TCP binding sites in PC12 cells.

Topics: Adrenal Gland Neoplasms; Animals; Cell Line; Cell Membrane; Dopamine Agents; Humans; Pheochromocytoma; Piperidines; Radioligand Assay; Receptors, Drug

We investigated the effects of phencyclidine (PCP), a psychotomimetic dissociative anesthetic, and several related drugs on voltage-dependent K+ currents in PC12 cells, a neuron-like clonal cell line derived from a rat pheochromocytoma. Whole-cell voltage clamp recordings demonstrated two kinetically distinct voltage-dependent outward (K+) current components in these cells: a rapidly activating and inactivating component, IA, that was selectively eliminated by 4-aminopyridine (2 mM) and a slowly activating, minimally inactivating (sustained) component, IK, that was specifically blocked by tetraethylammonium (20 mM). PCP (1-100 microM) produced a dose-dependent blockade of both IK and IA, however, at low doses the drug selectively reduced IK with little effect on IA; the IC50s for blockade of IK and IA were 4 and 25 microM, respectively. The blockade of IK was voltage-dependent so that the degree of block decreased with increasing depolarization, indicating that the blocking mechanism is likely one in which the positively charged PCP molecule is drawn into the channel pore. Several PCP related drugs also suppressed IK. Thienyl-PCP (TCP), a drug that is behaviorally more potent than PCP, partially blocked IK at low doses (31% at 1 microM), but even at high doses (25 microM) the degree of block was never as great as that produced by PCP. The optically active PCP congeners (+)-PCMP (1-(1-phenylcyclohexyl)-3-methyl-piperidine) and dexoxadrol were also potent blockers of IK. However, in contrast to the stereospecificity these compounds demonstrate in binding to high-affinity PCP receptors and in eliciting PCP-like behavioral responses, their enantiomers (-)-PCMP and levoxadrol showed similar potencies as the parent compounds in blocking IK. These results demonstrate that PCP and related drugs are powerful, selective blockers of IK in PC12 cells. The structure-activity studies indicate that this effect occurs at a site that is pharmacologically distinct from the behaviorally relevant PCP receptor. Blockade of K+ channels is unlikely to be responsible for the psychotomimetic or anti-convulsant properties of PCP, but could account for the convulsant potential of the drug.

Topics: Anesthetics; Animals; Dioxolanes; Electric Stimulation; Ion Channels; Membrane Potentials; Phencyclidine; Pheochromocytoma; Piperidines; Potassium; Rats; Tumor Cells, Cultured

Treatment of PC12 cells with AH5183 at concentrations of 40 nM to 40 microM inhibited the loading of newly synthesized acetylcholine into storage vesicles, but it had little effect on choline uptake, acetylcholine synthesis, or the vesicular content of previously loaded acetylcholine. AH5183 at 4 microM inhibited the Ba2+-evoked release of newly synthesized acetylcholine but not of older stores of acetylcholine. These data indicate that the vesicles are the source of the acetylcholine released from stimulated cells. AH5183 had little effect on the vesicular loading of dopamine and on the evoked release of dopamine, but at concentrations of 4-40 microM it did inhibit dopamine uptake by the cells.

Topics: Acetylcholine; Animals; Cells, Cultured; Cytoplasmic Granules; Dopamine; Phencyclidine; Pheochromocytoma; Piperidines; Rats; Secretory Rate