piperidines and Pituitary-Neoplasms

Endoscopic endonasal transphenoidal surgery has been recently proposed as a minimally invasive procedure for the treatment of pituitary adenomas. The main objective of the anaesthesiologist is to induce sufficient haemodynamic control together with rapid recovery at the end of surgery. The aim of this study was to examine recovery profile, surgical operative conditions and haemodynamic differences using remifentanil infusion with either propofol target controlled infusion system or sevoflurane.. Forty-four adult patients were enrolled in a prospective, randomized, single-blind, two-group study: Group P received propofol target controlled infusion system and remifentanil; Group S received sevoflurane and remifentanil for maintenance of anaesthesia.. No statistically significant differences between the two groups with regards to the haemodynamic changes, operative conditions as assessed by a four-step bleeding score (0-3), were obtained. Recovery times were considerably shorter after remifentanil-sevoflurane in comparison with remifentanil-propofol target controlled infusion system group (7.4 vs. 12.8 min, P < 0.01).. This study demonstrates that sevoflurane-remifentanil gives a faster recovery and equivalent intraoperative status compared with propofol target controlled infusion system with remifentanil for the endoscopic endonasal transphenoidal approach.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Endoscopy; Female; Heart Rate; Humans; Male; Methyl Ethers; Middle Aged; Minimally Invasive Surgical Procedures; Nasal Cavity; Piperidines; Pituitary Diseases; Pituitary Neoplasms; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Single-Blind Method; Sphenoid Bone; Treatment Outcome

In a multi-center trial, the feasibility of combining remifentanil (RF) and target-controlled infusion of propofol (P) for patients undergoing transsphenoidal resection of the pituitary gland was tested. After IRB approval, 74 patients (29 male/45 female) were included in the study. The concentration of RF and the target concentration of P were recorded as were heart rate (HR) and mean arterial blood pressure (MAP). For intubation the RF dosage was 0.26 +/- 0.06 microgram.kg-1.min-1 and the target concentration of P was 3.16 +/- 0.63 micrograms.ml-1. After induction, HR and MAP decreased significantly. The painful events of the operation were preparation of the nasal mucous membrane and penetration of the sella turcica. By adjusting the RF dose to 0.31 +/- 0.09 microgram.kg-1. min-1 and the target concentration of P to 3.48 +/- 1.49 micrograms.ml-1, an increase of HR and MAP above initial values was avoided at this time. Hypotension and bardycardia were treated in eight patients (10.8%) with a vasopressor, in four patients (5.4%) with atropine and in four more patients (5.4%) with a combination of these drugs. Two patients (2.7%) needed antihypertensive therapy. The average time interval between the end of P-TCI and spontaneous breathing was 6 +/- 3 min (median 6 min) and till patients opened their eyes 9 +/- 4 min (median 9 min). After 13 +/- 4 min (median 13 min) the patients became orientated. The average doses of analgetics were 19.5 +/- 19.9 mg piritramide and 1.8 +/- 1.0 g metamizol during the first 12 hours postoperatively. Eight patients (10.8%) did not need any analgetics. We suggest that the combination of RF and P as a "fast track concept" can supplement the repertoire of anaesthetic managements used for transsphenoidal resection of the pituitary gland.

Topics: Adenoma; Adult; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Feasibility Studies; Female; Heart Rate; Humans; Hypophysectomy; Male; Middle Aged; Pain Measurement; Piperidines; Pituitary Neoplasms; Propofol; Remifentanil; Sphenoid Sinus

The authors have evaluated remifentanil for intraoperative analgesia in endonasal endoscopic surgery for pituitary lesions.. a perspective, randomized and comparative study between remifentanil and fentanyl for intraoperative analgesia was performed in an operating room of the neurosurgical department at University. Sixty patients of both sexes were studied and randomly divided into 2 groups. Patients were premedicated with fentanyl 0.15 microg.kg(-1) and atropine 0.01 microg.kg(-1) (group F) or with atro-pine and remifentanil 0.25 microg.kg(-1) min-1 (group R); induction was with propofol 2.0 microg.kg(-1) and maintenance with titrated infusion of propofol and for intraoperative analgesia, fentanyl as bolus injection of 1.0-1.5 microg.kg(-1) (group F) or a titrated infusion of remifentanil (group R). The following parameters were studied: MAP, HR, bleeding, awakening times, adverse effects and VAS.. Much more stable hemodynamic parameters during surgery in patients treated with remifentanil; labetalol was administered in 10% of patients in group F; no significant differences as regards the adverse effects and VAS. Faster awakening time was obtained in the remifentanil group as compared with the fentanyl group.. Remifentanil analgesia (mean dose of 0.37 microg.kg(-1).min-1) in patients undergoing endonasal endoscopic surgery of the sellar region provides a more efficacious cardiocirculatory control with reduced bleeding and faster psychosensorial recovery.

Topics: Adult; Analgesia; Analgesics, Opioid; Anesthetics, Intravenous; Blood Pressure; Endoscopy; Female; Heart Rate; Humans; Male; Middle Aged; Piperidines; Pituitary Gland; Pituitary Neoplasms; Propofol; Remifentanil

The availability of a new specific anti 5HT-2 compound, ritanserin (RTS), led us to further investigate the role of serotonin in controlling PRL secretion. The drug was administered to normoprolactinaemic subjects and to patients with differing hyperprolactinaemic conditions. While RTS failed to modify PRL levels in normoprolactinaemic subjects and in patients with PRL-secreting pituitary adenomas, a marked decrease in the hormone was obtained in patients with functional and puerperal hyperprolactinaemia. The lack of effect of RTS in PRL-secreting pituitary adenomas suggests that the reported suppression of PRL by other antiserotoninergic drugs, such as metergoline, is probably due to their concomitant dopaminergic activity.

Topics: Adenoma; Female; Follicular Phase; Humans; Hyperprolactinemia; Piperidines; Pituitary Neoplasms; Postpartum Period; Pregnancy; Prolactin; Ritanserin; Serotonin Antagonists; Single-Blind Method; Sulpiride

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson's syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing's disease and who had Nelson's syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson's syndrome. These results show that it is not indicated in these patients.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Ketanserin; Male; Middle Aged; Nelson Syndrome; Piperidines; Pituitary Neoplasms; Serotonin Antagonists

Topics: Azetidines; Craniopharyngioma; Female; Fluorescein Angiography; Fundus Oculi; Humans; MAP Kinase Kinase 1; Middle Aged; Piperidines; Pituitary Neoplasms; Protein Kinase Inhibitors; Retinal Diseases; Tomography, Optical Coherence; Vemurafenib

Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (

Topics: Animals; Benzazepines; Cations; Cell Line, Tumor; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Transport; Ivabradine; Kinetics; Patch-Clamp Techniques; Piperidines; Pituitary Neoplasms; Potassium; Shab Potassium Channels; Sodium

In patients undergoing pituitary surgery using a transsphenoidal approach, anesthesia emergence should be smooth with minimal coughing. Recent studies demonstrated that a target-controlled infusion of remifentanil effectively suppresses coughing induced by the endotracheal tube. We investigated the EC95 of remifentanil for smooth emergence without coughing from propofol anesthesia in patients undergoing transsphenoidal hypophysectomy.. A total of 41 patients undergoing transsphenoidal hypophysectomy, aged 20 to 65 years, with an ASA physical status of I or II, were enrolled. For all participants, anesthesia was induced and maintained with a target-controlled infusion of remifentanil and propofol using predicted effect-site concentration (Ce). A biased coin design up-and-down sequential allocation and isotonic regression method were used to determine the remifentanil EC95 to prevent emergence coughing. In addition, we observed recovery profiles after anesthesia.. According to the study design, 19 patients received remifentanil 2.6 ng/mL Ce and 22 patients received a lower Ce, ranging from 1.0 to 2.2 ng/mL. The EC95 of remifentanil to prevent coughing was estimated as 2.51 ng/mL (95% confidence interval, 2.28-2.57 ng/mL). Despite the exclusion of 1 case because of delayed emergence, 17 of 18 patients receiving 2.6 ng/mL of remifentanil had bradypnea (<10 breaths/min) until 3 minutes after extubation. However, end-tidal carbon dioxide was maintained below 55 mm Hg during anesthetic emergence and respiratory rate recovered within 20 minutes of admission to the postanesthetic care unit.. The EC95 of remifentanil for smooth emergence from anesthesia was 2.51 ng/mL after transsphenoidal hypophysectomy.

Topics: Adult; Algorithms; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Female; Humans; Hypophysectomy; Male; Middle Aged; Piperidines; Pituitary Neoplasms; Propofol; Remifentanil; Sphenoid Bone; Treatment Outcome

7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K(+) -channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study.. The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na(+) current (INa ) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca(2+) -activated K(+) current and the activity of large-conductance Ca(2+) -activated K(+) (BKCa ) channels were also studied.. KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa -channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A.. Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa . The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.

Topics: Calcium; Cell Line, Tumor; HEK293 Cells; Humans; Ion Channel Gating; Piperidines; Pituitary Neoplasms; Potassium Channels; Sodium; Xanthines

Combination of local and regional anesthetic agents are widely used in emergency and surgical setting and the interaction between the medications used in general anesthesia and these local and/or regional anesthetic becomes a growing concern in current patient management system. The interaction between general anesthetic agents and the local anesthetic agents given epidurally, spinally, intravenously or intramuscularly and the effects of BIS monitorisation on combined propofol-remifentanil anesthesia are examined in several studies. In literature, there is no research investigating the effect of lidocaine infusion on remifentanil and anesthetic dosage used in hypotensive anesthesia. The aim of this study is to examine this effect.. We studied 39, ASA I-II patients undergoing elective transsphenoidal endoscopic hypophyseal adenoma excision procedure. After preoperative examination and informed consent of the patient, monitorisation with non invasive blood pressure measurement, electrocardiography, pulse oxymeter and Bispectral Index (BIS) was performed. 0.9% NaCl infusion was started via a 20 G route. Lidocaine (1%) was given as 1.5 mg.kg(-1) hour-1 infusion after 1.5 mg.kg(-1) bolus dosage given in 10 minutes. Lidocaine infusion was started at the same time with anesthesia induction and was stopped after surgery. 0.9% NaCl was given as bolus dosage and as infusion in control group. Induction was maintained via propofol (1%) with 10 mg (1 ml) doses given in 5 seconds and it was applied in every 15 seconds until BIS < 45'. During maintenance of anesthesia desflurane-remifentanil-oxygen (50%)-air (50%) mixture was used. Desflurane was titrated by BIS measurement between 40 and 5012. Remifentanil infusion was started after propofol induction with 0.1 µg.kg(-1).min(-1) dosage and it was titrated between 0.1-0.5 µg.kg(-1).min(-1) levels. For intubation, rocuronium with 0.8 mg kg(-1) dosage was given during induction. After the surgical procedure, it was antagonised with neostigmine and atropine. For postoperative analgesia 1 g paracetamole was given IV after the surgery within 15 minutes and it was reapplied with 1 gr doses in every 6 hours. After extubation, the pain of the patients was examined at 15. minute at the recovery room with VRS (VRS; 0-no pain, 1-slight pain, 2-moderate pain, 3-severe pain). If VRS was greater than 2, 50 mg dolantine was given IM. For prevention of nausea and vomitting, 8 mg ondansetron was given IV. Perioperative total doses of remifentanil, desflurane (ml) (anesthesia machine records) and lidocaine (mg) were recorded after the surgery. Perioperative hemodynamic parameters (systolic, diastolic, mean blood pressures, heart rates) were recorded after monitorisation (basal), after intubation, after the start of the surgery and after extubation.. There were no statistically significant difference between two groups with respect to patient characteristics (age, gender, weight, length, Basal Mass Index = BMI) (p > 0.05). The duration of anesthesia and surgery were also not different statistically (p > 0.05). There were no statistically significant difference between two groups with respect to remifentanil dose (p > 0.05). There were no statistically significant difference between two groups with respect to eye opening and extubation times (p > 0.05). When usage rates and amounts of dolantine, paracetamole and novalgine were compared, we found no statistically significant difference between two groups (p > 0.05). Basal mean arterial blood pressure measurements of the patients and mean arterial blood pressure measurements of the patients after induction, after intubation, 1 minute, 5 minutes, 10 minutes, 15 minutes after discharge of surgery and after extubation showed no statistically significant difference (p > 0.05). Basal heart rate measurements and the heart rates after induction, after intubation, 1 minute, 5 minutes, 10 minutes, 15 minutes after discharge of surgery and after extubation showed no statistically significant difference (p > 0.05). Basal BIS measurements and BIS measurements after induction, after intubation, 1 minute, 5 minutes, 10 minutes, 15 minutes after discharge of surgery and after extubation showed no statistically significant difference (p > 0.05).. We found no statistically significant difference between two groups about different parameters. But new investigations with different local anesthetic agents may show sigificant difference and usage of these local anesthetic agents may be advised.

Topics: Adenoma; Adolescent; Adult; Aged; Anesthetics, Combined; Anesthetics, Intravenous; Anesthetics, Local; Blood Pressure; Blood Pressure Monitors; Consciousness Monitors; Drug Administration Schedule; Electrocardiography; Endoscopy; Female; Heart Rate; Humans; Hypotension; Infusions, Parenteral; Intraoperative Neurophysiological Monitoring; Lidocaine; Male; Middle Aged; Operative Time; Oximetry; Pain, Postoperative; Piperidines; Pituitary Neoplasms; Predictive Value of Tests; Remifentanil; Time Factors; Treatment Outcome; Young Adult

Deregulation of the G1-S transition of the cell cycle is a common feature of human cancer. Tumor-associated alterations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27Kip1), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development. Using gene-targeted mouse models, we report in this article that Cdk4 resistance to INK4 inhibitors, due to the Cdk4 R24C mutation, strongly cooperates with p27(Kip1) deficiency in tumor development. No such cooperation is observed between Cdk4 R24C and p18(INK4c) absence, suggesting that the only function of p18INK4c is inhibiting Cdk4 in this model. Cdk4(R/R) knock in mice, which express the Cdk4 R24C mutant protein, develop pituitary tumors with complete penetrance and short latency in a p27Kip1-/- or p27Kip1+/- background. We have investigated whether this tumor model could be useful to assess the therapeutic activity of cell cycle inhibitors. We show here that exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumor-free survival in a significant percentage of treated mice. These data suggest that genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer.

Topics: Alleles; Animals; Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p18; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Disease Models, Animal; Flavonoids; Mice; Mice, Inbred C57BL; Mutation; Piperidines; Pituitary Neoplasms; Proto-Oncogene Proteins; Tumor Suppressor Proteins

A severe intractable delirium caused by the basal forebrain vascular lesion and its dramatic recovery after donepezil administration were reported. A 68-year-old man had suffered for a month from delirium of mixed type caused by the right basal forebrain vascular lesion after surgery for craniopharyngioma. Magnetic resonance imaging (MRI) showed hemorrhagic infarcts in the head of the right caudate nucleus and the right basal forebrain of the medial septal nucleus, diagonal band of Broca and nucleus basalis of Meynert. He had been treated with anti-psychotics, anti-depressants and hypnotics, which resulted in little improvement. Donepezil administration dramatically improved his intractable delirium at the 19th post-donepezil administration day, but this was followed by amnestic symptoms. Clinical correlates of delirium with the basal forebrain lesion and efficacy of donepezil support the hypocholinergic theory of delirium.

Topics: Aged; Basal Ganglia Cerebrovascular Disease; Basal Nucleus of Meynert; Craniopharyngioma; Delirium; Donepezil; Humans; Indans; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Pituitary Neoplasms; Postoperative Complications; Prosencephalon; Sleep Wake Disorders; Vision Disorders

Linoleoylamide is physiological constituent of neurons. The effects of this agent, also a sleep-inducing agent, on ion currents in pituitary GH(3) cells were investigated. Hyperpolarization-elicited K(+) currents in GH(3) cells bathed in a high-K(+), Ca(2+)-free solution were studied to determine the effects of linoleoylamide and other related compounds on the I(K(IR)) that was sensitive to inhibition by E-4031 and identified as an erg (ether-à-go-go-related-gene) current. Linoleoylamide suppressed the amplitude of I(K(IR)) in a concentration-dependent manner with an IC(50) value of 5 microM. Oleamide (20 microM) inhibited the amplitude of I(K(IR)), while neither arachidonic acid (20 microM) nor 14,15-epoxyeicosatrienoic acid (20 microM) had an effect on it. In GH(3) cells incubated with anandamide (20 microM) or arachidonic acid (20 microM), the linoleoylamide-induced inhibition of I(K(IR)) remained unaltered. In inside-out patches, arachidonic acid (20 microM) and 14,15-epoxyeicosatrienoic acid (20 microM) stimulated large-conductance Ca(2+)-activated K(+) channels; however, linoleoylamide (20 microM) had little or no effect on them. Under current-clamp mode, linoleoylamide (20 microM) increased the firing rate. In IMR-32 neuroblastoma cells, linoleoylamide also suppressed I(K(IR)). This study provides the evidence that linoleoylamide has a depressant effect on the erg current, and suggests that this effect may affect hormonal secretion.

Topics: 8,11,14-Eicosatrienoic Acid; alpha-Linolenic Acid; Amides; Animals; Arachidonic Acid; Arachidonic Acids; Calcium; Calcium Channels, L-Type; Dose-Response Relationship, Drug; Endocannabinoids; Humans; Hydantoins; Imidazoles; Imidazolidines; Infant, Newborn; Linoleic Acids; Membrane Potentials; Neuroblastoma; Patch-Clamp Techniques; Piperazines; Piperidines; Pituitary Neoplasms; Polyunsaturated Alkamides; Potassium Channels; Pyridines; Tumor Cells, Cultured

Hyperpolarization-elicited potassium currents in GH3/B6 cells bathed in high-potassium external solution were recorded to assess effects of the class III antiarrhythmic agent E-4031 on the inactivating inward-rectifying potassium current (IK,IR). E-4031 potently blocked IK,IR with an IC50 value of 10 nM. The complete block of IK,IR achieved with concentrations >/= 1 microM revealed the presence of a non-inactivating outward-rectifying current which contributed to the membrane currents recorded under control conditions. The time dependence of the IK,IR block depended on the concentration of E-4031. Two other methanesulfonanilides were investigated: WAY-123,398 (10 microM) also totally blocked IK,IR, while sotalol (100 microM) was almost ineffective. Also lanthanum (100 microM) had only a very small effect on IK,IR. E-4031 did not affect sodium, calcium and voltage-dependent outward-rectifying potassium currents, suggesting a selective block of IK,IR in GH3/B6 cells. In an external solution containing 16 mM potassium, the E-4031-sensitive current was present as a steady outward current within a broad potential range positive to the potassium equilibrium potential, EK. In many, but not all, cells E-4031 induced an increase in the frequency of action potentials suggesting an important role of IK,IR in controlling cell excitability. Our experiments show that E-4031 is a valuable tool in characterizing IK,IR and its physiological function.

Topics: Animals; Anti-Arrhythmia Agents; Dose-Response Relationship, Drug; Piperidines; Pituitary Neoplasms; Potassium Channels; Pyridines; Rats; Tumor Cells, Cultured

Two series of (N-benzylpiperidin-4-yl)- and (9-azabicyclo[3.3.1]nonan- 3 beta-yl)benzamides were prepared, and in vitro binding assays were used to measure the affinity of these compounds for dopamine D2, dopamine D3, serotonin 5-HT2, and alpha 2-adrenergic receptors. The results of these studies indicated compounds 23, 26b, and 34 have the selectivity needed for in vivo studies of the D2 (and possibly D3) receptors. 18F-Labeled analogues of 23, 26b and 34 were prepared by N-alkylation of the corresponding desbenzyl precursors with [18F]-4-fluorobenzyl iodide. Preliminary in vivo studies demonstrated that [18F]-23 and [18F]-26b are suitable candidates for further evaluation in positron emission tomography imaging studies. The slow rate of washout of [18F]-34 from nondopaminergic regions and its comparatively high lipophilicity indicates that this compound may not be suitable for imaging studies because of a high level of nonspecific binding.

Topics: Animals; Baculoviridae; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Fluorine Radioisotopes; Molecular Structure; Moths; Piperidines; Pituitary Neoplasms; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Serotonin; Recombinant Proteins; Structure-Activity Relationship; Tomography, Emission-Computed; Tumor Cells, Cultured

The effects of diphenylbutylpiperidine (DPBP) antipsychotics on Ca2+ currents and prolactin (PRL) synthesis were studied in rat pituitary growth hormone (GH) cell lines (GH3 and GH4C1). In whole-cell patch-clamp experiments, DPBPs including fluspirilene, penfluridol, and pimozide at concentrations ranging from 0.25 to 5 microM each blocked current through low threshold T-type as well as high threshold L-type channels. Each of the drugs preferentially blocked T-type current, and complete inhibition was observed at concentrations as low as 1 microM. Inhibition of L-type channels by DPBPS was enhanced at depolarized holding potentials and promoted by prolonged channel activation. At concentrations similar to those which blocked Ca2+ currents, each of the three DPBPs markedly reduced basal PRL production by GH cells. PRL synthesis stimulated by the dihydropyridine Ca2+ agonist R5417 or thyrotropin releasing hormone (TRH) was also inhibited. The inhibitory effects of the DPBPs were observed at the level of gene transcription. Penfluridol and fluspirilene inhibited basal, Ca2(+)- and TRH-stimulated expression of a fusion gene construct containing the 5'-flanking sequence of the rat PRL gene linked to the luciferase gene. The effect was concentration-dependent with the IC50 values for both drugs of less than 1 microM. Nimodipine also reduced basal, R5417, and TRH-stimulated expression of the reporter gene construct. Similar results were obtained with a reporter gene construct containing the 5'-flanking sequence of the rat GH gene. The GH luciferase construct was only slightly responsive to R5417 and TRH; however, these responses were reduced by fluspirilene and nimodipine at concentrations of less than 1 microM. These studies demonstrate that the DPBP antipsychotics block T- as well as L-type Ca2+ channels in GH cells and inhibit PRL production at the level of transcription. They also indicate that functioning Ca2+ channels are necessary for TRH-stimulated PRL gene transcription.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium Channels; Cell Line; Fluspirilene; Gene Expression; Kinetics; Luciferases; Membrane Potentials; Penfluridol; Pimozide; Piperidines; Pituitary Neoplasms; Prolactin; Recombinant Fusion Proteins; Spiro Compounds; Thyrotropin-Releasing Hormone

This study was carried out to test the hypothesis that sustained hyperprolactinaemia in patients with prolactinomas stimulates hypothalamic dopaminergic activity via a short loop positive feedback effect of prolactin (PRL). The intensity of dopamine (DA) effects on the pituitary around the adenoma was evaluated by measuring thyroid stimulating hormone (TSH) responses to intravenous injection of domperidone (10 mg) a new DA receptor blocking drug that does not penetrate the blood-brain barrier. TSH responses have been compared with those of PRL to the same agent. Eight females with prolactinomas showed greater TSH release after domperidone than nine normal females (sum of TSH increments over 20 min 17.5 +/- 1.7 v. 8.9 +/- 1.5 mu/l, P less than 0.001) whilst PRL release was reduced (sum of PRL increments over 120 min 5.9 +/- 2.4 v. 21.8 +/- 3.8 mu/l x 10(-3), P less than 0.01). Amongst nineteen hyperprolactinaemic females with apparently normal pituitary fossae (plain skull X-ray), ten showed an exaggerated TSH response (delta TSH, 4.2 +/- 0.6 mu/l, range 2.5-9.0 mu/1) and reduced PRL response to domperidone, comparable with established tumor cases. In the remaining nine normal fossa hyperprolactinaemic females, the TSH and PRL responses to dopaminergic were similar to normal females. These results support the initial hypothesis and indicate the coexistence of a defect in the dopaminergic inhibition of PRL release and increased dopaminergic inhibition of TSH release in patients with prolactinomas. The presence of an exaggerated TSH response to DA antagonism in a euthyroid, radiologically normal (plain skull X-ray), hyperprolactinaemic patient is compatible with the presence of an autonomously-functioning, PRL secreting, pituitary microadenoma and the TSH changes seen in these patients after DA antagonist administration can be readily detected by sensitive TSH radioimmunoassay.

Topics: Adenoma; Adolescent; Adult; Benzimidazoles; Domperidone; Female; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypothalamus; Middle Aged; Piperidines; Pituitary Function Tests; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Thyrotropin; Thyrotropin-Releasing Hormone

Forty-one subjects with hyperprolactinemia underwent testing on separate occasions with nomifensine, an indirectly acting dopamine agonist, and domperidone, a dopamine receptor-blocking agent. Nomifensine (200 mg orally) did not significantly modify plasma levels of prolactin (PRL) in 17 subjects in whom the existence of a pituitary tumor had been established at surgery (12 subjects) or was highly probable (5 subjects). Of the remaining 24 patients with hyperprolactinemia of uncertain etiology, 6 had PRL responsiveness to nomifensine (decrease of baseline PRL levels greater than or equal to 30%) and 18 had PRL unresponsiveness to the drug. The administration of domperidone (4-mg bolus injected intravenously) showed in 36 of the 41 patients the existence of a homogeneity between PRL responsiveness to nomifensine and PRL responsiveness to domperidone. In only five patients was failure of nomifensine to lower plasma PRL levels associated with an increase in plasma PRL levels after domperidone administration (at least doubling of baseline PRL levels). The combined application of nomifensine and domperidone tests holds promise of being a useful method for distinguishing among hyperprolactinemic subjects those with a prolactinoma.

Topics: Adenoma; Adult; Benzimidazoles; Domperidone; Female; Humans; Isoquinolines; Male; Menstruation; Middle Aged; Nomifensine; Piperidines; Pituitary Neoplasms; Postpartum Period; Pregnancy; Prolactin; Sella Turcica

The prolactin (PRL)-releasing effect of domperidone (DOM), a novel antidopaminergic drug which does not cross the blood-brain barrier, was investigated in normoprolactinemic subjects, in subjects with physiologic puerperal hyperprolactinemia or pathological hyperprolactinemia. DOM (4 mg i.v.), administered to 8 normoprolactinemic women, induced a clear-cut and sustained rise in plasma PRL, with peak levels occurring 15-30 min postinjection; the effect of the drug was also evident in 3 normoprolactinemic women at the dose of 0.25 mg i.v. Also in 8 puerperal women (postpartum day 2) intravenous administration of 4 mg DOM was followed by an increase in plasma PRL (51-517% of baseline levels, 15-45 min postinjection). Administration of DOM (4 mg i.v.) to 16 subjects with pathological hyperprolactinemia, evidenced the presence of 14 DOM-nonresponder (maximum percent increase of baseline PRL 48%) and 2 DOM-responder subjects. In 8 of the DOM-nonresponder subjects the existence of a pituitary tumor was established at surgery by selective removal of an adenoma (7 subjects) or a teratoma (1 subject): of the 6 subjects who did not undergo surgery, 3 had biochemical and/or radiologic evidence suggestive of a PRL-secreting tumor and 1 was acromegalic. These results indicate that DOM is capable of releasing PRL both in normoprolactinemic subjects and subjects with puerperal hyperprolactinemia. In contrast, DOM is unable to modify PRL levels in most subjects with pathological hyperprolactinemia, with proven or suspected pituitary tumors.

Topics: Adenoma; Adult; Benzimidazoles; Blood-Brain Barrier; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Piperidines; Pituitary Neoplasms; Postpartum Period; Pregnancy; Prolactin; Teratoma

Dopaminergic receptors were observed on the membranes of 26 human PRL-secreting adenomas. Two binding sites were found for [3H]domperidone, a selective dopamine antagonist, with a Kd1 of 0.29 +/- 0.06 nM and a Kd2 of 4.19 +/- 0.7 nM (n = 5). Bmax1 and Bmax2 (maximum numbers of binding sites, first and second sites, respectively) varied from one adenoma to another. When considering Bmax1, two different categories of PRL-secreting adenomas were distinguished, one with a concentration of receptor over 250 fmol/mg protein and others with lower concentrations of receptor (< 250 fmol/mg protein). In the latter, when considering the volume of the tumor, a higher plasma PRL level was found. Two binding sites for [3H]domperidone also were found in the normal human hypophysis with Kd values similar to those of the adenomas (0.18 +/- 0.04 and 3.95 +/- 0.35 nM). The same number of binding sites was observed in normal pituitaries and in PRL-secreting adenomas. However, when considering the density of PRL-secreting cells in the two different tissues (prolactinomas contain 2 or 3 times more PRL-secreting cells than human pituitary tissue), one may suspect a defect in the dopaminergic inhibiting control in PRL-secreting adenomas.

Topics: Adenoma; Adolescent; Adult; Aged; Benzimidazoles; Binding, Competitive; Cell Membrane; Domperidone; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Pituitary Gland; Pituitary Neoplasms; Prolactin; Receptors, Dopamine

3H Domperidone binding on cellular membranes from human prolactin adenomas demonstrates the presence of two dopaminergic binding sites. The mean value of the dissociation constant (Kd) for five adenomas is of 0.29 +/- 0.14 nM for the first site and of 4.19 +/- 1.56 nM for the second site. The maximal number of binding sites (Bmax) varies from one adenoma to another. The binding is completely displaced at 30 nM of tritiated Domperidone by apomorohine, a specific dopaminergic agonist.

Topics: Adenoma; Apomorphine; Benzimidazoles; Binding, Competitive; Humans; Kinetics; Piperidines; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Receptors, Dopamine