Kegg Pathway: Butyrophenones

Bioorg Med Chem. 2008 Jun 20;
Ablordeppey SY, Altundas R, Bricker B, Zhu XY, Suresh Kumar EV, Jackson T, Khan A, Roth BL

The synthesis and exploration of novel Butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.

Ann Clin Psychiatry. 2008 Apr-Jun; 20(2): 113-4
Ahuja N, Lloyd AJ

Ugeskr Laeger. 2008 Jun 2; 170(23): 2035-8
Gärtner R, Kroman N, Callesen T, Kehlet H

INTRODUCTION: Every year 4000 women in Denmark undergo surgery for breast cancer. According to published literature approximately 50% suffer from post-operative nausea and vomiting (PONV) and moderate pain. No national guidelines are available regarding the treatment or prevention of pain and PONV associated with surgery for these patients. MATERIALS AND METHODS: 116 consecutive patients scheduled for breast cancer surgery were prospectively scored according to pain, PONV and sedation after being introduced to a combined evidence-based, empiric multimodal opioid-sparing prevention and treatment regime consisting of Paracetamol, Celecoxib, Dextromethorphan, Gabapetin, Dexamethason and Ondansetron. RESULTS: In the recovery room, 75% of the patients scored either no or light pain at rest compared to 68% under mobilization. In the department, 94% of the patients scored no or light pain at rest as well as under mobilization on the evening of the operation and the next morning. Morphine consumption in the recovery room was, on average, 2 mg per patient. Only 1.5% of the patients were given morphine in the department. Five patients were troubled by light PONV, one by moderate PONV and another suffered from severe PONV and vomiting resistant to treatment. Upon arrival at the recovery 15% of the patients were in a state of moderate to severe sedation. This number was 1.5% 75 minutes later. CONCLUSION: It is possible with a multimodal opioid-sparing prevention and treatment regime for pain and PONV to gain optimal postoperative pain and nausea control without significant problems with respect to sedation.

Ugeskr Laeger. 2008 Jun 2; 170(23): 2032-4
Gärtner R, Callesen T, Kroman N, Kehlet H

The most common postoperative inconveniences after breast cancer surgery are pain, nausea and vomiting, which contribute to reduced patient satisfaction, prolonged hospital stays and delayed courses of rehabilitation. This article summarizes the literature regarding available procedure-specific evidence for prophylactic nausea, vomiting and pain treatment supported by transferable evidence from similar types of surgery. We propose a prophylactic combination of Dexametason, Ondansteron, Paracetamol, Celecoxib, Gabapentin and Detromethorphan as future treatment.

J Neurosci. 2008 May 28; 28(22): 5671-85
Bertran-Gonzalez J, Bosch C, Maroteaux M, Matamales M, Hervé D, Valjent E, Girault JA

Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D(1) receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D(2) receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of drd1a-EGFP in striatonigral and drd2-EGFP in striatopallidal neurons. Drd2-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.

Anesth Analg. 2008 Jun; 106(6): 1922; author reply 1922-3
Dürsteler C, Mases A, Puig MM

Recenti Prog Med. 2008 Mar; 99(3): 146-8
Cesario V

A case of serious undesirable, effect arisen in a 24-year old male treated with intravenous injection of haloperidol, is presented. The patient has been affected by acute psychosis and was treated with intravenous injection of haloperidol, successively a serious uneasiness with muscular rigor, perspiration, high blood-pressure, serious shortness of breath with cyanosis appeared. This case arouses interest for an unusual symptomatology and for a difficult diagnostical framing too, because was too much serious to consider it a simple acute extrapiramidal crisis, however without all characteristics to consider it a neuroleptic malignant syndrome. With this experience is possible to suppose a continuity between these two syndromes that several authors consider expression of different aetiological processes. Final aim of this report is to put in evidence the serious undesirable effects risk with using of a parenteral giving of traditional neuroleptic medications, without consider the alternative opportunity to using other new antipsycotic medications available nowadays, perhaps not quick enough than a traditional neuroleptic for effectiveness, but more sure about the tolerability.

Indian J Physiol Pharmacol. 2007 Oct-Dec; 51(4): 375-86
Dhavalshankh AG, Jadhav SA, Gaikwad RV, Gaonkar RK, Thorat VM, Balsara JJ

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

Biochem Biophys Res Commun. 2008 Jul 18; 372(1): 179-85
Zhang Y, Yang C, Xu X, Jiao R, Jin H, Lv Y, Yang H, Xu M

Droperidol causes the blockage of the dopamine receptors in the central nervous system that are involved in pain transmission. However, the mechanism of action of droperidol in pain-related neurons is not clear, and it is still unknown whether opioids are involved in the modulation of this processing. The present study examines the effect of droperidol on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the caudate nucleus (Cd) of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. Our results revealed that droperidol decreased the frequency of PEN discharge, and increased the frequency PIN discharge evoked by the noxious stimulation in the Cd of normal rats, while administration of droperidol to morphine-dependent rats produced the opposite response. Those demonstrated that droperidol is involved in the modulation of nociceptive information transmission in Cd, and there were completely opposite responses to painful stimulation between normal and morphine-dependent rats after administration of droperidol.

Behav Pharmacol. 2008 May; 19(3): 183-96
Rygula R, Abumaria N, Havemann-Reinecke U, Rüther E, Hiemke C, Zernig G, Fuchs E, Flügge G

Chronic social stress is one of the most important factors responsible for precipitation of depressive disorder in humans. In recent years, the impact of social stress on the development of psychopathologies has been thoroughly investigated in preclinical animal studies. We have shown recently that behavioural effects of chronic social stress in rats can be reversed by citalopram and fluoxetine. This study has been designed for further pharmacological validation of the chronic social stress paradigm as a model of depressive symptoms in rats. For this, rats were subjected to 5 weeks of daily social defeat and were in parallel treatment for a clinically relevant period of 4 weeks with the antidepressant drug reboxetine (40 mg/kg/day) and the neuroleptic drug haloperidol (2 mg/kg/day). The anxiolytic diazepam (1 mg/kg) was administered acutely at the end of the stress period. Stress caused decreased locomotor and exploratory behaviours, decreased sucrose preference and increased immobility in the forced swim test, but did not affect behaviour in the elevated plus maze. Four weeks of oral treatment with reboxetine ameliorated the adverse effects of social stress and normalized behaviours related to motivation and reward sensitivity. The treatment with haloperidol worsened the adverse effects of chronic social stress having effects similar to stress on reward and motivation-related behaviours. Diazepam reduced anxiety-related behaviours as measured in elevated plus maze in control animals having no effects on socially stressed individuals. Neither sucrose preference nor performance in forced swim test was affected by diazepam. The effectiveness and selectivity of the treatment with the antidepressant reboxetine in ameliorating socially induced behavioural disturbances supports the validity of the chronic social stress as a model of depressive-like symptoms in rats.

Bull Exp Biol Med. 2007 Sep; 144(3): 282-7
Skurikhin EG, Minakova MY, Pershina OV, Dygai AM, Goldberg ED

The role of the dopaminergic system in the regulation of the granulocytic hemopoietic stem was studied after administration of cyclophosphamide and 5-fluorouracil. Dopamine in the central nervous system promotes the development of cytostatic-induced myelosuppressions. The inhibitory effect of dopaminergic structures on granulocytopoiesis after administration the fluoropyrimidine antimetabolite was of shorter duration compared to that observed in experiments with the alkylating agent. The inhibitory effect of brain dopamine is associated with a decrease in proliferative activity and differentiation of granulomonocytic precursors, prevention of hemopoietic islet formation, and impairment of secretion of colony-stimulating activity in adherent cells of the hemopoiesis-inducing microenvironment. Cyclophosphamide and 5-fluorouracil had different effects on the rate of hemopoietic tissue regeneration, which was related to specific interaction between distant regulatory structures and hemopoiesis-inducing microenvironment and differences in the influence of cytostatics on hemopoietic and stromal cells.

Lancet. 2008 May 3; 371(9623): 1501; author reply 1502
Trollor JN, Somerville ER, Somerville HM

J Clin Psychopharmacol. 2008 Apr; 28(2 Suppl 1): S29-35
Kane JM, Lauriello J, Laska E, Di Marino M, Wolfgang CD

This research compared the long-term efficacy and safety of iloperidone with those of haloperidol in individuals with schizophrenia. Data were pooled from 3 prospective multicenter studies, each with 6-week stabilization followed by 46-week double-blind maintenance phases. Patients were randomized to iloperidone 4 to 16 mg/d or haloperidol 5 to 20 mg/d. Patients included in this analysis completed the initial 6-week phase with at least 20% reduction in Positive and Negative Syndrome Scale (PANSS) total score at weeks 4 and 6, had 7-item Clinical Global Impressions of Change (CGI-C) scores less than 4, received 1 or more doses of long-term phase medication, and had 1 or more efficacy/safety assessments during the long-term phase. The primary efficacy variable was time to relapse, defined as a 25% or more increase in PANSS total score, including at least a 10-point change; discontinuation because of lack of efficacy; aggravated psychosis with hospitalization; or 2-point increase in the 7-item CGI-C after week 6. Of 1644 patients randomized and 1326 completing the 6-week phase, 473 (iloperidone, n = 359; haloperidol, n = 114) were included in the long-term efficacy analysis, and 489 (iloperidone, n = 371; haloperidol, n = 118) in the safety analysis. Iloperidone was equivalent to haloperidol in time to relapse. The most common adverse events were insomnia (18.1%), anxiety (10.8%), and schizophrenia aggravated (8.9%) with iloperidone, and insomnia (16.9%), akathisia (14.4%), tremor (12.7%), and muscle rigidity (12.7%) with haloperidol. The Extrapyramidal Symptoms Rating Scale scores improved with iloperidone and worsened with haloperidol. Metabolic changes were minimal for both groups. Mean changes in Fridericia's QT interval correction were 10.3 msec (iloperidone) and 9.4 msec (haloperidol) at end point. Iloperidone demonstrated long-term efficacy equivalent to haloperidol and a favorable long-term safety profile, potentially making this agent a suitable option as maintenance therapy for schizophrenia.

Tidsskr Nor Laegeforen. 2008 May 1; 128(9): 1060-1
Selbaek G, Engedal K

Antipsychotic medication is often prescribed to persons with dementia exhibiting behavioural and psychological symptoms (BPSD). Use of atypical antipsychotics in elderly persons with dementia is associated with an increased risk of serious cerebrovascular adverse events and increased mortality. Based on a review of available literature, we conclude that atypical antipsychotics have a modest effect on BPSD and potentially serious side effects and that conventional antipsychotics appear to have even less favourable effects and adverse event profiles. Antipsychotic medication in patients with dementia exhibiting BPSD should only be prescribed for short-term treatment of severe symptoms associated with considerable distress or serious risk. Non-pharmacological interventions should be the first-line treatment approach in most cases.

Arch Pharm Res. 2008 Apr; 31(4): 474-81
Kim JH, Cho EY, Min C, Park JH, Kim KM

Dopamine D(2)R and D(3)R (D(2)R, D(3)R) show very high sequence homology and employ virtually identical signaling pathways even though D(2)R is 2 approximately 5 times more active. Among the structural motifs identified, a triplet sequence, Asp-Arg-Tyr (DRY motif), plays critical roles in the determination of receptor conformations for signaling and intracellular trafficking of G protein-coupled receptors by forming intramolecular interactions. Thus, it is possible that different signaling efficiencies of D(2)R and D(3)R might be caused by the receptor activation levels stabilized by their own DRY motifs. In this study, the Arg and Asp residues of D(2)R and D(3)R were mutated, and resulting changes in their signaling and intracellular trafficking properties were comparatively studied. Mutation of the Arg residues of D(2)R and D(3)R abolished their signaling but differently affected their intracellular localizations. The wildtype and R132H-D(2)R were expressed mainly on the plasma membrane. On the other hand, compared with the wildtype D(3)R, a substantial amount of R128H-D(3)R was localized intracellularly. The expression of receptor proteins on the plasma membrane and their signaling efficiencies were more drastically affected by the mutation of the Asp residue of D(3)R than D(2)R. Therefore, it was concluded that the different levels of conformational strain exerted by the DRY motif might partly determine the quantitative differences in the signaling efficiencies between D(2)R and D(3)R.

J Opioid Manag. 2008 Jan-Feb; 4(1): 34-40
Tukenmez B, Memis D, Pamukcu Z

AIM: Inadequate sedative techniques may adversely affect morbidity and mortality in the intensive care unit (ICU), and the search for the ideal sedative agent continues. Combinations of hypnotics and opiates have are commonly used for sedation. In this study, the authors aimed to assess whether or not the addition of a haloperidol, propofol, or midazolam infusion decreased the sufentanil requirements by using bispectral index (BIS). MATERIAL AND METHODS: The study involved 60 patients in the ICU. All patients received 0.5 microg/kg sufentanil IV bolus. Immediately after, group S received 0.25 microg/kg sufentanil infusion, group SH received sufentanil infusion + haloperidol 3 mg/h infusion, group SP received sufentanil infusion + propofol 25 microg/kg/min infusion, and group SM received sufentanil infusion + midazolam 0.04 mg/kg/h infusion, for 6 hours. Average BIS values 61-80 and Ramsay Sedation Score 2-5 were kept at a range of by decreasing or increasing sufentanil levels in all groups and hourly sufentanil consumption was determined. Hemodynamic and biochemicalparameters and arterial blood gases were determined at baseline and were repeated in study hours. RESULTS: There was no significant difference in hemodynamic and biochemical parameters and arterial blood gases among the groups. Propofol, midazolam, haloperidol infusion, when added to sufentanil infusion, decreased the consumption of sufentanil in all the measured times (p < 0.001). CONCLUSIONS: The authors aimed to determine the effects of haloperidol, propofol, or midazolam infusion when added to sufentanil infusion in a short period of time. The authors found that propofol, midazolam, and haloperidol infusion decreased the sufentanil requirements in ICU patients.

Biochem Pharmacol. 2008 Jun 1; 75(11): 2192-203
Packeu A, De Backer JP, Van Liefde I, Vanderheyden PM, Vauquelin G

D(2)-dopamine receptors mediate most of the physiological actions of dopamine and are important recognition sites for antipsychotic drugs. Earlier binding studies were predominantly done with broken cell preparations with the tritiated D(2)-receptor antagonists [(3)H]-raclopride, a hydrophilic benzamide, and [(3)H]-spiperone, a highly hydrophobic butyrophenone. Here we compared [(3)H]-raclopride and [(3)H]-spiperone binding properties in intact Chinese Hamster Ovary cells stably expressing recombinant human D(2L)-receptors. Specific binding of both radioligands occurred to a comparable number of sites. In contrast to the rapid dissociation of [(3)H]-raclopride in both medium only and in the presence of an excess of unlabelled ligand [(3)H]-spiperone dissociation was only observed in the latter condition, and it was still slower than in broken cell preparations. However, this could not explain the pronounced difference in the potency of some unlabelled ligands to compete with both radioligands. To integrate these new findings, a model is proposed in which raclopride approaches the receptor from the aqueous phase, while spiperone approaches the receptor by lateral diffusion within the membrane.

Anesthesiology. 2008 May; 108(5): 966; author reply 966
Sosis MB

J Exp Anal Behav. 2008 Mar; 89(2): 225-46
Winsauer PJ, Moerschbaecher JM, Roussell AM

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors.

Anesth Analg. 2008 May; 106(5): 1592-3
Bruppacher HR, Brugger S, Kube T, Urwyler A