Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis.

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies with poor prognoses, since it is largely resistant to chemotherapy, radiotherapy, and targeted therapy. The persistence of cancer stem cells (CSCs) is the major cause of treatment failure with RCC. Recent evidence showed that dopamine receptor D2 (DRD2)-targeting antipsychotic drugs such as penfluridol exert oncostatic effects on several cancer types, but the effect of penfluridol on RCC remains unknown. Here, we uncovered penfluridol suppressed in vitro cell growth and in vivo tumorigenicity of various RCC cell lines (Caki-1, 786-O, A498, and ACHN) and enhanced the Sutent (sunitinib)-triggered growth inhibition on clear cell (cc)RCC cell lines. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) was critical for autophagy-mediated apoptosis induced by penfluridol. Transcriptional inhibition of OCT4 and Nanog via inhibiting GLI1 was important for penfluridol-induced stemness and proliferation inhibition. The anticancer activities of penfluridol on ccRCC partially occurred through DRD2. In clinical ccRCC specimens, positive correlations of DRD2 with GLI1, OCT4, and Nanog were observed and their expressions were correlated with worse prognoses. Summarizing, DRD2 antagonists such as penfluridol induce UPR signaling and suppress the GLI1/OCT4/Nanog axis in ccRCC cells to reduce their growth through inducing autophagy-mediated apoptosis and stemness inhibition. These drugs can be repurposed as potential agents to treat ccRCC patients.

Oral long acting antipsychotic penfluridol as a harm reduction treatment in a patient suffering from untreated schizophrenia and multiple drug dependence: A case report.

Psychiatric disorders, including schizophrenic spectrum disorders, are common in People Who Use Drugs (PWUD). Promoting adherence to medication among PWUD with dual diagnosis is challenging. We present the case of a treatment-disrupted patient suffering from schizophrenia with co-occuring multiple drug dependence to whom penfluridol - an oral long acting typical antipsychotic - was proposed at the Supervised Drug Consumption Room (SDCR) of Paris. Penfluridol quickly improved patient's psychotic symptoms, increased engagement in addiction care and helped maintaining the patient in "Housing First" program. In harm reduction structure, penfluridol can be seen as a "hook treatment" while maintaining therapeutic alliance and favoring patients' engagement in specific care.

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer.

More effective therapy for patients with either muscle-invasive or high-risk non-muscle-invasive urothelial carcinoma of the bladder (UCB) is an unmet clinical need. For this, drug repositioning of clinically approved drugs represents an interesting approach. By repurposing existing drugs, alternative anticancer therapies can be introduced in the clinic relatively fast, because the safety and dosing of these clinically approved pharmacological agents are generally well known. Cationic amphiphilic drugs (CADs) dose-dependently decreased the viability of a panel of human UCB lines in vitro. CADs induced lysosomal puncta formation, a hallmark of lysosomal leakage. Intravesical instillation of the CAD penfluridol in an orthotopic mouse xenograft model of human UCB resulted in significantly reduced intravesical tumor growth and metastatic progression. Furthermore, treatment of patient-derived ex vivo cultured human UCB tissue caused significant partial or complete antitumor responses in 97% of the explanted tumor tissues. In conclusion, penfluridol represents a promising treatment option for bladder cancer patients and warrants further clinical evaluation.

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.

: Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood-brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.

Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice.

BACKGROUND & AIMS: Prolactin (PRL) signaling is up-regulated in hormone-responsive cancers. The PRL receptor (PRLR) is a class I cytokine receptor that signals via the Janus kinase (JAK)-signal transducer and activator of transcription and mitogen-activated protein kinase pathways to regulate cell proliferation, migration, stem cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to the growth of pancreatic tumors in mice. METHODS: We used immunohistochemical analyses to compare levels of PRL and PRLR in multitumor tissue microarrays. We used structure-based virtual screening and fragment-based drug discovery to identify compounds likely to bind PRLR and interfere with its signaling. Human pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), with or without knockdown of PRLR (clustered regularly interspaced short palindromic repeats or small hairpin RNA), were incubated with PRL or penfluridol and analyzed in proliferation and spheroid formation. C57BL/6 mice were given injections of UNKC-6141 cells, with or without knockdown of PRLR, into pancreas, and tumor development was monitored for 4 weeks, with some mice receiving penfluridol treatment for 21 days. Human pancreatic tumor tissues were implanted into interscapular fat pads of NSG mice, and mice were given injections of penfluridol daily for 28 days. Nude mice were given injections of Panc-1 cells, xenograft tumors were grown for 2 weeks, and mice were then given intraperitoneal penfluridol for 35 days. Tumors were collected from mice and analyzed by histology, immunohistochemistry, and immunoblots. RESULTS: Levels of PRLR were increased in PDAC compared with nontumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated signaling via JAK2-signal transducer and activator of transcription 3 and extracellular signal-regulated kinase, as well as formation of pancospheres and cell migration; these activities were not observed in cells with PRLR knockdown. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several diphenylbutylpiperidine-class antipsychotic drugs as agents that decreased PRL-induced JAK2 signaling; incubation of pancreatic cancer cells with these compounds reduced their proliferation and formation of panco spheres. Injections of 1 of these compounds, penfluridol, slowed the growth of xenograft tumors in the different mouse models, reducing proliferation and inducing autophagy of the tumor cells. CONCLUSIONS: Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of pancreatic cancer cells. Antipsychotic drugs, such as penfluridol, block PRL signaling in pancreatic cancer cells to reduce their proliferation, induce autophagy, and slow the growth of xenograft tumors in mice. These drugs might be tested in patients with PDAC.

Penfluridol: An antipsychotic agent suppresses lung cancer cell growth and metastasis by inducing G0/G1 arrest and apoptosis.

Lung cancer remains the leading cause of cancer mortality because of highly malignant and metastatic potential. The current status of lung cancer treatment is limited, and more treatment options are needed. Interesting, antipsychotic drugs have been reported to show anti-cancer effects. In this present study, we investigated the anticancer potential of penfluridol (PF), an anti-schizophrenic drug, in lung cancer and its underlying mechanism in vitro and in vivo. In vitro, it could inhibit the viability of various lung cancer cells with G0/G1 phase arrest via increasing the expression level of p21/p27 and decreasing the expression levels of cyclin-CDK complex. Meanwhile, cell-cycle arrest causes DNA repair in the nucleus, which was associated with the upregulation of H2A.X and p-H2A.X. Moreover, PF could also decrease mitochondrial membrane potential and increase reactive oxygen species levels in the lung cancer cells. These results implied that PF might induce the mitochondria-mediated intrinsic apoptosis. In addition, PF inhibits the migration and invasion of lung cancer cells via downregulation of FAK-MMP signaling. In vivo, oral administration of PF at concentration of 10 mg/kg inhibited tumor growth in A549 xenograft model. Notably, PF is an approved drug and the price is exceedingly cheap, so this study demonstrates the potential of PF to treat lung cancer.

Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent.

Penfluridol has robust antipsychotic efficacy and is a first-generation diphenylbutylpiperidine. Its effects last for several days after a single oral dose and it can be administered once a week to provide better compliance and symptom control. Recently; strong antitumour effects for penfluridol were discovered in various cancer cell lines; such as breast; pancreatic; glioblastoma; and lung cancer cells via several distinct mechanisms. Therefore; penfluridol has drawn much attention as a potentially novel anti-tumour agent. In addition; the anti-cancer effects of penfluridol have been demonstrated in vivo: results showed slight changes in the volume and weight of organs at doses tested in animals. This paper outlines the potential for penfluridol to be developed as a next-generation anticancer drug.

Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response.

Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.

Penfluridol overcomes paclitaxel resistance in metastatic breast cancer.

Paclitaxel is a first line chemotherapeutic agent for the patients with metastatic breast cancer. But inherited or acquired resistance to paclitaxel leads to poor response rates in a majority of these patients. To identify mechanisms of paclitaxel resistance, we developed paclitaxel resistant breast cancer cell lines, MCF-7 and 4T1 by continuous exposure to paclitaxel for several months. Western blot analysis showed increased expression of HER2 and ß-catenin pathway in resistant cell lines as compared to parent cells. Hence, we hypothesized that HER2/ß-catenin mediates paclitaxel resistance in breast cancer and suppression of HER2/ß-catenin signaling could overcome paclitaxel resistance. Our data showed that penfluridol (PFL) treatment significantly reduced the survival of paclitaxel-resistant cells. Western blot analysis revealed that PFL treatment suppressed HER2, as well as, ß-catenin pathway. In vivo data confirmed that PFL significantly potentiated tumor growth suppressive effects of paclitaxel in an orthotropic breast cancer model. In addition, tumors from paclitaxel and PFL-treated mice showed reduced HER2 and ß-catenin expression, along with increased apoptosis. Taken together our results demonstrate a novel role of HER2/ß-catenin in paclitaxel resistance and open up new avenues for application of PFL as a therapeutic option for overcoming paclitaxel resistance.

Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity.

Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.

A CRISPR/Cas9-Based Screening for Non-Homologous End Joining Inhibitors Reveals Ouabain and Penfluridol as Radiosensitizers.

Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSB), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In this study, we demonstrated a screening for NHEJ inhibitors using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis. Because NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities were positively correlated with the mutation frequencies. Next, an approved drug library containing 1,540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors, which could promote the discovery of novel radiosensitizers. Mol Cancer Ther; 17(2); 419-31. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

Chlorpromazine versus penfluridol for schizophrenia.

BACKGROUND: The efficacy of chlorpromazine, a benchmark antipsychotic, has not been fully assessed in direct comparison with different individual antipsychotics. Penfluridol is another old antipsychotic with a long half-life so one oral dose may last up to one week. This could confer advantage. OBJECTIVES: To assess the clinical effects of chlorpromazine compared with penfluridol for adults with schizophrenia. SEARCH METHODS: On 31 March 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised clinical trials focusing on chlorpromazine versus penfluridol for adults with schizophrenia or related disorders. Outcomes of interest were death, service utilisation, global state, mental state, adverse effects and leaving the study early. We included trials meeting our selection criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we planned to estimate the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The review includes three studies with a total of 130 participants. Short-term results for hospital admissions showed no clear difference between chlorpromazine and penfluridol (1 RCT, n = 29, RR 0.19, 95% CI 0.01 to 3.60, low-quality evidence). No clear difference in the incidence of akathisia was found at medium term (2 RCTs, n = 85, RR 0.19, 95% CI 0.04 to 1.06, low-quality evidence), and similar numbers of participants - nearly half - from each treatment group left the study early (3 RCTs, n = 130, RR 1.21, 95% CI 0.83 to 1.77, low-quality evidence). The risk of needing additional antiparkinsonian medication was less in the chlorpromazine group (2 RCTs, n = 74, RR 0.70, 95% CI 0.51 to 0.95). No useable data reported clinically important change in global or mental state. No data were reported for relapse. No deaths were reported by the trials. AUTHORS' CONCLUSIONS: Only three small studies provided data and the quality of reporting and evidence is low. Limited data indicate the efficacy and adverse effects profiles of chlorpromazine and penfluridol are generally similar. Penfluridol, however, may confer advantage by needing to be given only once per week. Firm conclusions are not possible without good-quality trials, and where these treatments are used, such trials are justified.

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis.

Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the antimetastatic potential of penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, penfluridol treatment significantly reduced the expression of integrin α6, integrin ß4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of penfluridol in three different in vivo tumor models. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin ß4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC.

Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer.

We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib-sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the Connectivity Map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfluridol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.

Anti-tumor effects of penfluridol through dysregulation of cholesterol homeostasis.

BACKGROUND: Psychiatric patients appear to be at lower risk of cancer. Some antipsychotic drugs might have inhibitory effects on tumor growth, including penfluridol, a strong agent. To test this, we conducted a study to determine whether penfluridol exerts cytotoxic effects on tumor cells and, if so, to explore its anti-tumor mechanisms. METHODS: Growth inhibition of mouse cancer cell lines by penfluridol was determined using the 3- (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cytotoxic activity was determined by clonogenic cell survival and trypan blue assays. Animal tumor models of these cancer cells were established and to evaluate penfluridol for its anti-tumor efficacy in vivo. Unesterified cholesterol in cancer cells was examined by filipin staining. Serum total cholesterol and tumor total cholesterol were detected using the cholesterol oxidase/p- aminophenazone (CHOD-PAP) method. RESULTS: Penfluridol inhibited the proliferation of B16 melanoma (B16/ F10), LL/2 lung carcinoma (LL/2), CT26 colon carcinoma (CT26) and 4T1 breast cancer (4T1) cells in vitro. In vivo penfluridol was particularly effective at inhibiting LL/2 lung tumor growth, and obviously prolonged the survival time of mice bearing LL/2 lung tumors implanted subcutaneously. Accumulated unesterified cholesterol was found in all of the cancer cells treated with penfluridol, and this effect was most evident in LL/2, 4T1 and CT26 cells. No significant difference in serum cholesterol levels was found between the normal saline-treated mice and the penfluridol-treated mice. However, a dose-dependent decrease of total cholesterol in tumor tissues was observed in penfluridol-treated mice, which was most evident in B16/F10-, LL/2-, and 4T1-tumor-bearing mice. CONCLUSION: Our results suggested that penfluridol is not only cytotoxic to cancer cells in vitro but can also inhibit tumor growth in vivo. Dysregulation of cholesterol homeostasis by penfluridol may be involved in its anti-tumor mechanisms.

Penfluridol for schizophrenia.

BACKGROUND: Penfluridol, available since 1970, is an unusual long acting oral antipsychotic agent for the treatment of schizophrenia. It may be considered a depot medication as it is administered once a week. OBJECTIVES: To review the effects of penfluridol for treatment of those with schizophrenia and schizophrenia-like illnesses in comparison to placebo, other antipsychotic medication or no intervention. SEARCH STRATEGY: We undertook electronic searches of the Cochrane Schizophrenia Group's Register (2005), the Cochrane Central Register of Controlled Trials (2003-5) and LILACS (1982-2005). We hand searched references of all identified studies and sought citations of these studies in the Science Citation Index. We contacted the authors of trials and the manufacturer of penfluridol. SELECTION CRITERIA: We reliably selected all randomised clinical trials comparing penfluridol to placebo or typical or atypical antipsychotic drugs for schizophrenia or serious mental illness. DATA COLLECTION AND ANALYSIS: We independently extracted and analysed data on an intention-to-treat basis. We calculated the relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data using a random effects model, and where possible calculated the number needed to treat. We calculated weighted mean differences (WMD) for continuous data. MAIN RESULTS: We included twenty-five studies with a total of 1024 participants. Most of these studies were undertaken in the 1970s when penfluridol was launched. Ten studies, with 365 patients, compared penfluridol to placebo. In the meta-analysis of medium-term lasting studies, penfluridol was superior to placebo in the main efficacy measures: 'improvement in global state' (n=159, 4 RCTs, RR 0.69 CI 0.6 to 0.8, NNT 3 CI 2 to 10) and 'needing additional antipsychotic' (n=138, 5 RCTs, RR 0.43 CI 0.2 to 0.8, NNT 3 CI 1.8 to 20).A total of 449 patients from eleven studies were randomised to penfluridol or oral typical antipsychotics. There were no particular differences between penfluridol versus chlorpromazine, fluphenazine, trifluoperazine, thioridazine, or thiothixene for the main outcome measures in medium-term trials: 'improvement on global state' (N=2 studies), 'leaving the study early' (N=6), 'needing additional antipsychotic' (N=3), needing antiparkinsonian medication (N=2), and side-effects. Six studies, with 274 patients, compared penfluridol to depot typical antipsychotics. In general, for the efficacy and safety measures, no differences were established, but penfluridol was superior in keeping the patients in treatment; 'leaving the study early' (n=218, 5RCTs, RR 0.55 CI 0.3 to 0.97, NNT 6 CI 3.4 to 50). AUTHORS' CONCLUSIONS: Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The efficacy and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for chronic sufferers of schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.

Safety of haloperidol and penfluridol in pregnancy: a multicenter, prospective, controlled study.

OBJECTIVE: To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy. METHOD: The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001. RESULTS: We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)-78.2% (of 206) were in the first trimester-and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls. CONCLUSION: This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

The drug sensitivity characteristics and Plasmodium falciparum pfmdr1 status of five isolates of P. falciparum recently isolated from patients presenting for treatment from the Thailand/Myanmar border have been investigated. The aim of the study was to avoid the criticisms of some earlier studies by focusing on newly collected isolates from a specific geographic location. Three of the isolates studied exhibited clear resistance to chloroquine similar to that observed in the K1 Thai standard isolate obtained in the 1970s, and the other two isolates were of intermediate sensitivity to chloroquine with concentrations of drug that inhibit parasite growth by 50% of 50 and 43 nmol. The sensitivity of all isolates was enhanced by verapamil but we found no clear association between chloroquine sensitivity and gene copy number or intra-allelic variation of pfmdr1. In contrast, clear cross-resistance was seen between mefloquine and halofantrine, with the most sensitive isolates carrying the K1 mutation in pfmdr1.