Search

PURPOSE: The combination of a platinum compound and paclitaxel is a standard treatment for ovarian cancer. In this cooperative group trial, paclitaxel and carboplatin were combined in an outpatient schedule to determine the clinical benefit, toxicities, and effect on quality of life. PATIENTS AND METHODS: Women with International Federation of Gynecology and Obstetrics stage II to IV epithelial ovarian cancer with suboptimal residual disease (> 1 cm) were eligible. Paclitaxel, 150 mg/m2, was given over 3 hours, followed by carboplatin (area under the curve, 5). This was repeated every 4 weeks for six cycles. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Ovarian Cancer scale. Fifty-nine patients were enrolled, 38 with measurable disease and 21 with evaluable disease. RESULTS: The response rate (complete response + partial response) was 72%. The progression-free interval for patients with measurable disease was 17.5 months and for patients with evaluable disease was 11.1 months. Median survivals were 30.1 months (measurable) and 25.7 months (evaluable). Toxicities were modest. Quality-of-life scores improved significantly during therapy. DISCUSSION: This regimen is ideal for most women with advanced ovarian cancer because it is convenient and well tolerated, with response and survival comparable to those of more aggressive regimens. Overall quality-of-life scores and physical well-being scores improved throughout this outpatient treatment regimen for most patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study. [ABSTRACT FROM AUTHOR]

Introduction: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT., Methods and Analysis: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress., Ethics and Dissemination: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group., Trial Registration Number: ISRCTN41647111., Competing Interests: Competing interests: PW declares institutional unrestricted educational grant funding for a stroke reperfusion course from Stryker, Penumbra and Medtronic. MR declares that he is a Senior Clinician of the National Centre for Stereotactic Radiosurgery., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Effective management decisions depend on knowledge of species distribution and habitat use. Maps generated from species distribution models are important in predicting previously unknown occurrences of protected species. However, if populations are seasonally dynamic or locally adapted, failing to consider population level differences could lead to erroneous determinations of occurrence probability and ineffective management. The study goal was to model the distribution of a species of special concern, Townsend's big-eared bats ( Corynorhinus townsendii ), in California. We incorporate seasonal and spatial differences to estimate the distribution under current and future climate conditions. We built species distribution models using all records from statewide roost surveys and by subsetting data to seasonal colonies, representing different phenological stages, and to Environmental Protection Agency Level III Ecoregions to understand how environmental needs vary based on these factors. We projected species' distribution for 2061-2080 in response to low and high emissions scenarios and calculated the expected range shifts. The estimated distribution differed between the combined (full dataset) and phenologically explicit models, while ecoregion-specific models were largely congruent with the combined model. Across the majority of models, precipitation was the most important variable predicting the presence of C. townsendii roosts. Under future climate scenarios, distribution of C. townsendii is expected to contract throughout the state, however suitable areas will expand within some ecoregions. Comparison of phenologically explicit models with combined models indicates the combined models better predict the extent of the known range of C. townsendii in California. However, life-history-explicit models aid in understanding of different environmental needs and distribution of their major phenological stages. Differences between ecoregion-specific and statewide predictions of habitat contractions highlight the need to consider regional variation when forecasting species' responses to climate change. These models can aid in directing seasonally explicit surveys and predicting regions most vulnerable under future climate conditions., Competing Interests: The authors have no conflict of interest to report., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: Whilst rigid fixation for craniovertebral instability is the gold standard, in very young, small children conventional management may have to be modified. We present a single-centre experience of craniocervical fixation in children under 5 years., Methods: A retrospective review of cases that had undergone atlantoaxial (AA) or occipitocervical (OC) fixation aged under 5 years. Fusion was assessed using computerised tomography or flexion extension X-rays., Results: Twenty-six children (median age 2.3, range 0.8-4.9 years, 19 under the age of 3) underwent OC (n = 19) or AA (n = 7) fusion between 1999 and 2016. Pathology comprised 17 congenital, five trauma, two tumour and two post-infection cases. Twenty-one patients underwent sublaminar cable fixation with calvarial, autologous bone graft and halo-body orthosis immobilisation. An occipital plate and rods to sublaminar wire construct were used in four cases. A rigid instrumented fixation with occipital plate and C2 pedicle screws was utilised in one case. Follow-up was for a median of 2.8 years (range 0.03-16.3 years). Initial fusion rate was 91%, reaching 100% following two re-operations. Ninety-two per cent of patients were neurologically stable or improved following surgery. Twenty-one patients had a good overall outcome. Two patients had post-operative neurological deteriorations, and four died due to non-procedure related causes. Pin site morbidity secondary to halo use occurred in five cases., Conclusion: High fusion rates with good outcomes are achievable using semi-rigid fixation in the under 5-year-olds. Full thickness, autologous calvarial bone graft secured with wire cables and halo external orthosis offers a safe and effective alternative technique when traditional screw instrumentation is not feasible. These slides can be retrieved under Electronic Supplementary Material.

Background: Current healthcare providers function in an environment where there is increased emphasis on value-based models of reimbursement; therefore, the delivery of better patient outcomes is critical. Consequently, it is necessary to identify successful treatments that improve outcomes and can be applied across a broad range of clinic settings, treatment styles and therapist expertise., Methods: Data from 2,450 patients who received Astym therapy as component of their outpatient rehabilitation (treatment group) was matched to data from 2,450 randomly chosen patients with similar orthopedic impairments who did not receive Astym therapy during their rehabilitation (control group). Data was collected across 116 clinics in 17 U.S. states. All patients completed a standardized functional status survey at admission and at discharge. The effectiveness (discharge functional status score), efficiency (number of treatment visits, treatment duration) and utilization (unit of functional improvement per visit) was compared across two groups. Ethics approval was not required for this study as this is an observational study, with both sets of participants receiving actual (not placebo) treatment., Results: Compared to the control sample, patients who received Astym therapy as part of their rehabilitation had higher discharge functional status (FS) scores (68.5 vs . 64.5, F 1,4897 =53.1, P<0.001) and had more functional improvement per visit noted with a higher utilization index (2.0 vs . 1.9, ANCOVA F 1,4897 =5.5, P=0.019), and after risk adjustment, had the same number of visits. There was no difference in duration of treatment episode across groups (Astym, 47.8±31.1 days; control, 47.5±30.0 days) (ANCOVA F 1,4897 =1.7, P=0.199)., Conclusions: Patients with musculoskeletal disorders who received Astym therapy as part of the treatment process experienced increased treatment effectiveness as compared to those who did not receive Astym therapy. The addition of Astym therapy improved physical therapy outcomes for patients across a broad range of treatment styles, clinical settings and therapist expertise., Competing Interests: Conflicts of Interest: S Freedman, LS Harris, and YC Wang are paid consultants of Performance Dynamics Inc., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Peritoneal effluent from peritoneal dialysis (PD) patients contains proteins, mainly transported from the circulation through large pores in the venular part of the peritoneal microvessels. Hydrostatic convection is the major driver for peritoneal protein transport, although in PD there is additional diffusion. Consequently, venous pressure may have a role in peritoneal protein transport. The aim of the study was to investigate the importance of venous congestion on the magnitude of peritoneal protein clearance in incident PD patients using non-invasive measurements., Methods: A total of 316 adult PD patients, on PD for 8 - 12 weeks and collecting 24-hour urine and dialysate for total protein determination, underwent standard peritoneal equilibration testing (PET) along with measurement of N terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), multifrequency bioimpedance analysis, and a transthoracic echocardiogram., Results: Statistically significant univariate relationships for peritoneal protein clearance with a Spearman correlation coefficient > 0.25 were present for 4-hour dialysate/plasma (D/P) creatinine, NT-proBNP, extracellular/total body water, extracellular water excess, left ventricular mass, and right atrial area. Negative correlations were found with serum total protein and residual renal function. On multivariate analysis, logNTproBNP (β 0.11, p = 0.007) and right atrial area (β 0.01, p = 0.03) were significant independent predictors of peritoneal protein clearance., Conclusion: Indicators of venous congestion showed the most important relationships with peritoneal protein clearance. These indicators have not been assessed in previous studies on the presence or absence of relationships between peritoneal protein clearance and mortality., (Copyright © 2019 International Society for Peritoneal Dialysis.)

Peritoneal protein clearance (PPCl) depends upon vascular supply and size selective permeability. Some previous reports suggested PPCl can distinguish fast peritoneal membrane transport due to local or systemic inflammation. However, as studies have been discordant, we wished to determine factors associated with an increased PPCl. Consecutive patients starting peritoneal dialysis (PD) who were peritonitis-free were studied. Data included a baseline peritoneal equilibration test (PET), measurement of dialysis adequacy, 24-h dialysate PPCl and body composition measured by multifrequency bioimpedance. 411 patients, mean age 57.2 ± 16.6 years, 60.8% male, 39.4% diabetic, 20.2% treated by continuous ambulatory peritoneal dialysis (CAPD) were studied. Mean PET 4-h Dialysate/Serum creatinine was 0.73 ± 0.13, with daily peritoneal protein loss 4.6 (3.3-6.4) g, and median PPCl 69.6 (49.1-99.6) mL/day. On multivariate analysis, PPCl was most strongly associated with CAPD (β 0.25, P < 0.001), extracellular water (ECW)/total body water (TBW) ratio (β 0.21, P < 0.001), skeletal muscle mass index (β 0.21, P < 0.001), log N-terminal brain natriuretic peptide (NT-proBNP) (β 0.17, P = 0.001), faster PET transport (β 0.15, P = 0.005), and normalized nitrogen appearance rate (β 0.13, P = 0.008). In addition to the longer dwell times of CAPD, greater peritoneal creatinine clearance and faster PET transporter status, we observed an association between increased PPCl and ECW expansion, increased NT-proBNP, estimated dietary protein intake and muscle mass, suggesting a link to sodium intake and sodium balance, increasing both ECW and conduit artery hydrostatic pressure resulting in greater vascular protein permeability. This latter association may explain reports linking PPCl to patient mortality., (© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Poor wound healing is an important surgical complication. At-risk wounds must be identified early and monitored appropriately. Wound surveillance is frequently inadequate, leading to increased rates of surgical site infections (SSIs). Although the literature demonstrates that risk factor identification reduces SSI rates, no studies have focused on wound management at a junior level. Our study assesses documentation rates of patient-specific risk factors for poor wound healing at a large district general hospital in the UK. It critically evaluates the efficacy of interventions designed to promote surveillance of high-risk wounds. We conducted a full-cycle clinical audit examining medical records of patients undergoing elective surgery over 5 days. Interventions included education of the multidisciplinary team and addition of a Wound Healing Risk Assessment (WHRA) checklist to surgical admissions booklets. This checklist provided a simple stratification tool for at-risk wounds and recommendations for escalation. Prior to interventions, the documentation of patient-specific risk factors ranged from 0·0% to 91·7% (mean 42·6%). Following interventions, this increased to 86·4-95·5% (mean 92·5%), a statistically significant increase of 117·1% (P < 0·01). This study demonstrates that documentation of patient-specific risk factors for poor wound healing is inadequate. We have shown the benefit of introducing interventions to increase risk factor awareness., (© 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Individuals with histories of childhood trauma may adopt a nonspecific memory retrieval strategy to avoid unpleasant and intrusive memories. In a sample of 93 adolescents and adults with or without histories of child sexual abuse (CSA), we tested the hypothesis that nonspecific memory retrieval is related to an individual's general tendency to use avoidant (i.e., distancing) coping as a personal problem-solving or coping strategy, especially in victims of CSA. We also examined age differences and other individual differences (e.g., trauma-related psychopathology) as predictors of nonspecific memories. Distancing coping was significantly associated with less specific autobiographical memory. Younger age, lower vocabulary scores, and non-CSA childhood maltreatment (i.e., physical and emotional abuse) also uniquely predicted less autobiographical memory specificity, whereas trauma-related psychopathology was associated with more specific memory. Implications for the development of autobiographical memory retrieval in the context of coping with childhood maltreatment are discussed.

Two experiments were conducted to examine eyewitness memory in children and adolescents (9- to 15-years-old) with and without known histories of maltreatment (e.g., physical abuse, exposure to domestic violence). In Experiment 1, participants (N = 35) viewed a positive film clip depicting a congenial interaction between family members. In Experiment 2, participants (N = 31) watched a negative film clip in which a family argument was shown. Younger age and higher levels of trauma-related psychopathology significantly predicted commission errors to direct questions when the positive family interaction had been viewed, but not when the negative family interaction had been shown. Maltreatment history was not a significant unique predictor of memory performance for the positive or negative film clip. Implications for a scientific understanding of the effects of child maltreatment on memory are discussed., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures., Results: This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone., Conclusion: Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.

The current study was designed to examine the relation between intimate partner violence (IPV) and children's memory and drew from a socioeconomically and racially diverse sample of children living in and around a midsized southeastern city (n = 140). Mother-reported IPV when the children were 30 months old was a significant predictor of children's short-term, working, and deliberate memory at 60 months of age, even after controlling for the children's sex and race, the families' income-to-needs ratio, the children's expressive vocabulary, and maternal harsh-intrusive parenting behaviors. These findings add to the limited extant literature that finds linkages between IPV and children's cognitive functioning and suggest that living in households in which physical violence is perpetrated among intimate partners may have a negative effect on multiple domains of children's memory development.

The present study examined the specificity of autobiographical memory in adolescents and adults with versus without child sexual abuse (CSA) histories. Eighty-five participants, approximately half of whom per age group had experienced CSA, were tested on the autobiographical memory interview. Individual difference measures, including those for trauma-related psychopathology, were also administered. Findings revealed developmental differences in the relation between autobiographical memory specificity and CSA. Even with depression statistically controlled, reduced memory specificity in CSA victims relative to controls was observed among adolescents but not among adults. A higher number of posttraumatic stress disorder criteria met predicted more specific childhood memories in participants who reported CSA as their most traumatic life event. These findings contribute to the scientific understanding of childhood trauma and autobiographical memory functioning and underscore the importance of considering the role of age and degree of traumatization within the study of autobiographical memory.

l-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid found in green tea (Camellia sinensis), is sold in the United States as a dietary supplement to reduce stress and improve cognition and mood. The observations that l-theanine has been shown to inhibit caffeine's stimulatory effects and that caffeine produces precipitated withdrawal signs in opioid-addicted monkeys and some opioid withdrawal signs in some normal monkeys, suggest that l-theanine may suppress opioid withdrawal signs. Additionally, l-theanine produces anxiolytic effects in humans indicating that it has anti-anxiety properties. Thus, in these studies we determined whether l-theanine attenuates opioid-withdrawal signs in morphine-dependent rhesus monkeys, a model for spontaneous opioid withdrawal in human opioid addicts. We also evaluated whether l-theanine decreases anxiety-like behavior in mice, using the elevated plus maze and marble burying assays. l-theanine significantly attenuated designated opioid withdrawal signs, including fighting, rigid abdominal muscles, vocalizing on palpation of abdomen, pacing, retching, wet-dog shakes, and masturbation. It had a relatively quick onset of action that persisted for at least 2.5h. l-theanine also produced anxiolytic-like effects in the elevated plus maze and the marble burying assay in naïve mice at doses that did not significantly affect motor behavior. The results of these studies suggest that l-theanine may be useful in the pharmacotherapy of treating opioid withdrawal as well as anxiety-associated behaviors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid β-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of β-FNA is clearly κ opioid receptor (KOR) mediated.

Rationale: Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4β2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment., Objectives: The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4β2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration., Methods: Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day)., Results: 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration., Conclusions: These results support the hypothesis that neuronal α4β2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4β2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.

MDAN-21, 7'-{2-[(7-{2-[({(5α, 6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006-0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032-0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain.

The purpose of the present research was to examine Deese-Roediger-McDermott false memory for trauma-related and nontrauma-related lists in adolescents and adults with and without documented histories of child sexual abuse (CSA). Individual differences in psychopathology and adult attachment were also explored. Participants were administered free recall and recognition tests after hearing CSA, negative, neutral, and positive Deese-Roediger-McDermott lists. In free recall, CSA and negative lists produced the most false memory. In sharp contrast, for recognition, CSA lists enjoyed the highest d' scores. CSA-group adolescents who evinced greater posttraumatic stress disorder (PTSD) symptoms had higher rates of false memory compared to (a) non-CSA group adolescents with higher PTSD symptom scores (free recall), and (b) CSA-group adolescents with lower PTSD symptom scores (recognition). Regression analyses revealed that individuals with higher PTSD scores and greater fearful-avoidant attachment tendencies showed less proficient memory monitoring for CSA lists. Implications for trauma and memory development and for translational research are discussed.

The introduction of transgenic and knockout mice has shaped new interest in developing novel and modified behavioral methods for mice that evaluate the various manifestations of nicotine withdrawal syndromes. This study assessed the disruption of operant baselines during drug withdrawal, an established rat model of nicotine dependence, in mice. Subjects were trained to lever press for food reinforcement during daily operant sessions. After stable operant baselines were established, mice were implanted with osmotic minipumps containing 0 (saline), 6, 12, 24, or 48 mg/kg/day nicotine base. Operant responding was assessed for disruptions in daily sessions throughout the experiment. Somatic signs of withdrawal were assessed after the operant session on day 7, following administration of mecamylamine (1 mg/kg), and on days 12, 13, and 14, following spontaneous removal of nicotine. Spontaneous removal of nicotine increased somatic signs of withdrawal but did not disrupt operant responding. Mecamylamine failed to produce signs of precipitated withdrawal in either procedure. This study demonstrated nicotine dependence in mice during spontaneous removal of nicotine. Moreover, since signs of behavioral withdrawal (i.e. disruptions in operant response rates) were not observed, these findings suggest the importance of considering differences in the apparent manifestations of withdrawal syndromes while evaluating nicotine dependence.

Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues 3-6, while 12b displayed predominant MOR agonist activity.

To investigate the effects of carboxylic ester and acid moieties as the N-substituent of opioids, a short series of racemic N-substituted normetazocines was prepared. The introduction of both groups as the normetazocine N-substituent produced compounds which displayed low potency in vitro and in vivo, with the esters displaying the greater activity. The pharmacology of the compounds is discussed with implications resulting from potential in vivo metabolic hydrolysis.

Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9alpha-methyl, C9-methylene, C9-keto, and C9alpha- and C9beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (Ki = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9beta-OH substituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the mu-opioid receptor.

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50=1.9 (0.7-5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50=0.75 (0.26-2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

The present study examined the effects of NIH 11082 ((-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride), a benzomorphan analogue, in the mouse tail-suspension, an assay used to detect anti-depressant agents. NIH 11082 significantly decreased immobility time during tail-suspension, with a comparable magnitude as the tricyclic anti-depressant desipramine. Importantly, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. The delta-opioid receptor antagonist naltrindole (AD50=2.0 mg/kg), but not the non-selective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocked the effects of NIH 11082 in the tail-suspension test. These results reinforce the notion that delta-opioid receptor agonists can produce significant effects in a behavioral model used to screen anti-depressant drugs.

Objective: Results of the ICON4/AGO-OVAR-2.2 trial suggest that a platinum/taxane combination provides a survival benefit in relapsed, platinum-sensitive ovarian cancer compared to platinum alone. The optimal specific combination has yet to be determined. The current study evaluates weekly docetaxel and carboplatin in this setting., Methods: Using a prospective phase II design, patients received weekly docetaxel (35 mg/m2) and carboplatin (AUC=2) administered days 1, 8, and 15 of a 28-day cycle. Initial treatment with a platinum-based regimen was required, with a treatment-free interval of at least 3 months. Patients could have received one prior regimen for recurrence. Biologically evaluable disease (CA-125) could be followed only if measurable disease was not present. Quality of life analysis utilized the FACT-O and FACT/GOG-Ntx scales., Results: Thirty-six patients enrolled in the trial over 29 months. The majority had ovarian cancer (89%) and stage III/IV (97%) disease, with a median initial disease-free interval of 12 months. Most subjects were treated for first recurrence (81%) and had measurable disease (58%). The overall response rate was 67% (PR=52%, CR=15%), with 22% stable disease. Grade 3/4 neutropenia was common (48%) while serious anemia and thrombocytopenia were not. Neuropathy was generally mild and manageable. Carboplatin hypersensitivity led to 11 subjects coming off trial (31%). Diphenhydramine premedication produced a nonsignificant decrease in reaction rate. There was no detectable difference in quality of life due to therapy., Conclusion: The weekly regimen of carboplatin and docetaxel has a good response rate with an acceptable toxicity profile.

Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the mu-, delta-, and kappa-opioid receptors was examined. The higher affinity ligands were further examined in the [(35)S]GTPgammaS assay to study their function and efficacy. 3-((1R,5S)-(-)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) was found to be a mu-agonist and delta-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(-)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) and several other ligands displayed inverse agonist activity at the delta-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (-)- to 1R,5S-(-)-.HBr.

This article is part of a supplemental issue of the journal devoted entirely to papers on how abuse liability of medications is affected by their formulation for medical use. This article reviews the history of the development of the concept of "exempt preparations" from its first use internationally to its current use, both nationally and internationally. The role of the WHO Expert Committee on Drug Dependence (ECDD) and the College on Problems of Drug Dependence (CDPP) is presented. Examples of exempt preparations are given and the use of the concept to permit useful therapeutic agents to be marketed with reduced regulatory control is discussed.

JDTic, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide, is a potent and selective kappa-opioid antagonist with a very long duration of action [Carroll, F.I., Thomas, J.B., Dykstra, L.A., Granger, A.L., Allen, R.M., Howard, J.L., Pollard, G.T., Aceto, M.D., Harris, L.S., 2004. Pharmacological properties of JDTic: A novel k-opioid receptor antagonist. Eur. J. Pharmacol. 501, 111-119.]. When given 24 h prior to a continuous 4-day infusion of morphine sulfate in rats, JDTic did not prevent the stereotypy that developed during the infusion of morphine. It had no effect on the dramatic loss of body weight associated with the abrupt withdrawal of morphine. However, it decreased the number of important withdrawal signs designated wet-dog shakes and facial rubs. These data suggest that JDTic may find some application in the treatment of opiate abuse.

In a continued effort to find new substitution patterns in morphinans that would produce strong antinociception while inducing lesser side effects, 4,5-oxygen bridge-opened 6-cyano-substituted N-methylmorphinans (1-3) were synthesized. All compounds showed high affinities in the low nanomolar range to the mu opioid receptor and decreased interaction with delta and kappa receptors, thus being mu selective. When tested in vivo, the 6-cyanomorphinanas acted as potent antinociceptive agents which were either more active or equipotent to their 6-keto analogues 4-6.

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.

Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a mu-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphine-dependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through mu-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects.

The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at mu, delta, and kappa opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the mu opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase mu affinity in the case of benzyloxy, while a phenylpropoxy group reduces mu affinity. The delta and kappa affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the mu opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at delta and kappa receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [(35)S]GTPgammaS binding assay, all tested compounds were partial agonists at mu and delta receptors. Compounds 8 and 17 showed antagonism at kappa receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.

The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (1).

The synthesis, biological, and pharmacological evaluations of 14beta-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14beta-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (mu, kappa, delta), with the N-propyl derivative 19 displaying the highest affinity for the mu-receptor (K(i) = 0.09 nM).

To further investigate the unusual profile of N-benzyl substituted opioids, N-trifluoromethylbenzyl normetazocines and norketobemidones were prepared. The introduction of trifluoromethyl substituents on the benzyl group of the (-)-metazocines reduced affinity at all three receptors, with the greatest loss at kappa receptors. Surprisingly, some of the (+)-normetazocines actually possessed higher affinity than the corresponding (-)-isomers. In the ketobemidone series, the effects were different-the 4-trifluoromethyl substituted ketobemidone actually possessed 3-fold higher mu affinity than the unsubstituted parent to give a ligand with good mu affinity. In functional in vitro assays, this compound was a weak antagonists, but in apparent contradiction it was inactive in in vivo assays.

Objective: This was a phase II study of perillyl alcohol in the treatment of advanced ovarian cancer. The primary endpoint was to evaluate the 6-month progression-free rate of perillyl alcohol as compared with historic controls. Secondary objectives were to evaluate the objective response rate, time to progression and survival, dropout rate, and number of cycles administered; define the qualitative nature of acute and chronic toxicities; and evaluate the effect of perillyl alcohol on triglycerides and total, HDL, and LDL cholesterol levels. Methods. Women who had received prior platinum-based therapy and had residual or recurrent disease were eligible. Perillyl alcohol was administered orally, four times daily, at a dose of 1200 mg/m(2). This was repeated until disease progression or unacceptable toxicity was experienced., Results: The 6-month progression-free rate was 17%. None of the patients achieved a complete or partial response. The median progression-free survival was 1.7 months. The median overall survival was 9.1 months. Compliance was greater than 90% but gastrointestinal toxicity (grade 1-2 nausea, satiety, eructation in 70%) and fatigue (grade 1-2 in 40%) were common and limited the ability to escalate the dose from 1200 to 1500 mg/m(2)., Conclusion: Perillyl alcohol administered at this dose and formulation did not exhibit signs of extending the time-to-progression in patients with advanced ovarian carcinoma.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED(50) = 0.05 mg/kg), and (-)-(1R,5R, 9R)-N-but-2-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan ((-)-(1R, 5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa-opioid receptor than the mu-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for delta-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective sigma(1)-ligands (K(i) = 2 nM, sigma(2)/sigma(1) = 1250, and 1 nM, sigma(2)/sigma(1) = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at sigma(1), and its sigma(1)/sigma(2) ratio was <100.

The position of the indole in the indolomorphinans, which includes the delta opioid antagonist naltrindole, is considered to be responsible for the delta opioid selectivity for this class of ligands. Herein is described the N-cyclohexylethyl substituted N-nor-derivative, which is shown to be mu preferring. Thus, the nature of the N-substituent is equally important to the receptor selectivity for this class of ligands.

In a previous study in this laboratory, exposure of rhesus monkeys to intermittent, high doses of dihydroetorphine for 42 days did not evoke behavioral signs of physical dependence on this opioid either after it was abruptly withdrawn or after challenge with a high dose of naloxone. To investigate further the physical dependence capacity of this opioid, it was given by infusion to rats thereby exposing receptors chronically and continuously to this opioid. Abstinence expressed as body weight loss, irritability, and wet-dog shakes was observed after abrupt withdrawal of the low-dose regimen (5,10, 40 and 40 microg/kg per day for 4 days, respectively). The high-dose regimen (10, 20 and 80 microg/kg per day for 3 days, respectively) produced stereotypy and physical dependence. Although many reported molecular events and dependence studies suggest otherwise, dihydroetorphine's propensity to produce physical dependence, an important determinant of opioid abuse, is real.

Background: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin., Methods: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria., Results: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale., Conclusion: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.