Drug-free Days Research Articles

Contingency Management for Patients With Dual Disorders in Intensive Outpatient Treatment for Addiction

Objective: This quality improvement program evaluation investigated the effectiveness of contingency management for improving retention in treatment and positive outcomes among patients with dual disorders in intensive outpatient treatment for addiction.Methods: The effect of contingency management was explored among a group of 160 patients exposed to contingency management (n = 88) and not exposed to contingency management (no contingency management, n = 72) in a six-week partial hospitalization program. Patients referred to the partial hospitalization program for treatment of substance use and comorbid psychiatric disorders received diagnoses from psychiatrists and specialist clinicians according to the Diagnostic and Statistical Manual of the American Psychiatric Association. A unique application of the contingency management “fishbowl” method was used to improve the consistency of attendance at treatment sessions, which patients attended 5 days a week. Days attending treatment and drug-free days were the main outcome variables. Other outcomes of interest were depression, anxiety and psychological stress, coping ability, and intensity of drug cravings. Results: Patients in the contingency management group attended more treatment days compared to patients in the no contingency management group; M = 16.2 days (SD = 10.0) versus M = 9.9 days (SD = 8.5), respectively; t = 4.2, df = 158, p <.001. No difference was found between the treatment groups on number of drug-free days. Psychological stress and drug craving were inversely associated with drug-free days in bivariate testing (r = −.18, p <.02; r = −.31, p <.001, respectively). Treatment days attended and drug craving were associated with drug-free days in multivariate testing (B =.05, SE =.01, β =.39, t = 4.9, p <.001; B = −.47; SE =.12, β = −.30, t = −3.9, p <.001, respectively; Adj. R2 =.21). Days attending treatment partially mediated the relationship between exposure to contingency management and self-reported drug-free days. Conclusions: Contingency management is a valuable adjunct for increasing retention in treatment among patients with dual disorders in partial hospitalization treatment. Exposure to contingency management increases retention in treatment, which in turn contributes to increased drug-free days. Interventions for coping with psychological stress and drug cravings should be emphasized in intensive dual diagnosis group therapy.

Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure.

Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure. The objective of the present study is to determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats. Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11-13 sessions. Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self-administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion, and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline. Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult-onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders).

Delayed onset, Long-term Efficacy of S-1 Monotherapy for an Elderly Patient with Squamous Cell Lung Cancer

The efficacy of S-1 monotherapy as a 2nd-line regimen for elderly patients with non-small cell lung cancer (NSCLC) has not been reported, nor has delayed onset regression after temporary progression of tumor during an identified therapeutic regimen. Here we report a 78-year-old man was diagnosed with T3N3M1b (BRA), stage IV squamous cell lung cancer. His primary lesion progressed after whole brain irradiation and 4 cycles of 1st-line chemotherapy with docetaxel. S-1 monotherapy was prescribed as the 2nd-line treatment. Each cycle of chemotherapy comprised 14 days of S-1 (40 mg, twice daily) followed by 14 drug-free days. After 6 months of S-1 monotherapy, primary and metastatic lesions had started regressing significantly. He continued S-1 monotherapy for 19 months (20 cycles) with a comfortable daily life until reaching progressive disease. S-1 monotherapy as a 2nd-line could be a therapeutic option for elderly patients with NSCLC. Moreover, long-term use of S-1 might be worth trying if adverse events and tumor growth are tolerable and other anti-cancer drugs are not applicable, because S-1 has a potential for delayed onset efficacy.

A Randomized Trial of Concurrent Smoking-Cessation and Substance Use Disorder Treatment in Stimulant-Dependent Smokers

To evaluate the impact of concurrent treatments for substance use disorder and nicotine-dependence for stimulant-dependent patients. A randomized, 10-week trial with follow-up at 3 and 6 months after smoking quit date conducted at 12 substance use disorder treatment programs between February 2010 and July 2012. Adults meeting DSM-IV-TR criteria for cocaine and/or methamphetamine dependence and interested in quitting smoking were randomized to treatment as usual (n = 271) or treatment as usual with smoking-cessation treatment (n = 267). All participants received treatment as usual for substance use disorder treatment. Participants assigned to treatment as usual with concurrent smoking-cessation treatment received weekly individual smoking cessation counseling and extended-release bupropion (300 mg/d) during weeks 1-10. During post-quit treatment (weeks 4-10), participants assigned to treatment as usual with smoking-cessation treatment received a nicotine inhaler and contingency management for smoking abstinence. Weekly proportion of stimulant-abstinent participants during the treatment phase, as assessed by urine drug screens and self-report, was the primary outcome. Secondary measures included other substance/nicotine use outcomes and treatment attendance. There were no significant treatment effects on stimulant-use outcomes, as measured by the primary outcome and stimulant-free days, on drug-abstinence, or on attendance. Participants assigned to treatment as usual with smoking-cessation treatment, relative to those assigned to treatment as usual, had significantly better outcomes for drug-free days at 6-month follow-up (χ(2)(1) = 4.09, P <.05), with a decrease in drug-free days from baseline of -1.3% in treatment as usual with smoking-cessation treatment and of -7.6% in treatment as usual. Participants receiving treatment as usual with smoking-cessation treatment, relative to those receiving treatment as usual, had significantly better outcomes on smoking point-prevalence abstinence (25.5% vs 2.2%; χ(2)(1) = 44.69, P < .001; OR =18.2). These results suggest that providing smoking-cessation treatment to illicit stimulant-dependent patients in outpatient substance use disorder treatment will not worsen, and may enhance, abstinence from nonnicotine substance use. ClinicalTrials.gov identifier: NCT01077024.

Weekend Ecstasy use disrupts memory in rats

3,4-Methylenedioxymethamphetamine (MDMA, or “Ecstasy”) is a popular recreational drug. However, its exposure is often limited to the weekends in a highly stimulating environment. The goal of this study was to investigate the behavioral domains of working and recognition memory within a model of “weekend” Ecstasy use. Rats self-administered MDMA during 2-h sessions on two consecutive days followed by five drug-free days. Coupling this intermittent dosing schedule with a novel object recognition task, we found non-spatial memory impaired after only two “weekends” of self-administered MDMA. Our findings suggest that MDMA at recreational use levels can disrupt memory processes.

Transplantation of engineered heart tissue as a biological cardiac assist device for treatment of dilated cardiomyopathy

The aim of this study was to characterize an alternative treatment for dilated cardiomyopathy (DCM) using a novel cardiac biological assist device created from engineered heart tissue (EHT). The EHTs were constructed in vitro from matrigel, collagen, and neonatal rat cardiomyocytes as small ring-like spontaneously contracting devices. DCM was induced in 50 rats by 6 weeks doxorubicin treatment (2.5 mg/kg/week). After 38 drug-free days, rats underwent either implantation of EHT (DCM-EHT, n = 13), which was sutured around the ventricles, or sham operation (DCM-Sham, n = 12). Eleven untreated healthy rats served as the control group. Rats were investigated using a Millar catheter for pressure-volume loop recording, and by echocardiography 30 days after operation. Thereafter, the hearts were excised and investigated functionally, histologically, and biochemically. Doxorubicin led to the development of DCM with reduced fractional shortening (FS), reduced dP/dt(max), increased systolic and diastolic LV diameters, and reduced response to dobutamine. In DCM-Sham, these changes were further enhanced, while in DCM-EHT we found improved FS, dP/dt(max), and dobutamine responsiveness. In isolated hearts, electrical multielectrode mapping revealed that EHT was electrically activated synchronously to the recipient heart. Histologically, we found increased vascularization in the EHT and the recipient heart, and EHT vessels connected to the coronary system. Implantation of EHT improves LV performance in rats with doxorubicin-induced DCM.

Reducing youth's drug abuse through training social workers for cognitive–behavioral integrated treatment

Abstract Cognitive–behavioral integrated treatment (CBIT) is an intervention that social workers can learn to treat youth's drug abuse by cognitive restructuring, behavioral modification, and goal setting. A way to enhance the learning is training specifically for CBIT. Evaluation of the effectiveness of such training in raising social workers' CBIT practice and their young service users' illicit-drug-free days is the aim of this experimental study. This study first randomly assigned 14 outreach social workers to receive training for CBIT and 14 outreach social workers not to receive the training. The study also assessed 222 young service users (aged 11–22 years) engaged by 28 outreach social workers before the training and 169 of them after the training in a six-month follow-up. Furthermore, the study identified the reduction in the youth's dysfunctional cognition of playfulness as a means to deter the youth's drug abuse, based on personal interviews with outreach social workers and their young service users before the training. Derived from the statistical analysis of assessment data, results principally showed cascading effects from the social worker's reception of the CBIT training to the young service user's reception of CBIT, reduced playfulness, and lengthened drug-free days. A supplementary finding was that the young service user's time in the outreach social work service prolonged drug-free days and reduced playfulness. These results imply that the outreach social work service, CBIT training, and CBIT are useful for treating youth's illicit drug abuse.

Evaluation of anxiolytic effect and withdrawal anxiety in chronic intermittent diazepam treatment in rats

This study evaluated the effect of intermittent administration in the development of dependence to diazepam in chronic use of the drug. Gabapentin was used to provide an anxiolytic effect on drug-free days. During a 28-day treatment schedule, rats were given diazepam (15 mg/kg) once daily continuously, or intermittently with saline or gabapentin (50 mg/kg) on days 5, 10, 15, 20, and 25. Anxiety-like behavior was assessed on days 10 and 30 using the elevated plus-maze test and novelty-induced grooming test. Contrary to continuous administration, intermittent diazepam did not provide anxiolytic-like activity on day 10; instead, it prevented withdrawal anxiety on day 30. Gabapentin produced anxiolytic-like effects during the withdrawal period, but not on day 10. These results suggest that intermittent administration of diazepam (given either alone or alternatively with a drug possessing anxiolytic activity) may be of value in preventing the development of physical dependence during the chronic use of the drug. However, further studies are needed to demonstrate that this protocol could effectively produce anxiolytic activity on diazepam-free days.

Cocaine modulates both glutaminase gene expression and glutaminase activity in the brain of cocaine-sensitized mice

Glutaminase is considered the main glutamate (Glu)-producing enzyme. Two isoforms, liver (LGA)- and kidney (KGA)-type glutaminases, have been identified in neurons. The role of both enzymes in psychopharmacological responses to cocaine remains unknown. We examined both mRNA and protein expression of KGA and LGA in the brain of mice sensitized to cocaine. Additionally, total glutaminase activity was also measured. Total glutaminase activity and mRNA and protein expression of KGA and LGA were measured on the dorsal striatum, prefrontal cortex, hippocampus and cerebellum of cocaine-sensitized mice. Cocaine-sensitized animals (20 mg/kg × 5 days, followed by 5 drug-free days) exhibited a decrease of total glutaminase activity in both the dorsal striatum and the prefrontal cortex. This was associated with an increase in KGA mRNA expression in both brain areas that was not observed when protein KGA levels were measured by western blot. LGA mRNA expression was increased as results of acute cocaine administration in sensitized animals, although protein levels were only enhanced in the prefrontal cortex of sensitized mice. These findings suggest that chronic cocaine administration modulates glutamate production through the regulation of glutaminase expression and activity. These actions are mainly observed in the prefrontal cortex-dorsal striatum circuit, the neuroanatomical target for the psychostimulant sensitization properties of cocaine. The present results indicate that glutaminase enzymes (mainly KGA) are modulated by cocaine in both the prefrontal cortex and the dorsal striatum, as part of the neuroadaptions associated with behavioural sensitization to this drug of abuse.

The response of Acne vulgaris to antibiotics both oral and topical

Background: Acne vulgaris is a chronic inflammatory skin disease that involves pilosebaceous units. Many systemic treatments used for acne vulgaris such as antibiotics, hormonal therapy, isotretinoin and occasionally, corticosteroids. Oral azithromycin has been advocated by some in the treatment of acne, but its efficacy has not been established.Objectives: To compare the efficacy and safety of Azithromycin and doxycycline in the treatment of inflammatory acne.Methods: This study was conducted on 50 patients who attended the outpatient clinic of the Royal medical services hospital, Jordan. In the first group, oral azithromycin 500 mg was administered daily before meals for 3 consecutive days in a l0-day cycle, with the remaining seven days in each cycle being drug-free days. The second group was given doxycycline 100 mg daily after meals. Topical erythromycin was prescribed to all patients. Clinical follow-up assessment was done at l0-day intervals for both the groups up to three months.Results: The study showed 70% improvement in azithromycin treated group in comparison to 60% in the doxycycline treated group. There was a statistically significant reduction in severity in the azithromycin treated group.Conclusion: The results show that azithromycin is a safe and effective alternative in the treatment of inflammatory acne with few side-effects and good compliance, a combination of azithromycin with topical erythromycin was significantly better than doxycycline with topical erythromycin in the treatment of acne vulgaris. The incidence of side effects were less with azithromycin.

Measurement of Substance Abuse Treatment Outcomes Over Time

There are many different ways of calculating the impact of treatment on drug use; percentage of positive drug tests, probability of drug use, percentage of patients abstaining from any use, total number of days of use, daily probability of use and average days till next use, are some examples reported in the literature. We prefer average days till next use because (1) it allows intermittent drug use and relapse; (2) it fits the client's count of drug-free days, and (3) it simultaneously accounts for both tests results and time between tests. We show by way of an example, how conclusions arrived at using average days till next use are likely to be different from other measures in analysis of recent data from impact of online treatment on drug use.

The involvement of type IV phosphodiesterases in cocaine-induced sensitization and subsequent pERK expression in the mouse nucleus accumbens

Cocaine exposure produces sensitization that is partly mediated by cyclic adenosine monophosphate (cAMP) pathways within the nucleus accumbens (NAc). Type IV phosphodiesterases (PDE4s) break down cAMP and are required for cocaine-induced conditioned place preference. Whether PDE4 disruption attenuates induction of behavioral sensitization to cocaine and subsequent NAc expression of phosphorylated extracellular signal-regulated kinase (ERK), which is involved in cocaine-induced sensitization, is unknown. The objective of this study was to determine whether inhibition of PDE4s prevents cocaine-induced locomotor sensitization and if reduced behavioral sensitization is accompanied by decreased expression of phosphorylated ERK (pERK) within the NAc. Mice were administered the PDE4 inhibitor, rolipram, or vehicle before or after five daily injections of cocaine or saline, and activity was monitored on days 1 and 5. After nine drug-free days, locomotor sensitization was tested. Some subjects were sacrificed following testing for behavioral sensitization to measure pERK expression in the NAc. PDE4 inhibition, during the induction of sensitization, reduced behavioral sensitization only if rolipram (1.0 mg/kg) was administered before cocaine. Re-exposure to the cocaine-paired environment following a 9-day drug-free period enhanced pERK expression in the NAc core and shell. Rolipram did not alter pERK induction despite blocking behavioral sensitization. Rolipram given during, but not following, cocaine treatment prevents development of locomotor sensitization to cocaine but does not affect subsequent pERK activation induced by exposure to a cocaine-paired context or following a cocaine challenge. Although PDE4 inhibition during the induction of sensitization blocks the locomotor component of sensitization, other long-term changes induced by repeated cocaine treatment remain.

Effects of self-administered cocaine in adolescent and adult male rats on orbitofrontal cortex-related neurocognitive functioning

Deficits in amygdala-related stimulus-reward learning are produced following 18 drug-free days of cocaine self-administration or its passive delivery in rats exposed during adulthood. No deficits in stimulus-reward learning are produced by cocaine exposure initiated during adolescence. To determine if age of initiating cocaine exposure differentially affects behavioral functioning of an additional memory system linked to cocaine addiction, the orbitofrontal cortex. A yoked-triad design (n = 8) was used. One rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling drug delivery (1.0 mg/kg) self-administered cocaine from either P37-P59 or P77-P99, and then underwent 18 drug-free days (P60-P77 vs. P100-P117). Rats next were tested for acquisition of odor-delayed win-shift behavior conducted over 15 sessions (P78-P96 vs. P118-P136). Cocaine self-administration did not differ between adults and adolescents. During the test phase of the odor-delayed win-shift task (relatively difficult task demands), rats from both drug-onset ages showed learning deficits. Rats with cocaine self-administration experience committed more errors and had longer session latencies compared to rats passively receiving saline or cocaine. Rats with adolescent-onset cocaine self-administration experience showed an additional learning deficit by requiring more sessions to reach criterion levels for task acquisition compared to same-aged passive saline controls or rats with adult-onset cocaine self-administration experience. Rats passively receiving cocaine did not differ from the passive saline control from either age group. Rats with adolescent-onset cocaine self-administration experience were more impaired in an orbitofrontal cortex-related learning task than rats with adult-onset cocaine self-administration experience.

Social isolation during perinatal development alters the behavioral response to cocaine in juvenile rats

Stress is a risk factor in drug addiction, enhancing development and increasing relapse. However its role during development has received little attention. This study will investigate if social isolation during early development alters the behavioral response to cocaine. Pregnant Sprague Dawley rats were housed 1 (prenatal isolation group) or 2 (control group) rats per cage. From postnatal day 2‐9, pups from the neonatal isolation group were isolated for 60 min in a separated cage. At day 21 (weaning), pups from the postnatal isolation group were housed individually. Another group was isolated during both prenatal and postnatal period. Control rats were maintained with dam and siblings and at weaning, housed 4‐5/cage of the same sex. At day 22, and for 5 consecutive days, pups were injected daily with saline or cocaine (15 mg/kg/i.p.) followed by 7 drug free days. A challenge injection of saline or cocaine (15 mg/kg,i.p.) was given on day 13. Locomotor activity was recorded on days 1, 5, and 13. Only rats that were isolated during both prenatal and postnatal period showed an increase in cocaine‐induced behavioral sensitization as compared to control rats. These data indicate that isolation stress during perinatal development enhances the behavioral response to drugs of adolescent rats. [Support contributed by NIH grants: U54NS39405 (SNRP); SO6‐GM08224 (MBRS/SCORE)]

Sensitizing regimens of (±)3, 4-methylenedioxymethamphetamine (ecstasy) elicit enduring and differential structural alterations in the brain motive circuit of the rat

Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received two daily injections of either 5.0 mg/kg (±)-MDMA or saline vehicle, ∼6 h apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.

Estrous cyclicity and the locomotor response to acute and repeated cocaine administration.

Several studies have shown that gonadal hormones modulate the behavioral response to cocaine. In this study we examined if endogenous changes in sex steroids throughout the estrous cycle affect the locomotor response to repeated cocaine administration. Adult female Sprague Dawley rats were cycled for 21 days. Rats then received a daily injection of saline or cocaine (15 mg/kg,i.p.) for 5 days, followed by 7 drug free days. A challenge injection of saline or cocaine (15 mg/kg,i.p.) was given on day 13. Behavioral activity was recorded on days 1, 5 and 13. Vaginal lavages were performed daily, and on days 1, 5 and 13, after behavioral testing.Cocaine increased horizontal activity and total distance traveled of drug naive female rats independent of the stage of the estrous cycle. A similar pattern was observed on day 5 of cocaine treatment. However, after 1 week of withdrawal, rats that were in estrous showed higher cocaine‐induced hyperactivity compared to females in proestrous or diestrous. If we compare cocaine‐induced hyperactivity of females at different stages of the estrous cycle we observe that only females in estrous show an increase from day 1 to day 13, indicating that females in estrous become sensitized to cocaine. These results are similar to those obtained by other groups. An unexpected finding was the shortening of the estrous cycle. In summary, we observed that the stage of the estrous cycle affects the locomotor response to repeated cocaine administration. These data may have implications in treatment strategies for female cocaine addicts.

Efficacy of the Novel Oral Iron Chelator Deferitrin in Metabolic Iron Balance Studies.

Deferiprone (L1, Ferriprox) and deferasirox (ICL670, Exjade), two orally effective iron-chelating agents, have revolutionized the management of iron overload. Nonetheless, neither drug is effective in all patients, deferoxamine (DFO) still being the only drug capable of placing all affected individuals in net negative iron balance. Deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, GT56-252), is a tridentate ligand with a demonstrated efficacy and an acceptable toxicity profile in preclinical evaluations in primates. In Phase 1 studies, it was well absorbed and no safety issues were identified. Thus, given the need for additional oral chelation options, we explored the efficacy of deferitrin in iron-overloaded patients with β-thalassemia major. Total iron balance studies were carried out wherein the effectiveness of single daily ascending doses of deferitrin (4.5, 6.75, 11 and 17 mg/kg/day) was compared with that of a standard DFO regimen (40 mg/kg infused subcutaneously over 8 hours). Twenty patients were admitted to our clinical research center for 28 days and placed on fixed individualized low-iron diets. On days 5 – 10 they were infused nightly with DFO and on days 15 – 24 given a dose of deferitrin with breakfast. Groups of 4 patients were studied at the three lowest doses of deferitrin, only 2 patients being given 17 mg/kg. Drug-free days allowed for washout of stool iron due to previous treatments, a stool marker being given at the beginning and end of each period of drug evaluation. Safety was assessed by hematology (CBC and coagulation parameters), chemistry (electrolytes, BUN, creatinine, liver function tests), urinalysis, and urinary β-2-microglobulin as well as by EKG, physical examination and monitoring of adverse events. Iron balance due to DFO ranged from 52% – 325% (mean 157%) with 40% – 77% (mean 61%) of total iron excretion appearing in the stool. Only 4 patients failed to achieve net negative iron balance. The response to deferitrin was highly variable at each dose studied, there being patients who responded poorly and others in whom there was a good response. Overall, iron balance ranged from 7% – 42%, nearly all of the iron excreted (0.04 – 0.14 mg/kg/day) appearing in the stool. Of note, total iron excretion appeared to reach a plateau at a deferitrin dose of 11 mg/kg/day. As animal studies suggested that more iron might be excreted upon giving the drug in divided doses, we interrupted our evaluation of 17 mg/kg/day and studied an additional 6 patients at 25 mg/kg/day, the drug being divided t.i.d. with breakfast, dinner and a bedtime snack. Iron balance in these patients ranged from 28% – 62% (mean 43%), stool iron excretion (0.14 – 0.29 mg/kg/day) accounting for 99% of the total. Their DFO-induced iron balance was similar to that of the patients previously studied, ranging from 123% – 233% (mean 173%). At all doses, no significant changes were noted in the EKGs or any hematological, biochemical or urinary parameters. There were no serious adverse events. These results suggest that deferitrin was orally effective and, while less effective than DFO, it was of sufficient efficacy to warrant further evaluation in a longer-term study as an alternative to DFO.

A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma

Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.

Successful treatment of S-1 + CDDP followed by salvage EMR for a case with metastatic Barrett's esophageal cancer

A 62-year-old woman with Barrett's esophageal cancer was hospitalized. Abdominal CT confirmed metastases to the liver and lymph nodes, for which surgical excision and radiotherapy were not indicated. We started chemotherapy with a course of daily oral S-1 at a dose of 80 mg/m(2) for 21 days, with a 2-hour drip of cisplatin at 60 mg/m(2) on day 8. Breaks of 14 drug-free days were given between courses. After two courses, a repeat CT confirmed that the liver and lymph node metastases had disappeared; after three courses, another CT confirmed that the metastatic foci were still absent, so we judged the disease to be in complete remission. Endoscopy and upper GI series confirmed that the primary tumor was reduced, and endoscopic mucosal resection performed using the strip biopsy method. The excision specimen was well differentiated adenocarcinoma, and mucosal invasion, and the excision stump was negative. After two more courses of S-1 + cisplatin, chemotherapy has been suspended with the patient's consent, and in the 21 months after endoscopic mucosal resection, no recurrence has been observed. This is a rare case of metastatic Barrett's esophageal cancer in which the metastases were eradicated by S-1 + cisplatin, and the primary tumor successfully excised by endoscopic mucosal resection after downstaging.

Olanzapine and JL13 induce cross-tolerance to the clozapine discriminative stimulus in rats

We have previously shown that chronic treatment with clozapine induces tolerance to the clozapine discriminative stimulus in rats. The studies reported here extended this work to assess whether chronic treatment with the clozapine-like antipsychotics olanzapine and 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate (JL13) induced cross-tolerance to clozapine. Two groups of rats were trained to discriminate clozapine (5 mg/kg, intraperitoneal). Training was suspended and the rats were treated with either olanzapine or JL13 at high doses (5 and 20 mg/kg, respectively). These doses were administered twice daily. The clozapine generalization curve was computed three times - before chronic drug treatment, after 10 days of chronic treatment, and after 16 drug-free days. Both olanzapine and JL13 induced cross-tolerance to the clozapine stimulus, shown by significant 3.4 and 3.9 fold parallel shifts to the right in the clozapine generalization curves. Cross-tolerance was lost spontaneously during the drug-free days after treatment as clozapine sensitivity returned to baseline. We interpret these findings as indicative of the development of pharmacodynamic cross-tolerance to clozapine. Possible neuroadaptive mechanisms involved in such cross-tolerance are discussed. The paradigm outlined here allows refinement of antipsychotic drug discrimination assays to identify common chronic effects of such drugs.