Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT2A, but not 5-HT2C, receptor

  Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a 15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT_2A and 5-HT_2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes in binding were observed in 5-HT_2A receptors but not 5-HT_2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT_2A receptors. Received: 17 July 1998 / Final version: 19 January 1999     

Combined finasteride and flutamide therapy in men with advanced prostate cancer

Objectives

To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1 ) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels.

Methods

Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage DO, 7 with rising PSA levels after radical prostatectomy [n = 2]or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized.

Results

Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P>0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P>0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P>0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13]and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19).

Conclusions

Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy.     

Equity and extramarital sexuality

Equity theory has recently been found to be a useful framework for under-standing the effects of imbalances in intimate contractual relationships such as marriage. Equitable couples seem to be happier, more satisfied with their relationship, and more confident that it will last than are their more mismatched, i.e., inequitable, counterparts. Furthermore, inequitable couples predictably act to set things right in their marriage. They either restore actual equity to the relationship or psychologically set their relationship in balance. If neither works, they may leave the field. Extramarital sex may be viewed as an equity restoration mechanism in that (1) it may be used by the deprived partner to achieve actual equity, (2) it may indicate a partner's readiness to leave the relationship because he feels he can do better, or (3) it may represent a desire to achieve equity in an alternative relationship(s) when inequity pervades the primary one. The hypothesis that the inequitable/underbenefited group should be more likely than the equitable group or the inequitable/overbenefited group to have engaged in extramarital sex was tested using data from a large-scale Psychology Todayquestionnaire. The results indicated that men and women in inequitable/under-benefited relationships had more extramarital affairs and began their extramarital activities earlier than did men and women in equitable and inequitable/over-benefited relationships. Alternative explanations of this finding, sex-role demands and length of the relationship, are explored and discarded as untenable. Research supported in part by National Institute of Mental Health Grant MH 26681.     

Gallium scintigraphy in Hansen's disease

Gallium 67 imaging was used in 12 patients with documented Hansen's disease undergoing treatment or not, in an attempt to determine the pattern of the disease. Diagnosis was confirmed by histopathology in all patients. The Mitsuda reaction was seen in all patients. Specific nuclear studies were performed when needed to evaluate particular organs better. Gallium 67 images show homogeneous, diffuse and moderate accumulation over the entire skin surface (except for the face) of untreated patients with multibacillary disease. The facial skin in these cases presented homogeneous, diffuse but very marked uptake of gallium. Internal organ involvement was variable. There was a very good correlation among clinical, scintigraphic, immunological and histopathological data. The pattern of the body skin (skin outlining) and facial skin (beard distribution) may be distinct for untreated patients with multibacillary leprosy.     

Discriminative stimulus properties of l-5-hydroxytryptophan: Behavioral evidence for multiple serotonin receptors

Rats were trained to discriminate the stimulus properties of l-5-hydroxytryptophan (l-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to l-5-HTP, greatly attenuated the disruptive effects observed on responding when l-5-HTP alone was injected. Following acquisition, the discrimination was dosedependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the l-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of l-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures.     

Modification of the noradrenergic cyclic AMP generating system in the rat limbic forebrain by amphetamine: Role of its hydroxylated metabolites

Summary The cyclic AMP responses to norepinephrine (NE) in slices of the rat limbic forebrain after the administration of (S)-amphetamine and the role of its para- and -hydroxylated metabolites were investigated. The chronic but not acute administration of (S)-amphetamine to rats causes a significant reduction in the sensitivity of the cyclic AMP generating system to NE without changing the basal level of the nucleotide. This change in the sensitivity of the system is not associated with a change in the EC₅₀ value for NE but reflects mainly a decrease in the maximal response. After withdrawal of the drug, the cyclic AMP response to NE returned to control values within 4 days. In vitro, (S)-p-hydroxyamphetamine (POH) and all stereoisomers of p-hydroxynorephedrine (PHN) except (S,R)-PHN enhanced the cyclic AMP response to low concentrations of NE. Since (S,R)-PHN [like the other stereoisomers of PHN and (S)-POH] inhibited in a dose-dependent manner the high affinity uptake of ³H-NE into crude synaptosomal fractions of the limbic forebrain, the results might suggest that the presumably physiological enantiomer of PHN also exerts receptor blocking properties. The inhibition by (S,R)-PHN of the cocaine induced potentiation of the cyclic AMP response to NE supports this supposition. The results provide evidence that the hydroxylated metabolites of (S)-amphetamine, (S)-POH and (S,R)-PHN, modify the action of the parent drug on central noradrenergic function at the level of the NE receptor coupled adenylate cyclase system.     

Improved therapeutic responses in a xenograft model of human B lymphoma (Namalwa) for liposomal vincristine versus liposomal doxorubicin targeted via anti-CD19 IgG2a or Fab' fragments.

PURPOSE: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates. EXPERIMENTAL DESIGN: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[alphaCD19]) or its Fab' fragments (SIL[Fab']). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model. RESULTS: SIL[alphaCD19] or SIL[Fab'] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab'] had longer circulation times than SIL[alphaCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab'] had better therapeutic outcomes than SIL[alphaCD19] for the drug DXR but were equally efficacious for the drug VCR. CONCLUSIONS: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab'] versus SIL[alphaCD19] led to superior therapeutics for DXR-loaded immunoliposomes.     

HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice.

PURPOSE: This study examined the effectiveness of early and prolonged mu4D5 (the murine form of trastuzumab/Herceptin) treatment in transgenic mice that overexpress human HER2 (huHER2), under the murine mammary tumor virus promoter, as a model of huHER2-overexpressing breast cancer. EXPERIMENTAL DESIGN: Mice were randomly assigned to one of three treatment groups and received i.p. injections from 17 weeks of age until either 52 weeks of age or morbidity. Fourteen mice received 100 mg/kg mu4D5, 14 mice received 100 mg/kg antiherpes simplex virus glycoprotein D control antibody, and 11 mice received a diluent control. RESULTS: High levels of huHER2 expression were detectable in mammary glands of young virgin founder mice. Mammary adenocarcinomas were frequently found in female founders and progeny at an average age of 28 weeks, with some progressing to metastatic disease. The incidence of mammary tumors was significantly reduced, and tumor growth inhibition was observed in mice receiving mu4D5 compared with control mice. In addition, Harderian gland neoplasms, highly associated with overexpression of huHER2 in this transgenic line, were entirely absent in the mu4D5 treatment group, indicating down-regulation of huHER2 in vivo activity. CONCLUSIONS: Early intervention with mu4D5 was of benefit in our transgenic mice at high risk for developing huHER2-overexpressing breast cancer. This study suggests a potential benefit of early treatment with Herceptin in HER2-positive primary breast cancer.