Perceptions of the community on the pricing of community mental health services.

In the past few years there has been a decrease in governmental support of Community Mental Health centers. Because of this, there has been some concern, on the part of Community Mental Health professionals, as to the overall impact of this decreased governmental support. Research has been conducted that speculates on how best to handle this mini-crisis. One article suggests moving to an overall marketing approach to help combat this dollar support decline (Day and Ford 1988). Others provide methods for surveying Community Mental Health users (Ludke, Curry & Saywell 1983). William Winston (1988) suggests an overall psychographic segmentation approach to developing market targets. There has also been research detailing promotional methods for expanded marketing coverage (Moldenhauer 1988), however little has been written defining the pricing impact on Community Mental Health services. This study addresses the perceptions of Community Mental Health Center users toward the price variable of the marketing mix.

Evaluation and clinical relevance of patient immune responses to intravenous therapy with murine monoclonal antibodies conjugated to adriamycin.

A retrospective study was performed in order to examine the clinical relevance of human anti-murine antibodies (HAMA) to concurrent clinical events in 21 patients receiving intravenous therapy with cocktails of murine monoclonal antibodies conjugated to Adriamycin. In vivo tumor localization of the murine antibodies was also evaluated. Serum levels of HAMA, human-murine immune complexes (HMIC), and murine antibodies were measured using an automated fluorescence immunoassay. Immunohistochemical staining was performed on frozen sections of tumor biopsies from eight of the patients to examine the in vivo binding of the murine antibodies. The patients were divided into low, intermediate, and high antibody dose groups. The incidence of allergic symptoms (80%) and HAMA correlation (75%) were highest in the low dose group. Specific IgM HAMA was the most highly correlated with allergic reactions, being present in 61.5% of the allergic patients. Thirteen of the 21 patients studied (61.9%) developed allergic symptoms after one or more doses of the murine monoclonal antibody conjugates. The percentages of total antibody doses in the patients' sera at varying intervals post-infusion varied widely from patient to patient for any given time point and dose, suggesting complex factors in the distribution and clearance of the murine antibodies. All eight of the patients biopsied during or post-therapy exhibited tumor localization of the murine monoclonal antibodies. Six of the eight had concurrent HAMA in their sera. Thus, the presence of HAMA did not prevent in vivo localization of the murine antibodies in the target tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Daunorubicin coupled to monoclonal antibodies via a cis-aconitic anhydride linker: biochemical and cytotoxic properties revisited.

Daunorubicin (DNR) was coupled to monoclonal antibodies (Mab) reactive to breast tumor cells using the acid-labile linking agents cis-asonitic anhydride and two other non acid-labile analogs, glutaric anhydride and citraconic anhydride. The acid derivatives of DNR formed by reaction with the anhydrides were converted to their N-hydroxysuccinimide (NHS) active esters for coupling to MAb. The molar input of drug NHS ester to MAb ranged from 1:1 to 100:1. The resulting MAb-DNR conjugates were purified by gel filtration and analyzed by high performance liquid chromatography. Monomeric conjugates contained 0.2 to 11.0 moles of DNR/mole of MAb. No evidence of cell killing was observed up to a concentration of 10 micrograms/ml DNR bound to MAb, while DNR exhibited 50% killing of the breast tumor cell line MCF-7 at a concentration of 1 microgram/ml.

Individually specified drug immunoconjugates in cancer treatment.

Forty-three patients with disseminated refractory malignancies each received an individually-specified combination of either Adriamycin (24 patients) or mitomycin-C (19 patients) conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies with both immunohistochemistry and flow cytometry. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells in the biopsy specimen. These monoclonal antibody cocktails were drug conjugated and administered intravenously. Seventeen out of twenty-four patients had reactions to the administration of Adriamycin immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients it was demonstrated that there was limited antigenic drift among various biopsies within the same patient over time. Up to 1 gram of Adriamycin and up to 5 grams of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody which unpredictably caused hemopoietic depression. Similar findings were noted in 19 patients with mitomycin-C conjugates. Thrombocytopenia at a 60mg dose of mitomycin-C in this schedule was dose limiting. Preliminary serological evidence suggests that the development of an IgM antibody which is specific against the mouse monoclonal antibody has the specificity and sensitivity to predict clinical reactions. These antibodies were quantitatively less in mitomycin-C patients. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions and two patients with tongue carcinoma had shrinkage of their lesions. No responses were seen with mitomycin-C conjugates but binding was noted to tumors and colon with likely drug induced colitis seen after colon binding. This study demonstrates the feasibility and illustrates technical considerations in preparing drug immunoconjugate cocktails for patients with refractory malignancies. Cocktail formulation and antibody delivery was accomplished. The major technical hurdle appears to be the selection of effective conjugation methods that can be used to optimally bind drugs to monoclonal antibodies for targeted cancer therapy.

Immunoconjugates of doxorubicin and murine antihuman breast carcinoma monoclonal antibodies prepared via an N-hydroxysuccinimide active ester intermediate of cis-aconityl-doxorubicin: preparation and in vitro cytotoxicity.

Doxorubicin (DXR) conjugated to murine monoclonal antibodies (MoAb) raised against human breast tumor cells demonstrated a MoAb-specific, molar ratio-dependent in vitro cytotoxicity. These conjugates were prepared on a scale sufficient to allow for subsequent clinical trials (1 to 3 g of MoAb per conjugation reaction). The conjugation reaction proceeded via an N-hydroxysuccinimide (NHS) active ester intermediate of cis-aconityl-DXR (CA-DXR), resulting in a cis-aconitate acid-sensitive linker between the DXR and MoAb. Molar ratios of DXR to MoAb ranged from 40 to 45. The immunoreactivity of conjugated MoAb was only slightly decreased from naked MoAb. When immunoconjugates were incubated with MoAb-reactive tumor cells for 3 hours, specific cell-killing was observed. If the exposure time was lengthened to 18 hours, however, nonspecific killing resulted. Incubation of the immunoconjugate with the nonspecific adsorbant Amberlite XAD-2 caused an average 30% decrease in the DXR-to-MoAb molar ratio, suggesting a population of drug that is tightly but noncovalently associated with MoAb.

Railroad accidents: a metropolitan experience of death and injury.

A review of all railroad-related deaths and significant injuries that occurred in a medium-sized metropolitan area from January 1, 1979, to June 30, 1986, was conducted. Autopsy reports were obtained for each fatality, and pre-hospital data were retrieved for all railroad-related injuries resulting in emergency medical services dispatch. There were ten fatalities (24%) and 31 survivors. The average age was 31.2 years (range, 1 to 67). Thirty-seven (90%) were men. Eleven persons (27%) were intoxicated (average blood alcohol of 279 mg/dL; range, 140 to 460). Of the 30 survivors transported, hospital records were available for 24. Thirteen were hospitalized and ten underwent surgery. Six major amputations occurred among survivors. Six patients had an Injury Severity Score of more than 15. Three mechanisms of injury occurred: falls on or from a train (56%); pedestrians hit by a train (41%), which accounted for all fatalities; and a train-automobile accident. This is the first comprehensive review of all significant railroad-related injuries in a metropolitan area.

Adriamycin custom-tailored immunoconjugates in the treatment of human malignancies.

Twenty-three patients with disseminated refractory malignancies each received a tailored combination of adriamycin-conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells as tested by immunoperoxidase and flow cytometry. These monoclonal antibodies were then conjugated to Adriamycin and administered intravenously. Seventeen of 23 patients had reactions to the administration of immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients there was limited antigenic drift among various biopsies within the same patient over time. This observation confirms the necessity for the use of a cocktail of antibodies if one wishes to cover all tumor cells. Preliminary serologic evidence suggests that the development of an IgM antibody, which is specific against the mouse monoclonal antibody, has the specificity and sensitivity to predict clinical reactions. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions and two patients with tongue carcinoma had shrinkage of their lesions. In the course of the study free Adriamycin released from the monoclonal antibodies was discovered to be a limiting factor in the amount of antibody that could be administered. Up to 1 g of Adriamycin and up to 5 g of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. This study demonstrates the feasibility and reviews technical considerations in preparing immunoconjugate cocktails for patients with refractory malignancies. The major technical hurdle appears to be the selection of an effective conjugation method that can be used to optimally bind Adriamycin to monoclonal antibodies for targeted cancer therapy.

Mapping regions of the matrix protein of vesicular stomatitis virus which bind to ribonucleocapsids, liposomes, and monoclonal antibodies.

The matrix (M) protein of vesicular stomatitis virus (VSV) appears to function as a bridge between the ribonucleocapsid (RNP) core and the envelope in assembly of the virion. Two such properties would necessitate at least one site for interaction with the nucleocapsid and one with the envelope. In this study M protein was found to mediate the in vitro binding to RNP cores of phospholipid vesicles, representing membrane structures. The M protein could bind initially to either the vesicles or the RNP cores to promote RNP-vesicle association. A trypsin-resistant fragment (MT) of M protein, missing the initial 43 amino acids from its amino terminus, reconstituted with acidic phospholipid vesicles with the same binding efficiency as did whole M protein, suggesting that the carboxy-terminal 81% retained those regions of the M protein which interact with a lipid bilayer. The MT protein, however, was considerably less efficient than intact M protein as an inhibitor of in vitro virus transcription; almost 2.5-fold more MT protein than intact M protein was required for 50% inhibition of VSV transcription, indicating that a site for interaction with the RNP core may have been lost. A monoclonal antibody which is able to reverse the in vitro inhibition of transcription by M protein did not react by immunoblotting with MT protein. Partial tryptic digests of the M protein probed with this monoclonal antibody indicated that epitope 1 lies between amino acid residues 18 and 43. This region appears to be a site that promotes interaction of the M protein with the RNP core of VSV. Monoclonal antibodies to epitopes 2 and 3, which exhibit some overlap in binding to M protein but do not reverse transcription inhibition, were mapped by cleavage with N-chlorosuccinimide at regions in a carboxy direction from epitope 1.

Monoclonal antibodies to the matrix protein of vesicular stomatitis virus (New Jersey serotype) and their effects on viral transcription.

Of 33 hybridomas raised by immunization of BALB/c mice with the matrix (M) protein of the New Jersey serotype of vesicular stomatitis virus (VSV), 17 secreted monoclonal antibodies (mAb) of the IgG isotype and, unexpectedly, 16 of the IgM isotype. All these monoclonal antibodies bound strongly to VSV-New Jersey M protein by ELISA, immunoprecipitation, and immunoblotting assays, but exhibited only slight or no cross-reactivity with the M protein of VSV-Indiana. Four antigenic determinants of VSV-New Jersey M protein could be identified by competitive binding of 125I-labeled monoclonal antibodies but three of these epitopes exhibited partial overlap. Monoclonal antibodies to two epitopes reversed the inhibitory effect of M protein on in vitro transcription of VSV-New Jersey ribonucleoprotein. However, monoclonal antibodies to the other two epitopes had little effect on M-protein transcription inhibition but actually increased significantly the transcriptional inhibitory effect of M protein under certain experimental conditions. Monoclonal antibodies to all four epitopes reacted strongly with the M protein of the tsC1 mutant of VSV-New Jersey which is restricted in transcription inhibition.

Synthesis and antiviral activity of certain 9-beta-D-ribofuranosylpurine-6-carboxamides.

To examine the structural parameters necessary for antiviral efficacy of certain purine nucleosides, several 9-beta-D-ribofuranosylpurine-6-carboxamides have been synthesized. Glycosylation of the Me3Si derivative of purine--6-carboxamide with protected ribofuranose in the presence of a Lewis acid gave the blocked nucleoside which on deprotection furnished 9-beta-D-ribofuranosyl-6-iodopurine with cyanide ion. Certain 2-amino- and 2-methyl-9-beta-D-ribofuranosylpurine-6-carboxamides have also been prepared. 8-Carbamoylguanosine (16) has been prepared by homolytic acylation of the parent nucleoside. These compounds were tested against several RNA and DNA viruses in cell culture. 9-beta-D-Ribofuranosylpurine-6-carboxamide (6a), the corresponding 6-thiocarboxamide (7b), and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (8) showed significant in vitro antiviral activity at nontoxic dosage levels. 6a employed in the treatment of Rift Valley fever virus infected mice at 50 (mg/kg)/day gave a 55% survival rate on day 21 compared to a 30% survival in the controls.