Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Natural history of the benign breast lump

A prospective study of 112 patients with clinically discrete benign breast lumps has shown that 68 per cent of patients experienced resolution of their lumps over a period of up to 2 years. Resolution of both fibro-adenomas and discrete areas of fibro-adenosis was observed. Diagnosis was achieved by clinical examination and fine needle aspiration cytology. Four patients thought clinically to have benign disease were proven by cytology to have a carcinoma, but no patient with a cytopathological diagnosis of benign disease has developed cancer during or subsequent to this study. We recommend that patients under 35 years of age with clinically and cytologically benign breast lumps can be offered the option of non-excision in the reasonable expectation of resolution of their lesion.     

Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding

Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05) than did fasting samples for polychlorinated biphenyls (PCBs, 4.81 vs 3.74 ng/g serum wt), hexachlorobenzene (HCB, 0.163 vs 0.134 ng/g serum wt), andp,p-dichlorodiphenyldichloroethylene (p,p-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.     

Comparison of conventional stool concentration and preserved-smear methods with Merifluor Cryptosporidium/Giardia Direct Immunofluorescence Assay and ProSpecT Giardia EZ Microplate Assay for detection of Giardia lamblia.

Giardiasis is the most common parasitic infection in the United States. Variation in the numbers of cysts and/or trophozoites that are present along with the need for a skilled microscopist offer challenges in diagnosis. We compared the sediment wet preparation and permanent stained smear results (concentration in formalin-ethyl acetate and preparation of a smear prepared from a polyvinyl alcohol-preserved specimen) from 512 consecutive specimens with the results obtained by using the Merifluor Cryptosporidium/Giardia Direct Immunofluorescence Assay (DFA; Meridian Diagnostics, Inc., Cincinnati, Ohio) and the ProSpecT Giardia EZ Microplate Assay (EIA; Alexon, Inc., Sunnyvale, Calif.). The Merifluor DFA detected 33 of 33 positive specimens, and the ProSpecT EIA detected 32 of 33 positive specimens. The diagnostic sensitivities of the Merifluor DFA and the ProSpecT EIA were 100 and 97%, respectively. The specificities of the assays were 99.8%. The Merifluor DFA and the ProSpecT EIA appear to be equally sensitive, and both are more sensitive than conventional microscopy.     

Antibody levels in mothers colonised with group B streptococci during pregnancy and in their newborn infants,as measured by an enzyme linked immunosorbent assay

An enzyme-linked immunosorbent assay (ELISA) was developed to measure serum antibodies to group B streptococci in 20 healthy pregnant women before delivery and in their newborn infants. The sera from 10 of these women who were colonised with group B streptococci and umbilical cord sera from their infants, had higher levels of type-specific lgG antibody than the 10 non-colonised controls and their neonates. All the babies remained well. The results demonstrate that infants from colonised mothers receive type-specific antibody. The possibility that this antibody may provide some degree of protection at birth against this potentially lethal organism warrants investigation.     

Binding of urokinase to specific receptor sites on human breast cancer membranes

The high molecular weight form of the plasminogen activator urokinase (54 kD) binds to specific receptor sites on the cell membrane of breast carcinomas by its inactive "A" chain. The binding is of high affinity (range of dissociation constants: 5.6 X 10(-11) to 4 X 10(-10) mol l-1 and there were between 20 to 250 fmol of binding sites per milligram of membrane protein) and equilibrium is reached in 60 min. No competition for binding sites was observed with epidermal growth factor, tissue plasminogen activator or the low molecular weight form of urokinase (33 kD). Cross-linking experiments suggest that the receptor is a monomeric unit of molecular weight of 50 kD. This binding site provides a mechanism for the incorporation of urokinase into the cell membrane.     

Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat

1. The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine.
2. Sibutramine (3 and 10 mg kg⁻¹, p.o.) and (+)-fenfluramine (1 and 3 mg kg⁻¹, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration.
3. Fluoxetine (3, 10 and 30 mg kg⁻¹, p.o.), and nisoxetine (3, 10 and 30 mg kg⁻¹, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg⁻¹, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration.
4. Venlafaxine (100 and 300 mg kg⁻¹, p.o.) and duloxetine (30 mg kg⁻¹, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration.
5. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.

     

N-Substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/5-HT(1A) partial agonists with potential as atypical antipsychotic agents.

A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.