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Biomedical subjects

D Donovan

Publications and source records attributed to D Donovan.

At least 19 recordsLinked to original sources
PubMed1999

Bone loss and fracture after lung transplantation.

BACKGROUND: Osteoporosis is very common in patients with end-stage pulmonary disease. However, there are few prospective data on fracture incidence after lung transplantation. METHODS: We prospectively evaluated changes in bone mass, fracture incidence, and biochemical indices of bone and mineral metabolism in 30 patients who completed 1 year of observation after lung transplantation. All received calcium, vitamin D, and therapy with one or more agents that inhibit bone resorption, initiated shortly after transplantation. RESULTS: Before transplantation, only 20% of the patients had normal lumbar spine (LS) and femoral neck bone mineral density (BMD). After transplantation, 15 patients (50%) sustained significant bone loss at either the LS (-8.6+/-1.0%) or the femoral neck (-11.3+/-2.2%). Eleven (37%) patients (10 women) sustained a total of 54 atraumatic fractures. Pretransplantation LS BMD and T scores were significantly lower in those who sustained fractures (-2.809+/-0.32 versus -1.569+/-0.29; P<0.01). Fracture patients were more likely to have had pretransplantation glucocorticoid therapy (chi-square 5.687; P<0.02). The duration of pretransplantation glucocorticoid therapy was also longer in fracture patients (4.9+/-0.8 versus 1.3+/-0.4 years; P<0.001). Biochemical markers of bone resorption were significantly higher in patients who sustained bone loss and/or fractures. CONCLUSIONS: We conclude that fractures are a significant problem in the first year after lung transplantation, even in patients who receive therapy to prevent bone loss. Women with low pretransplantation BMD and a history of pretransplantation glucocorticoid therapy are at greatest risk.

Adult↗
PubMed1999

Therapy of a xenografted human colonic carcinoma using cisplatin or doxorubicin encapsulated in long-circulating pegylated stealth liposomes.

We compared the therapeutic effects of low doses of cisplatin and doxorubicin hydrochloride encapsulated in long-circulating liposomes composed of cholesterol/hydrogenated soy phosphatidylcholine-polyethylene glycol-distearoyl-phosphatidyl-ethanolamine. The encapsulation of cisplatin and doxorubicin in these liposomes made ineffectively low doses of the free drugs able to inhibit the growth of and affect cures of a human colonic carcinoma growing in nude mice. Liposome-encapsulated cisplatin had minor systemic toxic side effects indicated by an average 9% weight loss which was recovered 3-4 weeks after the last treatment. Toxicity was not observed in mice treated with liposome-encapsulated doxorubicin.

Animals↗
PubMed1999

Vitamin D and calcium dysregulation in the polycystic ovarian syndrome.

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 +/- 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 +/- 6.9 ng/ml [normal (nl): 9-52], and the mean 1,25 dihydroxyvitamin D was 45.8 +/- 18 pg/ml. with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15-60). The mean intact parathyroid hormone level was 47 +/- 19 pg/ml (nl: 10-65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 +/- 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.

Adult↗
PubMed1999

The effects of low-intensity warfarin on coagulation activation in patients with antiphospholipid antibodies and systemic lupus erythematosus.

The optimal intensity of oral anticoagulant therapy for the prevention of thromboembolism in patients with antiphospholipid antibodies (APLA) and systemic lupus erythematosus is controversial. Retrospective studies have suggested that patients with APLA are resistant to oral anticoagulant therapy, with a targeted International Normalization Ratio (INR) of 2.0 to 3.0, and that a higher intensity of anticoagulation (INR: 2.6 to 4.5) is required to prevent recurrent thromboembolism. To investigate if patients with APLA are resistant to the anticoagulant effect of low intensities of warfarin therapy, we performed a randomized trial in which 21 patients with APLA and systemic lupus erythematosus were allocated to receive one of three intensities of warfarin (INR: 1.1 to 1.4, 1.5 to 1.9 or 2.0 to 2.5) or placebo for four months. The main outcome was the effect of each intensity of warfarin therapy on prothrombin fragment 1+2 level (F1+2), that was used as a marker of coagulation activation. When F1+2 levels in patients allocated to the three warfarin intensities were compared to F1+2 levels in the placebo group, there was a statistically significant decrease (p<0.05) in the patient group receiving warfarin with a targeted INR of 2.0 to 2.5 at two, three and four months, and in the patient group with a targeted of INR 1.5 to 1.9 at three months. We conclude that in patients with APLA and systemic lupus erythematosus, warfarin therapy, with a targeted INR of 2.0 to 2.5, is effective in suppressing coagulation activation, and therefore, might be effective in preventing thromboembolism.

Adolescent↗
PubMed1998

Detection of ventricular fibrillation by transvenous defibrillating leads: integrated versus dedicated bipolar sensing.

INTRODUCTION: Dedicated bipolar sensing has been suggested to be safer than integrated bipolar sensing due to an increased incidence of failure to redetect ventricular fibrillation after an unsuccessful shock with leads that use integrated bipolar sensing. We compared sensing characteristics during ventricular fibrillation of simultaneously recorded dedicated and integrated bipolar electrograms. METHODS AND RESULTS: Thirty patients undergoing transvenous defibrillator implantation with a Transvene lead were studied. Simultaneous recordings were made from the dedicated bipole and the integrated bipole from the distal tip to the coil (interelectrode distance 18.3 mm). The mean detection time and number of undetected beats for the initial episode of ventricular fibrillation were 2804 +/- 569 msec and 0.9 +/- 0.8 using the dedicated recordings and 2938 +/- 546 msec and 1.4 +/- 1.1 (P = 0.026) using the integrated recordings. The mean redetection times and number of undetected beats following a failed first shock (n = 13) were 2468 +/- 225 msec and 0.8 +/- 1.1 for the dedicated recordings and 3042 +/- 498 msec (P < 0.0003) and 4.2 +/- 4.2 (P < 0.005) for the integrated recordings. Frequency analysis of the ventricular fibrillation electrograms demonstrated that the signal energy in the dedicated electrograms was significantly greater than the energy in the integrated electrograms (P < 0.0001). There was a significant negative relationship between detection times and the ventricular fibrillation signal energy. There was no independent effect of recording type (dedicated versus integrated). CONCLUSION: There are only minor differences in detection/redetection of ventricular fibrillation between dedicated and integrated (with tip to coil spacing of 18.3 mm) recording configurations. Detection times during ventricular fibrillation are related to the signal variance or energy recorded. Differences in the sensing performance of the two recording configurations can be explained by the differences in signal energy between the dedicated and integrated recordings that occur during ventricular fibrillation.

Defibrillators, Implantable↗
PubMed1998

Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin.

BACKGROUND: Patients receiving long-term warfarin frequently develop asymptomatic excessive prolongation of their international normalized ratio (INR) results. The most appropriate management strategy in these patients is unknown. This prospective cohort study was designed to address whether 1 mg of oral vitamin K effectively reduces the INR value of such patients. METHODS: A prospective cohort study was performed in two tertiary care teaching hospitals, in which 62 patients receiving warfarin who had INR values between 4.5 and 10.0 received 1 mg of oral vitamin K. All patients had daily INR values and clinical assessments performed. RESULTS: The mean INR value at presentation was 5.79 (95% confidence interval (CI) 5.48 to 6.09, range 4.5 to 9.5). Sixteen hours after receiving the 1 mg of oral vitamin K, the mean INR was 2.86 (95% CI 2.50 to 3.23). On the second and third days after vitamin K, the mean INR values were 2.20 (1.93 to 2.47) and 2.14 (1.85 to 2.44), respectively. No adverse events or bleeding complications were observed. In three patients (6%) the INR value rose between the time of vitamin K administration and the next INR determination; two patients received a further 2 mg dose of subcutaneous vitamin K. CONCLUSIONS: In patients receiving warfarin who have asymptomatic excessive prolongations in their INR results, 1 mg of oral vitamin K reliably reduces the INR to the therapeutic range within 24 h. This therapy is more convenient, less expensive, and might be safer than parenteral vitamin K. Thus, it should be considered in all non-bleeding patients receiving warfarin, who present with INR results of 4.5 to 9.5.

Administration, Oral↗
PubMed1998

Compliance with treatment and follow-up protocols in project MATCH: predictors and relationship to outcome.

Treatment and follow-up session attendance data from Project MATCH, a multisite clinical trial investigating patient-treatment matching, were analyzed to study compliance. High rates of compliance to both therapy and research protocols were achieved, enhancing treatment integrity and data quality. Strong baseline predictors of compliance did not emerge, and the small relationships found were consistent with reports from previous studies. Attendance at therapy sessions was moderately correlated with research follow-up participation. Treatment compliance predicted drinking outcome, underscoring the importance of retaining patients in treatment. Future studies should examine the associations between compliance and structural features of the treatment environment, treatment delivery, and context-features that are often under the control of the clinician/investigator.

Adult↗
PubMed1997

TGF beta-1 regulation of VEGF production by breast cancer cells.

BACKGROUND: Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor identified to date. TGF beta-1 acts as an indirect angiogenic agent. METHODS: VEGF and TGF beta-1 were measured in the serum of breast cancer patients and age-matched controls and in tumor tissue of cancer patients by ELISA. VEGF protein and mRNA expression by breast tumor cell lines were examined, and the effect of TGF beta-1 on VEGF production in these cells was assessed. RESULTS: VEGF levels were significantly higher (P = .03) in the serum of patients with breast cancer compared to age-matched controls. A positive correlation was found between serum (r = 0.539) and tumor tissue (r = 0.688) levels of VEGF and TGF beta-1. Metastatic MDA-MB-231 breast cancer cells produce more VEGF than do the primary BT474 cells. TGF beta-1 significantly (P < .05) increased production of VEGF. CONCLUSIONS: Breast cancer cells constitutively produce VEGF protein and mRNA. There is a relationship between VEGF and TGF beta-1 levels in breast cancer patients, and TGF beta-1 regulates VEGF expression by breast cancer cells.

Analysis of Variance↗
PubMed1997

Tumour uptake of doxorubicin in polyethylene glycol-coated liposomes and therapeutic effect against a xenografted human pancreatic carcinoma.

This study tested the therapeutic efficacy of doxorubicin hydrochloride in two formulations: free in saline suspension and encapsulated in polyethylene glycol-coated, long-circulating liposomes. The drug formulations at a dose level of 3 mg doxorubicin per kg body weight were injected intravenously to treat the human pancreatic carcinoma AsPC-1, implanted s.c. into nude Swiss mice. Liposome-encapsulated doxorubicin was significantly more effective in inhibiting tumour growth and in effecting cures, and had only minor systemic toxic side-effects, indicated by a transient weight loss. Confocal laser scanning microscopy was used to determine the tumour uptake and the clearance of doxorubicin in the free and in the liposomal forms. The liposome-encapsulated doxorubicin entered the tumour in greater quantity, and remained in the tumour longer, than the free drug. The liposome formulation produced a sixfold or greater increase in doxorubicin at the disease site. It is probable that increased penetration into the tumour, and long presence with slow drug release from liposomes in the tumour, account for the enhanced therapeutic effect when the drug was encapsulated in polyethylene glycol-coated liposomes.

Adenocarcinoma↗
PubMed1997

Locomotion in the abalone Haliotis kamtschatkana: pedal morphology and cost of transport

Morphological analyses of pedal sole area and pedal waves were conducted for a range of speeds and body sizes in the abalone Haliotis kamtschatkana. The pedal sole of resting abalone increased in size disproportionately with animal volume (slope of log10-transformed data, b=0.83; expected slope for isometry, b0=0.67) and length (b=2.51; b0=2.0). Pedal wave frequency increased linearly with speed, confirming that abalone increase speed by increasing the velocity of pedal waves. Total area of the pedal sole decreased by 2.1 % for each shell length per minute increase in speed. Likewise, the area of the foot incorporated into pedal waves increased by 1.8 % for each shell length per minute increase in speed. Together, these changes translated into a 50 % decrease in the pedal sole area in contact with the substratum at a maximum escape speed of 15 shell lengths min-1, relative to the pedal sole at rest. The amount of mucus secreted by resting animals during adhesion to the substratum increased isometrically with foot area (slope of log10-transformed data, b=1.08). The amount of mucus secreted during locomotion did not vary with speed, but was less than the amount needed for adhesion. We suggest that these morphological and physiological changes reduce the energy expenditure during locomotion. Cost of transport was investigated for a range of speeds and abalone sizes. The rate of oxygen consumption O2 (in &micro;l O2 g-1 h-1) increased linearly with increasing absolute speed v (in cm min-1): O2=40.1+0.58v-0.15m (r2=0.35, P=0.04), where m is body mass (in g). Minimum cost of transport, calculated from the slope of absolute speed on O2, was 20.3 J kg-1 m-1. Total cost of transport (COTT) and net cost of transport (COTN) were high at low speeds and decreased as speed increased, to minima of 86.0 J kg-1 m-1 and 29.7 J kg-1 m-1, respectively, at speeds measured in the respirometer. Log10-transformation of both cost of transport and speed data yielded linear relationships with the following regression equations: log10COTT=3.35-0.90log10v-0.21log10m (r2=0.89; P<0.006) and log10COTN=2.29-0.69log10v-0.09log10m (r2=0.48; P<0.006), respectively.

Journal Article↗
PubMed1996

Osteoporosis in lung transplantation candidates with end-stage pulmonary disease.

PURPOSE: Fractures, a common complication of cardiac and liver transplantation, have not been reported in association with lung transplantation. However, many patients with end-stage pulmonary disease have multiple risk factors for osteoporosis, and several studies have suggested that osteoporosis before transplantation may increase the risk of fracture after transplantation. Therefore, we evaluated a group of patients with end-stage pulmonary disease who were awaiting lung transplantation to determine the prevalence of osteoporosis. METHODS: Seventy patients (aged 18-70 years) were evaluated consecutively with bone densitometry by dual-energy x-ray absorptiometry. The patients were predominantly Caucasian (96%). Bone mass was expressed as bone mineral density (BMD; g/cm2), as the number of standard deviations (SD) below peak bone mass (T score), and as bone mineral apparent density (BMAD; g/cm3), a measurement that minimizes the effects of bone size on BMD. Spine radiographs were obtained in a subset of 50 consecutive patients to detect vertebral compression fractures. Vitamin D status was assessed with serum concentrations of 25-hydroxyvitamin D. The patients were sorted into groups by pulmonary diagnosis: chronic obstructive pulmonary disease (COPD; n = 28); cystic fibrosis (n = 11); idiopathic pulmonary fibrosis; and other lung diseases (Other; n = 31). RESULTS: In the group as a whole, osteoporosis (T score below -2.5) was present in 30% of the patients at the lumbar spine and 49% at the femoral neck. Osteopenia (T score between -1 and -2.5) was present in an additional 35% at the lumbar spine and 31% at the femoral neck. The average femoral neck T score of patients with COPD and cystic fibrosis fell into the osteoporotic range (-2.7 +/- 0.3 and -2.6 +/- 0.3, respectively), significantly (P < 0.01) below that of the patients in the Other category (-1.5 +/- 0.3). The average lumbar spine T score fell into the osteopenic range in all three groups. Low BMAD in patients with cystic fibrosis confirmed that their low BMD was not due to their smaller body size. The prevalence rate of vertebral fractures was 29% in patients with COPD and 25% in those with cystic fibrosis. Vitamin D deficiency (25-hydroxyvitamin D levels < or = 10 ng/ml) was present in 36% of patients with cystic fibrosis and 20% with COPD and Other lung diseases. Lumbar spine BMD tended to be lower in cystic fibrosis patients with vitamin D deficiency. Patients with exposure to glucocorticoids (n = 46) had significantly more vertebral fractures (P < 0.05) and duration of exposure correlated negatively with lumbar spine BMD (r = -0.398; P = 0.008). COPD and Other patients not on glucocorticoids had mild lumbar spine osteopenia (0.972 +/- 0.06 g/cm2; T = -1.2 +/- 0.6). Very few of the patients on glucocorticoids were on any regimen to prevent osteoporosis. CONCLUSIONS: Osteoporosis and vitamin D deficiency are extremely common in patients with end-stage pulmonary disease. Only 34% of patients had normal lumbar spine BMD and only 22% had normal BMD at the hip. Patients with cystic fibrosis and glucocorticoid-treated patients with COPD were most severely affected. Therapies to prevent bone loss and treat established osteoporosis are uncommonly utilized in glucocorticoid-treated patients with end-stage pulmonary disease. Candidates for lung transplantation should be evaluated for osteoporosis and vitamin D deficiency at the time of acceptance to the transplant waiting list.

Absorptiometry, Photon↗
PubMed1996

Hypercalcitoninemia and inappropriate calciuria in the acute trauma patient.

PURPOSE: This study was undertaken to determine the role of calcium-regulatory hormones (calcitonin [CT], parathyroid hormone [PTH], and vitamin D analogs) during the first 48 hours after acute trauma. METHODS: Eleven acutely traumatized patients admitted to the shock-trauma intensive care unit (STICU) in a tertiary care teaching hospital were enrolled. Eleven same-day elective surgery patients served as the control group. Levels of ionized calcium (Ca2+), total calcium, magnesium, phosphate, CT, PTH, vitamin D analogs, electrolyte supplementation, and renal electrolyte loss were recorded during the first 48 hours after admission to the STICU. Control-group measurements consisted of Ca2+ and CT. RESULTS: At admission, 91% of the patients had ionized hypocalcemia (1.04 +/- 0.10 mmol/L). Ca2+ levels increased significantly over time (1.13 +/- 0.08 at 24 hours; 1.16 +/- 0.07 at 48 hours) but remained below the control-group value (1.28 +/- 0.05; P < .05) despite supplementation. Ninety-one percent of the patients had increased CT values at admission, 91% at 24 hours, and 78% at 48 hours. Median CT values in the trauma patients were higher throughout the study than in the control group (P < .05). Urinary calcium loss in the trauma patients was within the normal range. PTH and vitamin D analog values were within the normal range throughout the study. Multiple regression analysis did not show any significant correlation between electrolytes and hormone or protein concentrations. CONCLUSIONS: Acute trauma patients have ionized hypocalcemia associated with inappropriate urinary calcium loss, increased CT levels, and normal PTH and vitamin D analog values. We believe the degree of calciuria we observed was inappropriate in the context of ionized hypocalcemia. The cause of these increased CT levels is unclear. Our results suggest that Ca(2+)-regulatory mechanisms may be disrupted in the acute trauma patient.

Adult↗
PubMed1996

Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study.

Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) (10-50 mcg/kg, administered intramuscularly one to three times weekly) was given for < or = 56 months to 38 patients with malignant gliomas. There was minimal or no toxicity. Twenty of 30 patients (66%) receiving at least twice weekly poly-ICLC showed regression or stabilization of gadolinium-enhancing tumor, as revealed by magnetic resonance imaging (median = 65% volume decrease). All but one patient with anaplastic astrocytomas who received continuous poly-ICLC remain alive, with a median progression-free survival of 54 months from diagnosis. Median Kaplan-Meier survival is 19 months for patients with glioblastomas who receive at least twice weekly poly-ICLC treatments. Tumor response was associated with 2',5' -oligoadenylate synthetase activation (P = 0.03) but not with serum interferon. We hypothesize clinical activation by poly-ICLC of a basic host tumor suppressor system. Prolonged, quality survival with tumor stabilization or regression confirmed by magnetic resonance imaging for most patients with anaplastic astrocytomas and glioblastomas suggests that more extensive laboratory and controlled clinical studies are warranted. The concept of long-term, broad spectrum stimulation of host defenses with nontoxic, inexpensive double-stranded ribonucleic acids, such as low-dose poly-ICLC, may be applicable to the treatment of other malignancies.

Adult↗
PubMed1996

Evaluation of a soluble fibrin assay in patients with suspected pulmonary embolism.

In order to determine the clinical utility of an enzyme immunoassay (EIA) for soluble fibrin in patients with suspected pulmonary embolism (PE), 195 unselected patients with suspected PE underwent blood sampling for measurement of plasma levels of soluble fibrin, and objective testing for PE. A soluble fibrin result of < or = 0.75 micrograms/ml showed a sensitivity of 100% for PE and a specificity of 12.8%, whereas a soluble fibrin result of < or = 1.35 micrograms/ml showed a sensitivity of 90.3% and a specificity of 49.4% for PE. The soluble fibrin assay has potential clinical utility in excluding PE.

Adolescent↗
PubMed1995

Retained cocaine conditioned place preference in D1 receptor deficient mice.

The role of the D1 dopamine receptor subtype in mediating cocaine effects was examined in mice in which the D1 receptor gene had been ablated by homologous recombination. Cocaine reward was assessed by conditioned place preference experiments using mice which had either one allele (+/-) or both alleles (-/-) of the D1 dopamine receptor gene disrupted and in their wild type (+/+) littermates. Cocaine conditioning resulted in similar increases in preference for drug-paired environments in mice of each of the three genotypes. Cocaine did not alter locomotor activity levels in homozygous, D1 knockout mice -/-, whereas increased activity was noted in both +/+ and +/- animals. These results are consistent with the idea that the D1 receptor is involved in the locomotor stimulant effects of cocaine, but has little role in a major test of the rewarding and reinforcing effects of the drug.

Animals↗
PubMed1995

Antiphospholipid antibodies and venous thromboembolism.

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no association between the presence of ACLA and VTE (odds ratio, 0.7; 95%CI, 0.3 to 1.7) because of the high frequency of positive ACLA assays in patients without VTE. None of the 16 patients with VTE and APLA developed recurrent VTE while receiving warfarin therapy. There was no difference in rates of recurrent VTE in patients with or without APLA after anticoagulant therapy was discontinued. The strong association between LA and VTE suggests that testing for LA in patients with VTE is useful. The measurement of ACLA in patients with VTE has no clinical usefulness because the results are abnormal in a high proportion of patients without VTE. Although the presence of APLA in patients with VTE was not associated with resistance to a conventional intensity of warfarin or an increased risk of recurrent VTE after discontinuation of warfarin, a larger study should address these issues in a subgroup of patients with VTE and LA.

Adolescent↗
PubMed1995

Prophylaxis and therapy of mouse mammary carcinomas with doxorubicin and vincristine encapsulated in sterically stabilised liposomes.

This study tested the prophylactic efficacies of doxorubicin hydrochloride and vincristine sulphate, encapsulated in sterically stabilised long circulating liposomes, against the spontaneous development of mammary carcinomas in C3H/He mice. Monthly prophylactic intravenous (i.v.) injections of 6 mg/kg doses of liposome-encapsulated doxorubicin (DOX-SL) or 1 mg/kg doses of liposome-encapsulated vincristine (VIN-SL) were begun when retired breeding mice were 26 weeks old. Mice that developed a mammary carcinoma while on the monthly prophylactic protocols were then given weekly i.v. injections of 6 mg/kg DOX-SL or 1 mg/kg VIN-SL to test the therapeutic efficacies of the drugs, and to determine whether the tumours were susceptible or resistant to therapy. The monthly prophylactic injections reduced the incidence of first mammary carcinomas from 87/88 (99%) in untreated mice to 24/42 (57%) in DOX-SL-treated mice and to 26/32 (81%) in VIN-SL-treated mice. Of the mice that developed a mammary tumour while on the prophylactic protocols, 12 of 30 mice were cured by the weekly therapeutic use of DOX-SL, and the growth of 18 tumours was inhibited. The weekly therapeutic use of VIN-SL cured 3 of 8 mice, and inhibited the growth of five tumours. Weekly DOX-SL therapy cured 7 of 22 previously untreated mice. The mean survival of tumour-bearing mice was extended from 24 days in untreated mice to 87 days in DOX-SL-treated mice, which had not received prophylactic treatment. Metastases were found in 29 of 54 untreated mice, and in 3 of 72 mice treated with DOX-SL and VIN-SL. Toxic side effects were limited to a transient weight loss during the weekly treatments. Drug resistance as a result of treatments was not observed.

Animals↗