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R L Page

Publications and source records attributed to R L Page.

At least 73 records · Page 4Linked to original sources
PubMed1996

An in vitro-in vivo validation of the isolated perfused tumor and skin flap preparation as a model of cisplatin delivery to tumors.

The isolated perfused tumor and skin flap (IPTSF) is a unique model system in which drug disposition is evaluated in tumor tissue and surrounding normal tissue, both of which are supplied by the same vascular system. We compared tissue Pt concentrations obtained following systemic administration of cisplatin (CDDP) to whole pigs bearing tumored skin flaps with data obtained from IPTSF treated similarly. During the in vivo study, CDDP was administered intravenously to six pigs that had tumor and skin flaps. IPTSF were created in four pigs and isolated in a perfusion chamber and perfused with medium containing CDDP for 180 min. Venous plasma or perfusate samples were serially collected throughout perfusion. Tissue samples were collected after perfusion was complete. All samples were assayed for Pt by atomic absorption spectroscopy. Area under the curve of Pt profiles from IPTSF and in vivo perfused flaps were not significantly different. Pt concentrations were significantly higher in tumor samples from in vivo perfused flaps than in samples from IPTSF. Pt concentrations in skin and subcutaneous tissue were not significantly different. When consideration is given to all of the potential variables that were operative in these experiments, the results of this study demonstrate that Pt distribution within the IPTSF was comparable to that obtained in vivo.

Animals↗
PubMed1996

Partial cystectomy for urinary bladder neoplasia: surgical technique and outcome in 11 dogs.

Partial cystectomy was performed in 11 dogs with bladder neoplasia (10 with transitional cell carcinoma and one with rhabdomyosarcoma). Between 40 and 70 per cent of the bladder was excised during the partial cystectomies. In eight dogs, all the grossly visible tumour was excised but on histopathological examination of the excised tissue, neoplastic tissue was found to extend to the surgical margins in four of these dogs. A ureteral stoma was excised with the tumour in four dogs necessitating ureteral reimplantation; one dog had both ureteral stomas excised and bilateral ureteral reimplantation. The bladder incision dehisced in two dogs, necessitating a second surgery. Six dogs were pollakiuric after surgery. Pollakiuria resolved within two months in four dogs and persisted in two dogs. None was incontinent. Local tumour recurrence was suspected in nine dogs based on imaging studies and confirmed in five dogs during post mortem examination. Five dogs were euthanased two to seven months after surgery. Six dogs survived at least one year, two of these dogs remain alive at 17 and 27 months after surgery. It is concluded that partial cystectomy may provide local control of bladder neoplasia.

Animals↗
PubMed1995

Absence of whole body hyperthermia effect on cisplatin distribution in spontaneous canine tumors.

PURPOSE: This study was conducted to evaluate the effect of whole body hyperthermia (WBH) on cisplatin (CDDP)-derived platinum (Pt) disposition in tumor and normal tissue in dogs with spontaneously arising neoplasia undergoing conventional pretreatment diuresis. METHODS AND MATERIALS: Cisplatin was administered to 12 dogs with terminal stage, metastatic neoplasia. Cisplatin (50 mg/M2 over 1 h) was administered following 4 h of forced fluid diuresis (0.9% saline at 10 ml/kg/h). Six of the 12 dogs underwent a WBH procedure (42 degrees C rectal temperature x 90 min) simultaneously with CDDP infusion. Dogs were euthanized following the CDDP infusion, and samples from critical organs, tumor, and normal tissue adjacent to the tumor were immediately collected. RESULTS: No significant differences existed between groups in serum or normal tissue Pt content. Thirty-eight tumor samples were obtained from 27 tumors in the six dogs included in the normothermic group and 43 tumor samples were obtained from 29 tumors in the six dogs undergoing WBH. Tumor volume varied from 0.08 cm3 to 2270 cm3 and multiple samples were obtained from tumors greater than 3 cm in diameter. Twenty-five paired tissue samples of tumor and adjacent normal tissue were collected from dogs in the normothermic group and 31 paired samples were obtained from the hyperthermic group. No differences were observed between groups in tumor Pt content or in the tumor/normal tissue Pt ratios. CONCLUSION: Pt disposition was unaffected by WBH under conditions reported in this study. A forced diuresis is necessary to clinically administer CDDP at maximally tolerable doses. This maneuver results in increased blood flow to critical normal tissue that seemingly obviates any hyperthermia-induced alterations in drug disposition.

Animals↗
PubMed1995

Transgenesis in mice by cytoplasmic injection of polylysine/DNA mixtures.

Pronuclear injection is currently the most often used method to make transgenic animals, but in some animal species it is temporally restrictive due to difficulty in visualizing pronuclei. However, the injection of construct DNA into the cytoplasm does not result in transgenesis. The production of transgenic mice by a cytoplasmic microinjection technique of polylysine complexed DNA into pronuclear stage zygotes is described. Transgenic mice were produced from cytoplasmic microinjection of mixtures of a 5.3 kb linearized DNA and poly-L-lysine (degree of polymerization = 51). Effects on transgenic frequency of both the lysine to phosphate ratio of polylysine to DNA and DNA concentration were studied. About 12.8% of the pups born from zygotes cytoplasmically microinjected with a polylysine/DNA mixture having a lysine to phosphate ratio (L:P) of 1:1 at a DNA concentration of 50 micrograms ml-1 were transgenic. The transgenic frequency for the pronuclear microinjection positive control of DNA alone was 21.7%. No transgenic pups were born from microinjection of DNA alone into the cytoplasm. Complexes of polylysine/DNA were detected using agarose gel electrophoresis at the conditions which produced transgenic mice. The presence of polylysine with construct DNA altered the in vitro activities of restriction endonuclease and DNA ligase on the construct DNA. The production of transgenic animals using DNA and polylysine in the absence of any other signal protein suggests that a DNA/polylysine complex but not DNA alone can act as a substrate for transgenesis from the cytoplasm.

Animals↗
PubMed1995

Transgene detection during early murine embryonic development after pronuclear microinjection.

The polymerase chain reaction (PCR) technique was used to detect a whey acidic protein (WAP) gene and transgene presence in mouse ova cultured to various stages of development after pronuclear microinjection at the one-cell stage. The PCR technique detected an endogenous 442 bp WAP DNA sequence in 78% of one-cell, 88% of two-cell and 94% of four-cell ova, and in 95% of morulae and 97% of blastocysts. The heterologous WAP-human protein C transgene was detected in 88% of one-cell, 88% of two-cell and 44% of four-cell ova, and in 40% of morulae and 29% of blastocysts. For comparison, the integration frequency for transgenic mouse production using the same DNA construct was 22%. After five days of in vitro culture, embryos that were either developmentally arrested or fragmented were tested for the presence of the transgene. The injected construct was detected in 83% of arrested one-cell, 85% of arrested two-cell, and 85% of fragmented ova. In culture, only 28% of zygotes microinjected with DNA developed to the blastocysts stage compared to 74% of noninjected zygotes, while 63% of zygotes developed to the blastocyst stage after injection of buffer alone. Pronuclear injection of the transgene at concentrations of 1.5, 15 and 50 micrograms ml-1 resulted in 28, 11 and 9% development to blastocysts and 29, 86 and 88% transgene detection, respectively. Transgene detection was 85, 96 and 97% in degenerate embryos at the respective doses of DNA. These data show that pronuclear microinjection of the transgene is detrimental to subsequent embryonic development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Treatment of arrhythmias during pregnancy.

The treatment of arrhythmias during pregnancy is complicated by concerns for fetal well-being. Although no drug is absolutely safe, most are well tolerated. Nonpharmacologic therapy includes vagal maneuvers and esophageal pacing. Temporary and permanent pacing have been used safely during pregnancy, as has direct current cardioversion. Cardiopulmonary resuscitation is complicated by concerns for the fetus, which may be viable at 25 weeks. Diagnosis of the cause of tachyarrhythmias may be enhanced by roving chest leads or esophageal recording. Both supraventricular and ventricular tachycardias may become manifest during pregnancy, and conservative management is desirable if the symptoms are mild. Supraventricular tachycardias respond acutely to adenosine. Ventricular arrhythmias during pregnancy often occur in the absence of structural heart disease and are responsive to drug therapy. The safe use of an implantable cardioverter-defibrillator has been described.

Anti-Arrhythmia Agents↗
PubMed1995

Importance of complete system removal of infected cardioverter-defibrillators.

We describe a case of device infection after implantable cardioverter-defibrillator implantation managed by removal of all hardware except a portion of the epicardial sensing electrodes. Recurrent septic complications developed until all residual foreign material was eliminated. Despite anecdotal reports of successful management without device removal, extraction of all hardware components should be considered standard treatment for this complication.

Aged↗
PubMed1995

Incidence of symptomatic atrial fibrillation in patients with paroxysmal supraventricular tachycardia.

OBJECTIVES: This study was performed to determine the incidence of symptomatic, sustained atrial fibrillation in a group of patients with paroxysmal supraventricular tachycardia. The effects of the mechanism of paroxysmal supraventricular tachycardia (atrioventricular [AV] node reentry vs. AV reentry through an accessory pathway) and heart rate during the tachycardia on the occurrence of atrial fibrillation were also assessed. BACKGROUND: There is a substantial incidence of atrial fibrillation in patients with paroxysmal supraventricular tachycardia, but the precise incidence and the factors that determine it are unknown. METHODS: One hundred sixty-nine patients with paroxysmal supraventricular tachycardia were followed up by regular clinic visits and transtelephonic electrocardiographic monitoring during symptomatic episodes of arrhythmia. The Kaplan-Meier product-limit method was used to estimate the proportion of patients remaining free of atrial fibrillation during the observation period. The Cox proportional hazards model was used to assess the effect of mechanism and heart rate during paroxysmal supraventricular tachycardia on the atrial fibrillation-free period. RESULTS: Thirty-two (19%) of the 169 patients had an episode of atrial fibrillation during a mean follow-up period of 31 months. The cumulative percent of patients experiencing an episode of atrial fibrillation was 6% within 1 month, 9% within 4 months and 12% within 1 year. The mechanism of paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio corresponding to classification in the AV node reentry group was 0.8 (p > 0.6). The heart rate during paroxysmal supraventricular tachycardia was not associated with the time to occurrence of atrial fibrillation; the hazard ratio associated with an increase in heart rate of 50 beats/min during the tachycardia was 1.15 (p > 0.5). CONCLUSIONS: This study suggests that atrial fibrillation will develop in approximately 12% of patients with paroxysmal supraventricular tachycardia during a 1-year follow-up period. The occurrence of atrial fibrillation is not related to the mechanism or heart rate of the paroxysmal supraventricular tachycardia.

Atrial Fibrillation↗
PubMed1995

Heart rate during spontaneous and induced paroxysmal supraventricular tachycardia.

It is generally assumed that paroxysmal supraventricular tachycardia (PSVT) induced during invasive electrophysiological study reproduces the patient's spontaneous, clinical arrhythmia. Even in the absence of antiarrhythmic drugs, however, there may be significant differences in characteristics of the induced and spontaneous arrhythmias. We compared the heart rate of PSVT in 38 patients who had undergone electrophysiological study with induction of PSVT who also had a spontaneous episode of PSVT documented by transtelephonic ECG monitoring during a period when all antiarrhythmic drugs were withheld. The heart rate during spontaneous PSVT was faster than the heart rate of PSVT induced during electrophysiological study; the mean difference was 16 beats/min (P < 0.001). We conclude that heart rate of PSVT induced during electrophysiological study generally underestimates the heart rate of spontaneous PSVT in the antiarrhythmic drug-free state. This may be due to differences in the autonomic and hemodynamic states during spontaneous and induced arrhythmias.

Adult↗
PubMed1995

Diagnosis of ICD lead failure using continuous event marker recording.

Stored electrograms enhance the ability to evaluate therapy episodes in the third-generation implantable cardioverter defibrillator. These electrograms are recorded from either the shocking or rate sensing leads, but not both. As a result, differentiation of certain types of sensing abnormalities may be difficult prior to surgical exploration. We present a case of rate sensing lead failure due to an insulation break. Several minutes of recording of the event marker in the laboratory failed to document any abnormal sensing; the diagnosis was made by recording the event marker on a 24-hour continuous (Holter) monitor. The Holter monitor/event marker combination was of substantial diagnostic value and allowed for a more focused surgical evaluation and treatment.

Defibrillators, Implantable↗
PubMed1995

Comparison of nebulised salbutamol and ipratropium bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease.

BACKGROUND: Patients admitted with acute exacerbation of chronic obstructive pulmonary disease (COPD) are often prescribed ipratropium bromide in combination with a beta 2 agonist such as salbutamol. Studies have not shown any benefit in adding ipratropium bromide to salbutamol in acute exacerbations of COPD, but these studies have only assessed patients for 60-90 minutes and short term studies may not predict long term clinical response. Combination therapy with the two drugs was compared with salbutamol alone in the treatment of acute exacerbations of COPD during a hospital admission. METHODS: Seventy patients admitted to hospital with an acute exacerbation of COPD were randomly allocated to receive either nebulised salbutamol 5 mg and ipratropium bromide 500 micrograms, or nebulised salbutamol 5 mg alone (all four times a day) on admission. All other treatment was prescribed at the discretion of the attending physician. Length of stay in hospital and spirometric values on days 1, 3, 7, 14, and discharge were assessed. Patients completed a subjective symptom score each day. RESULTS: There was no difference between the two groups in the mean (SD) length of stay (salbutamol 10.5 (4.7) days, salbutamol + ipratropium bromide 11.8 (4.4) days; 95% CI -1.02 to 3.62). There was no difference in spirometric values on days 1, 3, 7, 14, or discharge between the two groups. The subjective improvement was similar with both treatments. CONCLUSIONS: The routine addition of nebulised ipratropium bromide to salbutamol appears to be of no benefit in the treatment of acute exacerbations of COPD.

Administration, Inhalation↗
PubMed1994

Platinum drug delivery and radiation for locally advanced prostate cancer.

Combined therapies of cisplatin and radiation have resulted in clinical reports of apparent efficacious control of locoregional cancer and enhanced survival. Mechanisms of interaction between platinum and radiation that may explain these clinical observations all have in common the prediction that higher concentrations of platinum in all tumor cells close in time to irradiation should lead to greater potentiation of radiation-induced killing of those cells. Cisplatin is thus viewed as providing some radiation-equivalent, or a radiation dose-effect factor, for sterilization of tumors. One disease site that has not been well investigated for response to cisplatin plus radiation therapy, but that could benefit from it, is locally advanced prostate cancer. A body of literature now supports the view that local control of stage C (T3, N0, M0) prostate cancer is correlated with disease-free survival. This correlation makes prostate cancer a candidate for potentially achieving improved cure rates following local tumor sterilization by combining cisplatin with radiation therapy. The need and approaches to optimize delivery of cisplatin within tumor tissue is explored. Increasing cisplatin concentration to all the cells of a tumor, i.e., homogeneously delivering systemic high-dose cisplatin, should benefit the efficacious response otherwise expected for cisplatin combined with radiation. Strategies to increase the homogeneity of cisplatin delivery to a tumor are considered to be those that increase perfusion to that tumor. Vasoactive agents used in anticancer protocols are especially considered for their potential value in serving to increase tumor perfusion. These protocol-inclusive agents include certain cytokines and L-arginine antagonists, and should be better managed and accepted in practice compared to other vasoactive agents that need to be developed as specific additives to protocol designs.

Amino Acid Oxidoreductases↗
PubMed1994

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy.

PURPOSE: The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. METHODS AND MATERIALS: Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorous spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. RESULTS: A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of > or = 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. CONCLUSION: Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.

Adenosine Triphosphate↗
PubMed1994

Gene transfer efficiency during gestation and the influence of co-transfer of non-manipulated embryos on production of transgenic mice.

Litter size of DNA microinjected zygotes is lower than for non-manipulated zygotes. The rate of embryonic and fetal survival in early, mid and late gestation was determined to assess whether DNA integration was responsible for embryonic losses. Also, the effect of including non-microinjected embryos with injected embryos on pregnancy rate and transgenic pup production was determined. In Experiment 1, one-cell embryos from immature CD-1 mice were microinjected with a whey acidic protein promoter-human protein C gene construct. One hour after microinjection embryos were transferred to pseudopregnant recipients (45 transfers of 30 embryos each). Fifteen recipients were sacrificed on day 4, 12 and 18 of gestation and the embryos/fetuses analysed for the transgene. The percentage of embryos or fetuses that were positive for the transgene was not significantly different at any day. However, the number of viable embryos at day 4 was significantly greater than fetuses on days 12 or 18. In addition, a high degree of mosaicism was observed in day 18 fetuses and placentae recovered. In Experiment 2, one-cell embryos from CD-1 mice were microinjected and co-transferred with non-manipulated embryos (C57BL/6). Pregnancy rate and the total number of pups born were improved by addition of non-injected embryos. However, the number of transgenic mice produced was similar whether non-injected embryos were included or not. There were 32.2% (15/46) transgenic pups when 0 non-injected embryos were transferred compared with 15.1% (13/86) transgenic pups when 4 or 8 non-injected embryos were added to the transfers. In summary, a high degree of embryonic and fetal mortality occurs among microinjected embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Ovulation rate, zygote recovery and follicular populations in FSH-superovulated goats treated with PGF(2alpha) and/or GnRH.

Follicular development and ovulation were examined in superovulated Nubian and Nubian-cross dairy goats following prostaglandin F(2alpha) (PGF(2alpha)) and/or gonadotropin releasing hormone (GnRH) treatment. Estrus was synchronized with Synchromate-B((R)) implants. Superovulation was induced with follicle stimulating hormone (FSH) and augmented with GnRH and/or PGF(2alpha). The PGF(2alpha) treatment was administered on Day 2 of superovulation. Implants were removed from all goats on Day 3 of superovulation. The GnRH treatment was administered 24 h after implant removal. All does were exposed to fertile males for 48 h at the time of GnRH injection. Surgical embryo recovery and ovarian response evaluation were conducted 64 to 78.5 h after implant removal. The number of ovulations was higher with GnRH treatment (18.5 +/- 7; x +/- SEM) than that in the controls (5.3 +/- 4.1; P < 0.05). There were fewer follicles in the GnRH-treated does than in the untreated does (10.9 +/- 2.9 vs 22.1 +/- 3.2; P < 0.05). The number of follicles smaller than 4 mm in diameter (5.8 +/- 0.8) did not differ between treatments. The GnRH-treated does had fewer 4- to 8-mm follicles (4.2 +/- 2.0 vs 9.1 +/- 1.6; P < 0.05) and fewer follicles larger than 8 mm (0.7 +/- 1.4 vs 7.3 +/- 1.6; P < 0.01) than the controls. Predicted times for 1- and 2-cell embryo recoveries were 68.5 and 73.7 h following implant removal, respectively. This study demonstrates that GnRH is an effective supplement used with FSH superovulation regimens in dairy goats. Moreover, GnRH provides for enhanced early embryo collection for DNA microinjection studies.

Journal Article↗
PubMed1994

Preclinical evaluation and PET imaging of 18F-labeled Mel-14 F(ab')2 fragment in normal dogs.

The F(ab')2 fragment of monoclonal antibody Mel-14, reactive with human melanomas and gliomas, was labeled with 18F using two acylation agents, N-succinimidyl 8-[(4'-[18F]fluorobenzyl)amino]suberate (SFBS) and N-succinimidyl 4-[18F]fluorobenzoate (SFB). The immunoreactivity and affinity for Mel-14 F(ab')2 labeled using the two methods were similar. As a prelude to human clinical evaluation, PET imaging, tissue distribution and pharmacokinetic measurements were performed in two groups of normal foxhounds. Similar in vivo behavior was seen for Mel-14 F(ab')2 labeled using SFBS and SFB. Radiation dosimetry calculations suggest that a 10 mCi dose could be used for this F(ab')2 fragment labeled using either acylation agent.

Animals↗