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T G Burke

Publications and source records attributed to T G Burke.

At least 19 recordsLinked to original sources
PubMed2001

The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity.

The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant (K value) of 5000 M(-1). This association constant is significantly higher than the K(DLPC) value observed for camptothecin (K(DLPC) value of 110 M(-1)). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 microM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37 degrees C. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898; J. Med. Chem. 43 (2000) 3970]. Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development.

Anisotropy↗
PubMed2000

The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.

We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

Animals↗
PubMed2000

Treatment of thoracic disc herniation: evolution toward the minimally invasive thoracoscopic technique.

Thoracic disc herniation has always carried with it the potential for serious adverse neurological consequences if not treated appropriately. The authors review the historical evolution of treatment for thoracic disc herniation from the early surgical series using dorsal approaches (which were known to involve a significant risk of paraplegia) to later surgical series in which lateral and then ventral approaches to the disc were increasingly emphasized, with significant improvement in patient outcome. The evolution of minimally invasive thoracoscopic techniques is discussed, together with the results of several surgical series demonstrating significant reductions in morbidity compared with more traditional methods. The technique of thoracoscopic discectomy is presented in detail.

Animals↗
PubMed2000

Lack of latex allergen contamination of solutions withdrawn from vials with natural rubber stoppers.

The effect on latex allergen contamination and microbial growth of a latex-allergy precaution technique for preparing injectable products was studied. The study consisted of three parts: (1) preparation of 20 samples from vials with latex-containing stoppers in accordance with conventional guidelines, (2) preparation of 20 samples in accordance with latex-allergy precaution guidelines, and (3) preparation of 5 latex-free samples and 1 latex-contaminated sample as negative and positive controls, respectively. The conventional method involved swabbing a vial top with an alcohol prep pad, puncturing the dry natural rubber stopper with an 18-gauge needle attached to a latex-free syringe, and withdrawing the contents of the vial into the syringe. The latex-allergy precaution preparation technique was similar, except that the stopper was removed before the vial contents were withdrawn. There was essentially no difference in latex allergen concentrations between the two drug preparation methods. None of the samples prepared with the standard method supported any microbial growth. One sample prepared with the latex-allergy precaution method grew bacteria. Removal of the dry rubber stopper from vials did not yield solutions with less latex allergen than solutions prepared according to conventional guidelines.

Allergens↗
PubMed2000

Camptothecin design and delivery approaches for elevating anti-topoisomerase I activities in vivo.

The camptothecins as a class have exhibited unique dynamics and reactivity in vivo, with respect to both drug hydrolysis and blood protein interactions. These factors have confounded their pharmaceutical development and clinical implementation. Recent bench and clinical research alike indicates that the combination of medicinal chemical and drug delivery approaches has been and will continue to be highly valuable in improving the overall therapeutic indices of camptothecin-based anti-topoisomerase I therapies. In the future the development of camptothecin analogues that exhibit highly specific human albumin interactions will likely be avoided, and agents such as the highly lipophilic DB-67 analogue with improved tissue stability will be evaluated. Drug delivery scientists will also devise better ways of targeting camptothecin therapies to solid tumors by using carriers such as tumor-targeted long-circulating liposomes.

Animals↗
PubMed2000

Microendoscopic posterior cervical foraminotomy: a cadaveric model and clinical application for cervical radiculopathy.

OBJECT: Cervical radiculopathy caused by either soft herniated disc material or foraminal stenosis is a common problem. Anterior and posterior surgical approaches are commonly used to decompress the nerve root. The authors undertook a study to establish the feasibility of performing a microendoscopic posterior approach for cervical foraminotomy in the clinical setting. METHODS: The authors performed an endoscopic posterior foraminotomy technique in which they used a rigid endoscope, in both a cadaver model and in three clinical cases, including one in which a multiple-level procedure was undertaken. Postoperatively, all patients returned to functional work status within 4 weeks. The mean length of hospitalization was 1.3 days. CONCLUSIONS: The advantages to this technique include improved intraoperative visualization, a smaller incision, and significantly less postoperative discomfort compared with a traditional keyhole approach.

Adult↗
PubMed1999

Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo.

Although topoisomerase inhibitors, such as camptothecin and topotecan, have been widely used in the treatment of nonglial tumors, their application for gliomas has been limited by poor efficacy relative to toxicity that may in part reflect limited bioavailability and blood stability of these agents. However, the potential promise of this class of agents has fostered efforts to develop new, more potent, and less toxic inhibitors that may be clinically relevant. Using a cascade radical annulation route to the camptothecin family, we developed a series of novel camptothecin analogues, 7-silylcamptothecins ("silatecans"), that exhibited potent inhibition of topoisomerase I, dramatically improved blood stability, and sufficient lipophilicity to favor blood-brain barrier transit. We explored the efficacy of a series of these agents against a panel of five high-grade glioma cell lines to identify a promising compound for further preclinical testing. One of the most active agents in our systems (DB67) inhibited tumor growth in vitro with an ED50 ranging between 2 and 40 ng/ml, at least 10-fold more potent than the effects observed with topotecan, and at least comparable with those of SN-38, the active metabolite of CPT-11. Because DB67 also exhibited the highest human blood stability of any of the agents examined, this agent was then selected for in vivo studies. A dose-escalation study of this agent in a nude mouse U87 glioma model system demonstrated a concentration-dependent effect, with tumor growth inhibition at day 28 postimplantation (the day control animals began to require sacrifice because of large tumor size) of 61 +/- 7% and 73 +/- 3% after administration of DB67 doses of 3 and 10 mg/kg/day, respectively, for 5 days beginning on postimplantation day 7. Animals that continued treatment with 10 mg/kg/day in three additional 21-day cycles all remained progression free after >90 days of follow-up but later developed enlarging tumors after treatment was stopped. However, a slightly higher dose (30 mg/kg/day) induced complete tumor regression after only two cycles in all study animals and was effective even if treatment was delayed until large, bulky tumors had developed. Application of the 30 mg/kg/day dose to treat established intracranial glioma xenografts led to long-term (>90 day) survival in six of six animals, whereas all controls died of progressive disease (P < 0.00001). No apparent toxicity was encountered in any of the treated animals. In summary, the present studies indicate that silatecans may hold significant promise for the treatment of high-grade gliomas and provide a rationale for proceeding with further preclinical evaluation of their efficacy and safety versus commercially available camptothecin derivatives.

Animals↗
PubMed1999

The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins.

PURPOSE: The camptothecin (CPT) analogue, 10-hydroxycamptothecin (10-HCPT) has been shown previously to remain in its acid-stable (and active) lactone form when encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres (1). The purpose of this study was to determine the principal mechanism(s) of 10-HCPT stabilization. METHODS: CPTs were encapsulated in PLGA 50:50 microspheres by standard solvent evaporation techniques. Microspheres were eroded in pH 7.4 buffer at 37 degrees C. The ratio of encapsulated lactone to carboxylate was determined by HPLC as a function of time, initial form of drug encapsulated, fraction of co-encapsulated Mg(OH)2, CPT lipophilicity, and drug loading. Two techniques were developed to assess the microclimate pH, including: i) measurement of H+ content of the dissolved microspheres in an 80:20 acetonitrile/H2O mixture and ii) confocal microscopy of an encapsulated pH-sensitive dye, fluorescein. RESULTS: The encapsulated carboxylate converted rapidly to the lactone after exposure to the release media, indicating the lactone is favored at equilibrium in the microspheres. Upon co-encapsulation of Mg(OH)2, the trend was reversed, i.e., the lactone rapidly converted to the carboxylate form. Measurement of -log(hydronium ion activity) (paH*) of dissolved microspheres with pH-electrode and pH mapping with fluorescein revealed the presence of an acidic microclimate. From the measurements of H+ and water contents of particles hydrated for 3 days, a microclimate pH was estimated to be in the neighborhood of 1.8. The co-encapsulation of Mg(OH)2 could both increase the paH* reading and neutralize pH in various regions of the microsphere interior. Varying the drug lipophilicity and loading revealed that the precipitation of the lactone could also stabilize CPT. CONCLUSIONS: PLGA microspheres prepared by the standard solvent evaporation techniques develop an acidic microclimate that stabilizes the lactone form of CPTs. This microclimate may be neutralized by co-encapsulating a base such as Mg(OH)2, as suggested by previous work with poly(ortho esters) (2).

Antineoplastic Agents↗
PubMed1999

Fluorescence spectral properties of the anticancer drug topotecan by steady-state and frequency domain fluorometry with one-photon and multi-photon excitation.

Topotecan is an antitumor agent with activity against a variety of cancers. We examined the steady-state and time-resolved fluorescence spectral properties of topotecan with one- and two-photon excitation. Topotecan was found to display a high two-photon cross section near 20 GM for wavelengths within the fundamental output of a Ti:sapphire laser, 800-880 nm. In frozen solution the anisotropies of topotecan are near the theoretical maxima for one-photon and two-photon excitation with colinear electronic transitions. The intensity and anisotropy decays of topotecan fluorescence were found to be homogeneous (single exponentials) in phosphate-buffered saline and propylene glycol. The steady-state and time-resolved data indicate that topotecan binds to a double-helical DNA oligomer d(AT)10 resulting in increased anisotropies and multiexponential intensity and anisotropy decays. Subnanosecond components in the anisotropy decay of the DNA-topotecan complex suggest loose binding of the drug to DNA. Loose binding of topotecan to DNA is also revealed by accessibility of topotecan to collisional quenching by iodide.

Antineoplastic Agents↗
PubMed1998

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗
PubMed1997

Simple and versatile high-performance liquid chromatographic method for the simultaneous quantitation of the lactone and carboxylate forms of camptothecin anticancer drugs.

The well documented hydrolysis of the alpha-hydroxy-delta-lactone ring moiety in camptothecin and related analogues is routinely monitored using high-performance liquid chromatography (HPLC). Previous HPLC separations of the lactone and carboxylate forms of camptothecins have often required mobile phases containing three to four components; ion-pairing reagent to provide adequate retention of the carboxylate form of the drug; buffer to control the ionic strength and pH of the mobile phase; acetonitrile to control the retention of the lactone form and, in some instances, sodium dodecyl sulfate to reduce peak tailing. Because of the complexity of the mobile phases employed, development of these assays can be a laborious process, requiring re-optimization for each new analogue. In this study, we have developed a simple HPLC methodology for the simultaneous separation of the lactone and carboxylate forms of numerous camptothecin analogues. The mobile phase employed includes only triethylamine acetate (TEAA) buffer and acetonitrile. In this application, triethylamine serves multiple roles; as the ion-pairing reagent, as a masking agent for underivatized silanols and as the major buffer component. By altering only the composition of TEAA buffer with respect to acetonitrile, method development becomes a more streamlined and time efficient process. In this publication, we present the simultaneous separation of the lactone and carboxylate forms of camptothecin and four related analogues, namely, topotecan, GI147211, 10-aminocamptothecin and the CPT-11-SN-38 drug-metabolite pair. It is proposed that this new mobile phase, consisting of only triethylamine acetate buffer and acetonitrile, can be used for the analysis of the several camptothecin derivatives presently in clinical trials as well as the numerous other analogues in preclinical development.

Acetonitriles↗
PubMed1997

Stabilization of 10-hydroxycamptothecin in poly(lactide-co-glycolide) microsphere delivery vehicles.

PURPOSE: The purpose of this study was to investigate the potential of poly(lactide-co-glycolide) (PLGA) microspheres to stabilize and deliver the analogue of camptothecin, 10-hydroxycamptothecin (10-HCPT). METHODS: 10-HCPT was encapsulated in PLGA 50:50 microspheres by using an oil-in-water emulsion-solvent evaporation method. The influence of encapsulation conditions (i.e., polymer molecular weight (Mw), polymer concentration, and carrier solvent composition) on the release of 10-HCPT from microspheres at 37 degrees C under perfect sink conditions was examined. Analysis of the drug stability in the microspheres was performed by two methods: i) by extraction of 10-HCPT from microspheres and ii) by sampling release media before lactone--carboxylate conversion could take place. RESULTS: Microspheres made of low Mw polymer (inherent viscosity 0.15 dl/g) exhibited more continuous drug release than those prepared from polymers of higher Mw (i.v. = 0.58 and 1.07 dl/g). In addition, a high polymer concentration and the presence of cosolvent in the carrier solution to dissolve 10-HCPT were both necessary in the microsphere preparation in order to eliminate a large initial burst of the released 10-HCPT. An optimal microsphere formulation released 10-HCPT slowly and continuously for over two months with a relatively small initial burst of the released drug. Both analytical methods used to assess the stability of 10-HCPT revealed that the unreleased camptothecin analogue in the microspheres remained in its active lactone form (> 95%) over the entire 2-month duration of study. CONCLUSIONS: PLGA carriers such as those described here may be clinically useful to stabilize and deliver camptothecins for the treatment of cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Drug allergy assessment at a university hospital and clinic.

The accuracy of drug allergies reported in patients' medical records and the cost-effectiveness of pharmacist interviews to clarify these reports were studied. Fourteen pharmacists interviewed hospital and clinical patients about reported allergies and noted their assessments in the patients' charts. The patient's physician was notified of discrepancies between previous allergy documentation and the pharmacist's assessment. The pharmacy resident re-interviewed a convenience sample of the patients to determine consistency among the pharmacists. The reported reactions were classified as true allergies, severe adverse effects, or vague reactions (drug should be avoided); drug intolerance and mild or moderate adverse effects; excessive pharmacologic effects; or no reaction experienced. The medication profile for each patient was reviewed after discharge to identify the pharmacists' prevention of adverse effects or allergic reactions; cost avoidance was then estimated. The pharmacists assessed 347 reports of allergies in 195 patients. Anti-infective agents accounted for 53% of the stated allergies, followed by narcotics (18%), psychotropic medications (7%), nonsteroidal anti-inflammatory drugs (6%), cardiovascular medications (5%), and others (11%). For more than 80% of the reports of allergies to beta-lactam antibiotics and sulfonamides, pharmacists either found or could not rule out true allergies; this was the case for only 31% of reported allergies to narcotics. Nine percent of patients who reported allergy to a beta-lactam or sulfonamide had never experienced a reaction to the drug. Pharmacists intervened in four cases to prevent adverse reactions and a total of 4.4 additional hospital days, and in five instances the use of a less suitable or more expensive drug was avoided. Pharmacists found a large discrepancy between reported allergies and true allergies and helped prevent uses of drugs that could have prolonged patients' hospital stay.

Adolescent↗
PubMed1996

Fluorescence detection of the anticancer drug topotecan in plasma and whole blood by two-photon excitation.

The anticancer drug topotecan was detected in human plasma and whole blood using two-photon excitation at 730 or 820 nm. These wavelengths are longer than the main absorption bands of hemoglobin. Two-photon excitation of topotecan was demonstrated by a quadratic dependence of the emission intensity on the incident power, compared to a linear dependence for one-photon excitation at 410 nm. The observed emission centered at 525 nm was shown to be topotecan from the similarity of the emission spectrum and decay times observed for one-photon and two-photon excitation. Topotecan was detected at concentrations as low as 0.05 and 1 microM in plasma and whole blood, respectively. Since skin blood and tissues are translucent at long wavelengths, these results suggest the possibility of homogeneous or noninvasive clinical sensing with two-photon excitation.

Antineoplastic Agents↗
PubMed1996

Biomechanical comparison of the dewar and interspinous cervical spine fixation techniques.

STUDY DESIGN: This study evaluates and compares the stiffness of two cervical spine fixation techniques. OBJECTIVES: This biomechanical study was carried out to compare the interspinous and Dewar cervical spine fixation techniques. SUMMARY OF BACKGROUND DATA: Interspinous wiring is a commonly used method of fixation in the cervical spine. The Dewar technique is less commonly known and practiced, and clinical experience has suggested that it may be a more stable technique. METHODS: Cervical spine specimens stabilized with the interspinous and "Dewar" techniques were biomechanically tested in flexion and in torsion. Stiffness and energy absorption under moderate loads were compared. The Dewar technique uses contoured double corticocancellous iliac grafts as internal grafts/splints fixed to the spine with threaded pins and wire. The interspinous technique is a single interspinous wire loop. Eleven fresh human cervical spines were harvested from cadavers. The spines were destabilized at C4-C5 by sectioning all tissue except the anterior longitudinal ligament. Each fixation technique was applied alternatively and tested on each spine. RESULTS: In torsion testing (n = 5), the Dewar fusion was 61% stiffer than the interspinous technique (P < 0.02). Dewar: 11.3 N/mm (s.d. 4.9 N/mm) and interspinous: 8.4 N/mm (SD 3.3 N/mm). In flexion testing (n = 6), the Dewar technique was 35% stiffer than the interspinous technique (P < 0.10). Dewar: 655.4 Nmm/degree (SD 293 Nmm/degree) and interspinous: 406.8 Nmm/degree (SD 113.0 Nmm/degree). Energy absorption with the interspinous technique was greater in flexion (P < 0.10) and in torsion (P < 0.005), indicating more deformation with the interspinous technique. There was no statistically significant difference between the means of specimens tested first and those tested second independently of the fixation technique. CONCLUSIONS: These tests indicate that the Dewar cervical spine fixation is stiffer than the single interspinous wire in both flexion and particularly torsion. This project is the only biomechanical study of the Dewar technique that we are aware of, and the results support the clinical findings regarding the effectiveness of this technique.

Biomechanical Phenomena↗