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E Frenkel

Publications and source records attributed to E Frenkel.

26 records · Page 2Linked to original sources
PubMed1983

Neurotoxicity of chemotherapeutic agents after blood-brain barrier modification: neuropathological studies.

We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

Animals↗
PubMed1983

Inability of dimethyl sulfoxide and 5-fluorouracil to open the blood-brain barrier.

The inability of most chemotherapeutic agents to adequately penetrate the blood-brain barrier (BBB), in either normal brain or tumor-infiltrated brain, is a major factor limiting the use of chemotherapy in central nervous system malignancy. This barrier, however, can be opened in a reversible manner by the intra-arterial administration of hyperosmotic agents such as mannitol. It has been suggested that the intravenous administration of dimethyl sulfoxide (DMSO) or 5-fluorouracil (5-FU) can accomplish the same thing in a less invasive manner. We have not been able to confirm these findings. DMSO was administered to 25 rats intravenously at concentrations ranging from 25 to 90% or into the internal carotid artery at a concentration of 30%. The penetration of methotrexate, Evans blue-albumin, and hexosaminidase A was then evaluated at intervals ranging from 1.5 to 3.5 hours after administration. Significant barrier opening was not observed in animals receiving intravenous DMSO. Barrier modification, albeit generally modest, was obtained in animals receiving intracarotid DMSO, but this may have been the result of grand mal seizures, inasmuch as 5 of 6 of these animals had such seizures. Several of the animals receiving i.v. DMSO also had seizures, and all animals developed varying degrees of hematuria. Similarly, 5-FU was administered at a dose of 30 mg/kg i.v. and the permeability of the BBB to either Evans blue-albumin or methotrexate was evaluated. No increased permeability of the BBB to these two markers was observed. In summary, osmotic BBB opening in our hands remains the most consistent and reliable means available to open the BBB in a reversible fashion. Neither intravenous DMSO nor 5-FU seems to increase the delivery of chemotherapy or protein tracer to the central nervous system, and the use of DMSO can result in seizures and hematuria.

Animals↗
PubMed1983

Successful treatment of primary central nervous system lymphomas with chemotherapy after osmotic blood-brain barrier opening.

Three patients with primary central nervous system (CNS) lymphoma have had major tumor regression with multiagent chemotherapy given in association with reversible blood-brain barrier opening used to enhance drug delivery to the tumor. In addition, in one patient barrier modification was carried out in the posterior fossa by mannitol infusion into the vertebral artery without untoward effects, an approach not heretofore accomplished. Computed tomographic (CT) studies documented that discontinuation of steroids rapidly effected an increase in the delivery of contrast agent to the tumor. CT monitoring of the degree of barrier modification showed tumor nodules and tumor size not apparent on the control scans, thereby providing additional evidence of the existence of a blood-brain barrier in CNS tumors. These studies further show that drug (contrast) delivery to the tumor, as well as to the surrounding barrier, is enhanced after reversible blood-brain barrier modification. Finally, chemotherapy administered by this approach resulted in defined, objective tumor responses in these three patients.

Adult↗
PubMed1982

Barbiturate inhibition of lymphocyte function. Differing effects of various barbiturates used to induce coma.

The present studies evaluated the effect of phenobarbital, pentobarbital, and thiopental at concentrations comparable to those attained during therapeutic barbiturate-induced coma, on in vitro mitogen-induced lymphocyte activation. Lymphocytes from normal volunteers were incubated for 72 hours in culture medium containing mitogen (phytohemagglutinin) and a range of concentrations of the barbiturates (5 to 833 microgram/ml). Three parameters of lymphocyte activation (mitogen-induced blast transformation, 3H-thymidine incorporation, and cell proliferation) were all suppressed by the barbiturates. The suppression was dose-dependent. The greatest suppression was caused by the short-acting barbiturate, thiopental. Lymphocyte responses were much less affected by the long-acting barbiturate, phenobarbital. The intermediate-acting barbiturate, pentobarbital, was also intermediate in its ability to inhibit lymphocyte activation. The two-to threefold difference between the effects of thiopental and pentobarbital on lymphocyte function may have direct clinical relevance, since it is primarily these two agents that are employed to induce therapeutic "barbiturate coma." Since lymphocyte suppression appears to be much more marked in the presence of thiopental, these observations support a role for the other barbiturates in programs of induced coma.

Barbiturates↗
PubMed1981

Delivery of hexosaminidase A to the cerebrum after osmotic modification of the blood--brain barrier.

The present studies were undertaken to evaluate the possibility that hexosaminidase A, the enzyme deficient in Tay--Sachs disease, could be effectively delivered to brain. Previous studies from our laboratory have shown that hypertonic mannitol can be used to osmotically produce reversible disruption of the blood--brain barrier in animals (rat and dog) and man without significant neurotoxicity and that such barrier modification significantly increases the delivery of cytoreductive chemotherapy agents to selected areas of brain. By using the rat model of blood--brain barrier modification and radiolabeled enzyme, increased hexosaminidase A delivery to brain has been demonstrated in more than 85 animals. The time of injection of hexosaminidase A after blood--brain barrier disruption is critical for maximum delivery. Rapid (over 30 sec) intra-arterial administration of hexosaminidase A immediately after blood--brain barrier disruption resulted in a marked increase in enzyme delivery to the brain when compared with controls without prior barrier disruption. When the enzyme was administered 15-20 min after barrier disruption, approximately 50% less hexosaminidase A was delivered; when given 60-120 min after barrier modification, the amount delivered was the same as in control animals. This critical time course is very different than that seen in trials of low molecular weight chemotherapeutic agents (methotrexate and adriamycin). These preliminary studies suggest that hexosaminidase A can be delivered to the brain by blood--brain barrier modification and may be indicative of the potential for enzyme replacement in patients who hae Tay--Sachs disease.

Animals↗
PubMed1979

Malignant pineal region tumors. A clinico-pathological study.

Eight patients with primary malignant pineal tumors have been seen at this institution over the past 6 years; six of them underwent definitive surgical exploration. Complete gross microsurgical excision of well encapsulated tumors was possible in four of these patients. In two cases of pineal germinomas, a biopsy and a subtotal resection were carried out because of the known radiosensitivity of this tumor. These six surgical patients all received postoperative craniospinal radiation and continue to do well up to 6 years postoperatively. Two nonoperative patients were initially treated at other institutions by ventriculoperitoneal shunt and radiation and were the only ones to develop metastatic disease. One patient had metastasis of her pineoblastoma to her unirradiated spinal canal and the other patient had metastasis of his germinoma to the peritoneum. The former patient was quadriplegic on admission, although her pineal tumor was no longer visible on computerized tomography (CT), and she died of pneumonia. The latter patient's tumor secreted the beta chain of human chorionic gonadotropin (HCG). This patient's massive metastatic tumor burden completely regressed as determined by body CT scan and HCG levels after four courses of chemotherapy with bleomycin, vinblastine, and cis-platinum. In 20 patients with lesions of the pineal region, craniotomy was associated with only one death (a patient with metastatic adenocarcinoma). Thus, microsurgery for pineal tumors provides either a reasonably safe potential for complete tumor extirpation and possible cure, or a tissue diagnosis which is necessary for appropriate therapeutic planning for radiotherapy and/or chemotherapy. The traditional therapeutic approach of empiric radiotherapy without a tissue diagnosis for pineal lesions may no longer be warranted.

Adolescent↗