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Biomedical subjects

M Levitt

Publications and source records attributed to M Levitt.

At least 127 records · Page 7Linked to original sources
PubMed1987

Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. A multicenter, randomized clinical trial by the National Cancer Institute of Canada.

The National Cancer Institute of Canada Clinical Trials Group conducted a prospective randomized study comparing standard chemotherapy with alternating chemotherapy in patients with extensive small cell lung cancer. "Standard" treatment consisted of cyclophosphamide (1000 mg/m2 body surface area); doxorubicin (50 mg/m2), and vincristine (2 mg) every 3 weeks for six courses. Alternating chemotherapy was cyclophosphamide, doxorubicin, and vincristine alternating with etoposide (100 mg/m2 on days 1 to 3) and cisplatin (25 mg/m2 on days 1 to 3) every 3 weeks for six treatment cycles. Two hundred eighty-nine patients were eligible and evaluable for response to therapy and survival. Best response was higher in patients on alternating chemotherapy (complete plus partial response, 80% compared with 63.2%; p less than 0.002). Progression-free survival for patients on alternating chemotherapy was superior (p less than 0.0001) as was overall survival (p = 0.03). Major toxicities were equally frequent in both treatment groups. These results show a modest superiority of alternating chemotherapy over standard therapy in extensive small cell lung cancer.

Adult↗
PubMed1987

Second-line chemotherapy of stage III-IV ovarian carcinoma: a randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin.

A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.

Adult↗
PubMed1986

The predicted structure of immunoglobulin D1.3 and its comparison with the crystal structure.

Predictions of the structures of the antigen-binding domains of an antibody, recorded before its experimental structure determination and tested subsequently, were based on comparative analysis of known antibody structures or on conformational energy calculations. The framework, the relative positions of the hypervariable regions, and the folds of four of the hypervariable loops were predicted correctly. This portion includes all residues in contact with the antigen, in this case hen egg white lysozyme, implying that the main chain conformation of the antibody combining site does not change upon ligation. The conformations of three residues in each of the other two hypervariable loops are different in the predicted models and the experimental structure.

Amino Acid Sequence↗
PubMed1986

Possible mechanisms for lactate's induction of panic.

Forty-three patients with panic disorder or agoraphobia with panic attacks and 20 control subjects received 0.5 M racemic sodium lactate intravenous infusions, single-blind as to duration and sequence. During the procedure, pulse; blood pressure; blood L-lactate and pyruvate; plasma ionized calcium, phosphate, prolactin, epinephrine, norepinephrine, and cortisol levels; and venous PCO2, pH, and bicarbonate were measured in an attempt to clarify the mechanism of lactate-induced panic attacks. During the infusion, 72% of the patients but none of the control subjects had panic attacks. The laboratory findings suggest that peripheral catecholamine surge is not the mechanism by which lactate causes panic, although elevated epinephrine may be a predisposing factor. Heightened central noradrenergic activity was present in many but not all of the attacks. Contrary to previous hypotheses, neither depression of ionized calcium nor induction of metabolic alkalosis appears sufficient to cause panic during lactate infusion.

Agoraphobia↗
PubMed1986

The use of VP-16 plus cisplatin during induction chemotherapy for small-cell lung cancer.

In an attempt to circumvent innate or acquired tumor-cell resistance to chemotherapy, patients with small-cell lung cancer (SCLC) were treated with induction therapy that incorporated two active and potentially non-cross-resistant chemotherapy regimens on two National Cancer Institute of Canada (NCI-C) trials. Patients with limited disease (LD) SCLC were treated with cyclophosphamide, doxorubicin (Adriamycin [Adria Laboratories, Columbus, Ohio]) and vincristine (CAV) and VP-16 plus cisplatin in two different sequences. One arm was randomized to receive CAV alternating with VP-16 plus cisplatin for a total of six treatment cycles, and the other arm received three courses of CAV followed by three courses of VP-16 plus cisplatin. Both treatment strategies produced similar response rates and survival curves, and each treatment group has a projected 2-year survival of 20%. Patients with extensive disease (ED) were treated with either six cycles of CAV (standard regimen) or CAV alternating with VP-16 plus cisplatin for a total of six treatment cycles. In this study, the alternating regimen produced a higher complete response (CR) rate (40% v 27%) and overall response rate (61% v 39%; P less than .01). The progression-free survival was also superior for the alternating arm (P = .001), as was overall survival (P less than .05). The frequency of thrombocytopenia and severe gastrointestinal toxicity was slightly greater in the alternating arm, but the frequency of neutropenia and infection was less. The alternation of CAV and VP-16 plus cisplatin during induction therapy is an effective treatment strategy in the management of SCLC and superior to CAV alone in extensive SCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Superiority of methylprednisolone sodium succinate over low dose metoclopramide hydrochloride in the prevention of nausea and vomiting produced by cancer chemotherapy.

Methylprednisolone sodium succinate and metoclopramide were compared for their efficacy, tolerance, and safety in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy in patients with cancer. Previously untreated patients about to receive at least 2 cycles of identical chemotherapy were entered into a study using a randomized, double-blind, crossover design. Patients were given either 250 mg of methylprednisolone or 10 mg of metoclopramide intravenously before the first cycle of chemotherapy and were then crossed over to receive the alternate medication before the second cycle of chemotherapy. Prochlorperazine was prescribed in both cycles for postchemotherapy nausea and vomiting. After each treatment cycle patients recorded the degree of nausea, drowsiness and anxiety, the number of episodes of vomiting experienced, and the amount of prochlorperazine taken. After the second treatment cycle patients recorded their preference for either the first or the second antiemetic medication with respect to nausea, vomiting, and overall effectiveness. Of 157 patients entered into the study, 115 were fully appraisable. Methylprednisolone was superior to metoclopramide in preventing nausea and vomiting and in decreasing anxiety and the amount of prochlorperazine used. A majority of the patients expressing a preference preferred methylprednisolone to metoclopramide for control of nausea (p = 0.003), control of vomiting (p = 0.0006), and overall effectiveness (p = 0.00004). There were few side-effects. We conclude that methylprednisolone may have some utility as an antiemetic in patients receiving moderately emetogenic chemotherapy, and who are treated as outpatients.

Antineoplastic Agents↗
PubMed1985

Protein normal-mode dynamics: trypsin inhibitor, crambin, ribonuclease and lysozyme.

We have developed a new method for modelling protein dynamics using normal-mode analysis in internal co-ordinates. This method, normal-mode dynamics, is particularly well suited for modelling collective motion, makes possible direct visualization of biologically interesting modes, and is complementary to the more time-consuming simulation of molecular dynamics trajectories. The essential assumption and limitation of normal-mode analysis is that the molecular potential energy varies quadratically. Our study starts with energy minimization of the X-ray co-ordinates with respect to the single-bond torsion angles. The main technical task is the calculation of second derivative matrices of kinetic and potential energy with respect to the torsion angle co-ordinates. These enter into a generalized eigenvalue problem, and the final eigenvalues and eigenvectors provide a complete description of the motion in the basic 0.1 to 10 picosecond range. Thermodynamic averages of amplitudes, fluctuations and correlations can be calculated efficiently using analytical formulae. The general method presented here is applied to four proteins, trypsin inhibitor, crambin, ribonuclease and lysozyme. When the resulting atomic motion is visualized by computer graphics, it is clear that the motion of each protein is collective with all atoms participating in each mode. The slow modes, with frequencies of below 10 cm-1 (a period of 3 ps), are the most interesting in that the motion in these modes is segmental. The root-mean-square atomic fluctuations, which are dominated by a few slow modes, agree well with experimental temperature factors (B values). The normal-mode dynamics of these four proteins have many features in common, although in the larger molecules, lysozyme and ribonuclease, there is low frequency domain motion about the active site.

Aprotinin↗
PubMed1985

Lactate provocation of panic attacks. II. Biochemical and physiological findings.

Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.

Adult↗
PubMed1985

Biochemical effects of L-deprenyl in atypical depressives.

To examine the biochemical effects of 10-30 mg/day L-deprenyl, measurement of 24-hr urinary output of phenylethylamine (PEA), 3-methoxy 4-hydroxy phenylethyleneglycol (MHPG), and L-deprenyl's amphetamine metabolites were carried out before and during the treatment of atypical depressives. Platelet monoamine oxidase (MAO) activity was also assessed. With L-deprenyl 10-30 mg/day, the expected MAO B inhibition occurred, as indicated by significant increase in urinary PEA excretion and virtual disappearance of platelet MAO activity. Twenty-five to 33% of the daily dose of L-deprenyl was recovered as urinary methamphetamine or amphetamine. Excretion of MHPG was significantly decreased with L-deprenyl 10-20 mg/day. Overall, the results suggest that L-deprenyl's antidepressant effects are mediated by some mechanism other than, or in addition to, MAO B inhibition.

Adult↗
PubMed1985

Platelet monoamine oxidase activity in patients with panic disorder.

Preliminary reports have indicated that platelet monoamine oxidase (MAO) activity is elevated in patients with anxiety disorder. We compared MAO activity in 20 drug-free patients with panic disorder with 20 age- and sex-matched normal controls. MAO activity in patients was significantly higher than in normals. MAO activity was not correlated with age or plasma catecholamine levels. The authors speculate about the possible significance of elevated MAO activity in patients with panic disorder.

Adult↗
PubMed1985

Activated charcoal: in vivo and in vitro studies of effect on gas formation.

It has been reported that activated charcoal reduces intestinal gas production after ingestion of beans as evidenced by decreased breath hydrogen excretion and decreased passage of flatus. In the present study we assessed the ability of activated charcoal to reduce intestinal gas production by in vitro and in vivo methods. In vitro studies were performed using human fecal homogenates incubated with or without additional carbohydrate. In all studies hydrogen and carbon dioxide production and consumption occurred at similar rates in the charcoal-treated homogenate as compared with the untreated control. The influence of activated charcoal on gas production, in vivo, was studied by double-blind assessment of breath hydrogen excretion and flatus excretion after ingestion of a baked bean meal. No significant difference was observed in breath hydrogen concentration or number of passages of flatus in subjects who ingested 16 capsules of activated charcoal (4 g) as opposed to the placebo. We conclude that activated charcoal does not influence gas formation in vitro or in vivo.

Adult↗
PubMed1985

Genetic analysis of platelet monoamine oxidase activity in families of schizophrenic patients.

Platelet monoamine oxidase (MAO) has been implicated in the biology of several psychiatric disorders, including schizophrenia. Genetic factors contribute to the variance of MAO activity; however, its mode of inheritance is unknown. To assess the distribution and familial patterns of platelet MAO activity, we studied 73 chronic schizophrenic patients and 219 of their first-degree relatives. The activity distribution was skewed and admixture of two distributions gave a better fit to the data than a single distribution. Single-major-locus hypotheses were tested by pedigree analysis methods for quantitative traits. Using the transmission probability model, the familial transmission of MAO activity was consistent with either recessive or additive inheritance but not with dominant inheritance; the environmental hypothesis was strongly rejected. No effect of genotype on probability of illness was observed suggesting no relationship between the particular major locus tested and schizophrenia. The implications for genetic research in schizophrenia were discussed.

Adolescent↗
PubMed1985

Dysesthesias and self-mutilation in humans and subhumans: a review of clinical and experimental studies.

The chronic deafferentation syndrome includes a complex pattern of abnormal self-directed behavior and a stress response. Subhuman self-mutilation is a secondary consequence of the chronic deafferentation syndrome. The evidence indicates that the chronic deafferentation syndrome in subhumans is a valid model for the induced and the spontaneous dysesthesias in humans. Objective criteria for the definition of subhuman dysesthesias have been derived from independent sources of evidence, in neurally intact subjects; those criteria are then found to match the subhuman syndrome of deafferentation. Support for the validity of the inference of subhuman dysesthesias derives from the parallels with the various facts of the human dysesthesias. The credibility of this argument is significantly strengthened by reports of morphological and excitatory physiological abnormalities, in central somatosensory structures, in response to deafferentation. There is no independent subhuman evidence in support of alternate interpretations of the deafferentation syndrome, and those interpretations seem to be inadequate in several aspects. Doubts concerning the validity of this animal model have been allayed by reports of dysesthesias in humans with spinal posterior rhizotomies or ganglionectomies, and also those with congenital analgesia. Moreover, the occurrence of this syndrome in hypoalgesic areas as a consequence of anterolateral cordotomy in monkeys, can best be interpreted as a reflection of dysesthesias. This syndrome is released by neuropathological or neurosurgical lesions in the peripheral or central nervous system; lesions which involve small caliber peripheral afferents or the spinothalamic tract. Variability in the release of this syndrome has been associated with several different factors. So far, the chronic syndrome is intractable. Evidence relates the abnormalities of this syndrome to pathophysiological foci in central relays of the somatosensory system, and suggests that the chronic abnormalities of this syndrome can be sustained at brain levels.

Afferent Pathways↗
PubMed1985

Genetic analysis of plasma amine oxidase activity in schizophrenia.

Plasma amine oxidase (PAO) activity has been implicated in the biology of schizophrenia. PAO activity is, in part, under genetic control, but its mode of inheritance has not been determined. To assess the genetic pattern of PAO activity and its relation to the transmission of schizophrenia, we studied 73 chronic schizophrenic probands and 217 first-degree relatives (siblings and parents). Single-major-locus hypotheses were tested by pedigree analysis methods for quantitative traits. The distribution of PAO activity indicated significant admixture. When the transmission probability model was used, the familial pattern of PAO activity was consistent with mendelian transmission; the environmental hypothesis was rejected. PAO activity was lower in schizophrenic patients than in unaffected relatives, but the mean reduction in enzyme activity was small (10.7%) and the two groups of subjects overlapped greatly in their PAO values. The difference between ill and well relatives was not statistically significant. However, schizophrenia spectrum disorders segregated with low PAO activity in families of low-activity probands, and a greater proportion of ill than well subjects clustered in the low PAO activity mode. The results are interpreted as follows: (1) The transmission of PAO activity may be determined in part by a single major autosomal gene. (2) Low PAO activity does not qualify as a major risk factor in the schizophrenic population at large; however, a relationship may exist between low PAO activity and the transmission of schizophrenia in families of patients with extremely low enzyme activity.

Adolescent↗
PubMed1985

External beam pelvic radiotherapy plus intraperitoneal radioactive chronic phosphate in early stage ovarian cancer: a toxic combination. A National Cancer Institute of Canada Clinical Trials Group Report.

As part of a randomized trial evaluating several treatment programs in the management of poor prognosis, early stage ovarian cancer, 53 patients were randomized to receive a combination of pelvic external beam radiation, 4000 rad plus 10-20 millicuries of radioactive chromic phosphate given intraperitoneally. Only 35 patients (66%) actually received the chromic phosphate. The other 18 did not enter this phase of treatment for a variety of reasons documented in this report. Ten (29%) of the 35 patients receiving the full course of treatment had significant long term side effects with the median time to onset of symptom being 9 months after the chronic phosphate was given. There were no treatment-related deaths. The complications could not be related to the dose of the isotope, the technique of administration, nor any other definable predisposing factors. This combination is not recommended for further study.

Brachytherapy↗
PubMed1985

Molecular dynamics simulation of photodissociation of carbon monoxide from hemoglobin.

A molecular dynamics simulation of the photodissociation of carbon monoxide from the alpha subunit of hemoglobin is described. To initiate photodissociation, trajectories of the liganded molecule were interrupted, the iron-carbon monoxide bond was broken, and the parameters of the iron-nitrogen bonds were simultaneously altered to produce a deoxyheme conformation. Heme potential functions were used that reproduce the energies and forces for the iron out-of-plane motion obtained from quantum mechanical calculations. The effect of the protein on the rate and extent of the displacement of the iron from the porphyrin plane was assessed by comparing the results with those obtained for an isolated complex of heme with imidazole and carbon monoxide. The half-time for the displacement of the iron from the porphyrin plane was found to be 50-150 fs for both the protein and the isolated complex. These results support the interpretation of optical absorption studies using 250-fs laser pulses that the iron is displaced from the porphyrin plane within 350 fs in both hemoglobin and a free heme complex in solution.

Animals↗