The quiet drug revolution.
Routine approval of new products often requires a decade. But in a little-noticed change, people who are gravely ill can get breakthrough medicines much faster.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
M Graham
Publications and source records attributed to M Graham.
Carotid endarterectomy in a community hospital: a change in physicians' practice patterns.
A total of 243 consecutive carotid endarterectomies (CEA) performed at Providence Medical Center in Portland, Oregon, were retrospectively reviewed over a 22-month period. Of these, 137 patients (56%) underwent CEA for asymptomatic disease, 52 (37%) of whom had stenotic lesions of 79% or less. There were 6 deaths (3%) and 12 strokes (5%). Four strokes were in asymptomatic patients. These data prompted development of criteria for CEA: (1) hemisphere-specific transient ischemic attacks, reversible ischemic neurologic deficits, or amaurosis fugax with an appropriate carotid lesion; (2) completed stroke with major recovery and significant carotid stenosis; (3) asymptomatic lesion with greater than 80% stenosis (D+) either by carotid arteriogram or non-invasive lab evaluation; and (4) other indications only with a supporting second opinion from a disinterested vascular surgeon, neurosurgeon or neurologist. A prospective review followed institution of the guidelines. In 21 months, 148 operations were performed, a 36% reduction over the initial study period. Of these, 46 (31%) were for asymptomatic lesions. Two patients (4%) did not fulfill the guideline criteria. There were six strokes (4%) and no deaths. The reduction of CEAs appears to be related to a significant decrease in "inappropriate" operations being performed. Surgeons' familiarity with the data rather than external pressures seems to be the major factor in changing practice patterns. The decrease in stroke/death rate is not statistically significant.
Aged↗
Mitomycin-C/5-FU and radiation therapy for locally advanced uterine cervical cancer.
To assess the feasibility and effectiveness of combined therapy on locally advanced cervical cancer, we entered 38 patients into a study. The patients were treated with mitomycin-C (10 mg/m2) on Days 1 and 30 and 5-FU (1000 mg/m2) on Days 1 to 4 and Days 30 to 33. In 5 weeks 4500-5000 cGy was given concurrently, followed by radioactive implants. Twenty-six patients had an early-stage disease (IB-IIB) and twelve had a late-stage disease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring 5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-proven positive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response, complete (CR) vs partial (PR), was assessed in 36 patients 3 months after completion of therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic disease control (PDC), disease-free survival (DFS), and survival (S) while late stage correlated with the development of distant metastases (DM) and a poor DFS. PDC was obtained in 93% (27/29) of the patients who had a CR, as compared to only 43% (3/7) of those with a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for those with a PR; respective P values were 0.0340 and 0.0002. Eleven percent (3/26) of the patients with an early stage developed DM, as compared to 50% (6/12) of those with late stage, (P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developed transient neutropenia and one had transient thrombocytopenia. The second dose of mitomycin-C was omitted in 4 patients due to persistent neutropenia in 3 and to transfusion-related hepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence. Three patients developed non-cancer-related small bowel obstruction requiring surgery. We concluded that this combined regimen was well tolerated. Although it was effective in controlling the cancer in the pelvis, this regimen failed to control DM in late-stage patients.
Adult↗
Technical challenges associated with the radiolabeling of monoclonal antibodies utilizing short-lived, positron emitting radionuclides.
Many factors, both physical and chemical, affect the radiolabeling of a chemical compound. These factors add a new dimension of complexity when the labeling of monoclonal antibodies is attempted with short-lived, positron emitting radionuclides. A lack of appreciation for the unique chemical separations associated with the radionuclide incorporated into the synthetic precursor can often lead to unexpected or non-reproducible results.
Antibodies, Monoclonal↗
The differential expression of protein kinase C genes in normal human neonatal melanocytes and metastatic melanomas.
Expression of protein kinase C (PKC) genes (alpha, beta, gamma and epsilon) was measured in cultured normal human neonatal melanocytes and metastatic melanoma cell strains. Three of the PKC isotypes (alpha, beta and epsilon) were constitutively expressed in neonatal melanocytes. Protein kinase C beta RNA transcripts were induced in neonatal melanocytes cultivated in medium with serum and 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, PKC alpha and epsilon RNA transcripts were detected in melanocytes cultivated in medium without serum and TPA, but were repressed in melanocytes cultivated in medium with serum and TPA. Only PKC alpha and epsilon RNA transcripts were detected in the melanoma cell strains and the PKC RNA transcript expression levels varied among the five metastatic melanomas. In four metastatic melanoma cell strains, PKC alpha and epsilon RNA transcript expression levels were repressed by serum, but in one melanoma cell strain, PKC alpha and epsilon RNA transcript expression levels were induced by serum. Protein kinase C gamma RNA transcripts were not detected in either the melanocytes or melanoma cell strains. These data suggest an alteration of PKC isotype gene expression in the progression of primary melanocytes to metastatic melanoma. The absence of the PKC beta RNA transcripts and altered expression of PKC alpha and epsilon isotypes in particular may be a feature in the transformation of human primary melanocytes.
Gene Expression↗
31P NMR spectra of extremity sarcomas: diversity of metabolic profiles and changes in response to chemotherapy.
We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.
Animals↗
The metabolic effects of aspirin in fasting and fed subjects: relevance to the aetiology of Reye's syndrome.
As a possible model for the mechanism of precipitation of Reye's Syndrome in children the metabolic effects of oral aspirin were studied in normal subjects in the fasted and fed states, to determine whether aspirin altered fatty acid oxidation. Starvation increased blood 3-hydroxybutyrate concentrations, but aspirin had no effect on this or other metabolite concentrations in either the fasted or fed states.
3-Hydroxybutyric Acid↗
Frequency and duration of handwashing in an intensive care unit.
The effects on hand decontamination of the introduction of an antiseptic handrub lotion in an intensive care unit was studied. To obtain baseline data, nursing, medical, physiotherapy, radiology, and orderly staff members were observed. Further observations were carried out after the introduction of the handrub lotion. Patient care activities were classified as high or low, according to the degree of contact with the patients or their equipment. A total of 884 patient contacts and 341 hand decontamination episodes was observed: 440 contacts and 140 handwashes in stage one (32%) and 444 contacts and 201 handwashes in stage two (45%). There was an increase of 13% in hand decontamination frequency after the introduction of the handrub lotion. The data indicate that the frequency of hand decontamination is below levels recommended by infection control authorities. Increasing the accessibility of hand decontamination facilities did result in a slight increase in handwashing compliance.
Cross Infection↗
Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity.
Lymphokine activity in seven myelin basic protein (MBP)-specific T cell clones was examined. All of the clones recognize MBP peptide 1-9 in the context of I-Au. A strong positive correlation was found between levels of lymphotoxin (LT) and tumor necrosis factor alpha (TNF-alpha) mRNA and biological activity on L929 cells and their capacity to induce paralysis, the clinical hallmark of experimental allergic encephalomyelitis (EAE). No correlation was found between interleukin-2 or gamma interferon production and encephalitogenicity. LT and/or TNF-alpha may play a central role in the pathogenesis of EAE.
Animals↗
Pulse oximetry. An easy way to check oxygen saturation.
Explore the source record for details and available documents.
Humans↗
A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression.
Eighteen patients with relapsed non-Hodgkin's lymphoma (NHL) were infused with escalating doses of monoclonal antibody (mAb) OKB7, trace-labeled with iodine-131 (131I), in order to study toxicity, pharmacology, antibody localization, and dosimetry of radioiodine. OKB7 is a noncytotoxic mouse immunoglobulin G2b (IgG2b) mAb reactive with B cells and most B-cell NHL. Three patients each were treated at six dose levels ranging from 0.1 mg to 40 mg. All patients had radionuclide imaging and counting daily, had serial blood sampling to study pharmacokinetics, human antimouse antibody (HAMA), and circulating antigen, and had a biopsy of accessible lymphoma to determine delivery of isotope to tumors and assess the effect of tumor antigen expression on mAb delivery. Bone marrow biopsies were also done in the majority of patients. There was no toxicity. Serum clearance showed a median early phase half-life of 1.9 hours and a later phase half-life of 21.7 hours. Median total body clearance half-life was 22 hours. Pharmacokinetics were not dose-related. HAMA was detected in five patients. Circulating blocking antigen was detected in the serum of four patients, but at levels that were of pharmacologic consequence only in one. Biopsied tumor tissue from five patients did not express OKB7 antigen. No significant uptake of antibody was seen in these tumor sites. Mean total uptake of isotope into lymphoma measured in biopsies correlated linearly over the 400-fold increase in injected mAb dose. However, the percent of injected dose found per gram of tumor was unrelated to dose, but correlated inversely with tumor burden. In two patients with minimal tumor burden, 1.0 mg and 5.0 mg doses of OKB7 resulted in tumor to body radioisotope dose ratios of 22 and 7, which would theoretically permit tolerable delivery of 4,400 and 1,400 rads to these tumors, respectively, if OKB7 were conjugated with higher doses of 131I.
Adult↗
Phencyclidine and violent deaths in St. Louis, Missouri: a survey of medical examiners' cases from 1977 through 1986.
A survey of 104 deaths involving phencyclidine (PCP) occurring from 1981 through 1986 in metropolitan St. Louis, Missouri, is presented. Four black males (22-33 yr) died from fatal PCP intoxication. PCP was detected in an additional 100 deaths: 81 homicides, 13 suicides, and 6 accidental deaths. Seventy-five of these deaths were homicides of Black males (mean age 27 years) typically dying from gunshot wounds, 64 cases. In 50% of deaths where PCP was detected, other drugs were co-administered: ethanol (35%) and cocaine (20%) being the most common mixtures. A dramatic continuous increase in PCP abuse from 1984 through 1986 was demonstrated by drug abuse indicator data: treatment admissions, emergency room episodes, police exhibits, and driving under the influence of PCP arrests. Increased abuse of PCP in St. Louis has been associated with increased medical emergencies and violence against persons.
Accidents↗
The effects of TCDD on receptors for epidermal growth factor, glucocorticoid, and estrogen in Ah-responsive and -nonresponsive congenic mice and the effects of TCDD on estradiol metabolism in a liver tumor promotion model in female rats.
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Animals↗
Magnetic resonance imaging demonstrates that electric stimulation of cerebellar fastigial nucleus reduces cerebral infarction in rats.
We sought to determine whether high spatial resolution magnetic resonance imaging is useful for noninvasive quantitation of the ischemic infarct produced by occlusion of the middle cerebral artery and for detection of reduced infarct volume elicited by electric stimulation of the cerebellar fastigial nucleus. Male rats of the spontaneously hypertensive strain were anesthetized, the middle cerebral artery was occluded, and the fastigial nucleus was stimulated for 1 hour. Twenty-four hours later, rats were reanesthetized and T1- and T2-weighted images were obtained. Rats were killed and the volume and distribution of the lesion was established by histopathology. Magnetic resonance imaging estimates of the lesion volume were 271 +/- 41.0 mm3 (middle cerebral artery, n = 5) and 148 +/- 8.4 mm3 (middle cerebral artery + fastigial nucleus stimulation, n = 6; 45% reduction, p less than 0.05). Histopathological analysis revealed a lesion of 229.8 +/- 15.4 mm3 involving somatosensory cortex, lateral caudate putamen, and lateral hippocampus. Fastigial nucleus stimulation resulted in a 36% reduction in infarct volume to 146.0 +/- 10.3 mm3. The retrieved zone was largely in the cortex dorsal and ventral to the lesion and mostly posterior to the lesion. The estimates of lesion volume by magnetic resonance imaging and histopathology did not differ and were highly correlated (r = 0.90; p less than 0.001). This study confirms our previous finding that fastigial nucleus stimulation reduces the volume of a focal ischemic infarct and demonstrates that magnetic resonance imaging not only accurately estimates the volume of the lesion but also can detect changes as small as 50-100 mm3.
Animals↗
Hypercholesterolaemia and a silent MI.
Results of investigations in extraordinary patients should be dealt with cautiously; it is often prudent to repeat tests. Though the aims of treatment in such cases are often the same, differences in approach to the problem are illuminating.
Adult↗
Screening for raised cholesterol in a small suburban town.
Raised serum cholesterol (above 7.8 mmol/l) occurs as frequently as diabetes mellitus. A voluntary screening programme to identify people with raised cholesterol has proved popular.
Adult↗
Circulating lymphocytes, neutrophils and immune complexes in pigs after feeding.
There are reports in the literature claiming that pigs experience a lymphopenia after feeding. This is not observed in other species. We set out to investigate this phenomenon because of the unusual route of lymphocyte recirculation in pigs. for it suggested that this might be a specific response to dietary antigens. We were unable to confirm this phenomenon. A lymphopenia was observed in both test and control groups as a non-specific response to restraint and blood sampling. In contrast, feeding was associated with a significant neutrophilia (mean 58%, P less than 0.002). There were no increases in circulating IgA, IgG or IgM immune complexes after feeding but IgG immune complexes remained at a higher level than in the control group.
Animals↗
The use of lymphoscintigraphy in treatment planning of primary breast cancer.
A technique is described for the use of lymphoscintigraphy in treatment planning of primary breast patients. During simulation of the treatment fields, the positions of the internal mammary nodes are projected back toward the source onto the patient skin surface and are marked by radio-opaque markers for visualization on films. Exact solutions for the coordinates of these surface projection points are derived. Approximate solutions are also given which are independent of the isocenter location and primarily dependent on the treatment field gantry angle. If a typical couch angle and field size are assumed, the projection points can be calculated for various gantry angles prior to simulation. Generally, a decision can then be made beforehand whether it would be better to use deep tangents or a separate field to treat the internal mammary nodes. During simulation, the surface projection points serve as visual and fluoroscopic guides to field design and optimization. A method is also presented for projecting the internal mammary node positions onto a single transverse patient contour for conventional 2-dimensional treatment planning. By accurately showing the projected location of the node with respect to the field edge, adequate treatment margin can be assured.
Breast Neoplasms↗