Pharmacokinetics of cefoperazone in patients with neoplastic disease.

The pharmacokinetics of cefoperazone, a new semisynthetic cephalosporin, were studied in 34 patients with neoplastic disease. This compound was administered in a variety of doses and schedules without observable toxicity in any patient. The mean peak serum concentration after a 15-min intravenous infusion of 2 g was 264 microgram/ml after the first dose; the serum half-life was 2.1 h. There was no significant change in half-life or serum concentrations after 4 or 7 days of therapy. The mean peak serum concentration after infusion of 1 g over 15 min was 133 microgram/ml, with a mean of 10.7 microgram/ml at 6 h. The serum half-life was 2 h. The mean peak serum concentration after infusion of 1 g over 0.5 h was 101 microgram/ml. When 8 g was subsequently administered daily by a continuous infusion schedule, levels were maintained at 80 microgram/ml. When the dose was increased to 16 g daily, serum concentrations were maintained at an average of 153 microgram/ml. Only 37% of cefoperazone was recovered in the urine in a 12-h period after the initial dose, suggesting the importance of other mechanisms of excretion; however, serum concentrations in one patient with renal insufficiency were significantly higher than serum concentrations in patients with normal renal function.     

Minimal nephrotoxicity with cephalosporin-aminoglycoside combinations in patients with neoplastic disease.

Patients with cancer and suspected sepsis were treated in a prospective, randomized trial with one of four cephalosporin-aminoglycoside combinations: cephalothin and tobramycin; cephalothin and gentamicin; cefamandole and tobramycin; or cefamandole and gentamicin. Carbenicillin was added if the absolute granulocyte count was less than 1,000/mm3. Of 199 patients receiving 20 to more doses of an aminoglycoside and having serial determination of serum creatinines, nephrotoxicity developed in seven (3.5%) given any of the four combinations. There were no significant differences between patients receiving either cephalosporin or either aminoglycoside. Nephrotoxicity developed less frequently among children (2 or 125; 1.6%) than adults (5 of 74; 6.8%).     

Switching cholinesterase inhibitors in patients with Alzheimer's disease

Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.     

IgM antiavian antibodies in sera from patients with pigeon breeder's disease

The authors' objective was to study the presence of IgM antiavian antibodies in sera from patients with pigeon breeder's disease. We studied 93 patients with interstitial lung disease admitted for the assessment of pigeon breeder's disease. Eighty sera from healthy donors with no history of bird contact and 47 asymptomatic pigeon breeders were included as controls. The presence of IgM, IgG, and IgA antiavian antibodies was detected by ELISA and Western blot using avian-pooled serum antigen. Fifty-three patients were classified as having definite pigeon breeder's disease, whereas 40 did not fulfill these diagnostic criteria. The levels of IgM antiavian-antibodies in pigeon breeder's disease by ELISA exceeded both the values of healthy subjects with no history of avian contact (P = 2.5 x 10(-8)) and the results of asymptomatic breeders (P = 0. 03). Positive IgA antiavian antibodies were the most frequent abnormalities in pigeon breeder's disease showing values over the reference levels of control groups that reach significant statistical differences. Both precipitin-positive and -negative samples demonstrated IgM reactivity. IgM antiavian antibodies were confirmed by Western blot. A relationship of IgM positive tests with a recent history of avian antigen exposure and acute disease was found. Additionally, the positive IgM group included patients having subacute and chronic lung disease. Antiavian antibodies have previously been considered of minor significance in hypersensitivity pneumonitis; nevertheless, recent studies support their use in clinical diagnosis. Although no specific laboratory tests can confirm the diagnosis in pigeon breeder's disease, IgM antiavian antibodies may be useful for detecting recent antigen exposure and the acute stage of the disease.     

Observer error in the characterization of hepatic lesions in patients with neoplastic liver disease

Sixteen patients with known neoplastic liver disease underwent 20 ultrasound examinations by two separate teams to determine the level of agreement in the measurement of lesion size and sonographic characteristics. The intraclass correlation coefficient for the observations on lesion size was r = 0.97 (95% lower confidence limit r = 0.96). We conclude that sonographic estimation of the size of neoplastic liver lesions in highly reproducible and that the measurements obtained may be safely incorporated into the criteria of response for cancer clinical trials.     

Demonstration and characterization of immunosuppressive factors in sera from patients with Crohn's disease

The effect of sera from 17 patients with Crohn's disease, 8 with ulcerative colitis or 5 with intestinal tuberculosis on the proliferative response of mouse spleen cells induced by phytohemagglutinin (PHA) was studied. Sera from patients with Crohn's disease markedly suppressed the blastogenesis of mouse spleen cells (S.I. = 6.8 +/- 2.0, % suppression = 83%), as compared with normal sera (S.I. = 41.0 +/- 5.2, p less than 0.001, % suppression = 0). Conversely, ulcerative colitis sera did not suppress the blastogenesis of mouse spleen cells (S.I. = 43.5 +/- 8.7, % suppression = -6%), nor the sera of intestinal tuberculosis (S.I. = 38.9 +/- 4.0, % suppression = 6%). Thus, we confirmed the possible existence of immunosuppressive factors in Crohn's disease. Moreover, immunosuppressive factors in Crohn's disease were characterized for biochemical properties. The approximate molecular weight is 45,000 estimated by diafiltration and gel filtration on a Sephadex G-75 column. Analytical isoelectric focusing showed an increased amount of acidic protein in fractionated sera (m.w. ranging 30,000-50,000) from patients with Crohn's disease and ulcerative colitis, in comparison with that in normal sera. Furthermore, the main peak of this acidic protein in Crohn's disease was an isoelectric point (pI) of 2.8, while the pI of that from ulcerative colitis was 3.0. These results suggest that qualitative differences of such acidic protein may serve to discriminate between the sera of Crohn's disease and ulcerative colitis.     

Reduced level of non-esterified fatty acids in sera from patients with infectious respiratory disease

Sera from 103 fasting individuals 3 to 76 years of age and free of clinical infectious disease and sera from 183 patients with infectious disease were assayed for serum total non-esterfied fatty acids (tNEFA) and compared. Data were also separated into five groups according to age of donor: 3--7, 8--19, 20--35, 36--60, and 61--76 years. The mean group serum levels of tNEFA increased with age. Among patients with infectious diseases sixty-five were diagnosed as having hepatitis, 41 with infectious mononucleosis, 18 with cellulitis, 12 with pulmonary tuberculosis, 11 with non-pneumococcal pneumonia, 9 with pneumococcal pneumonia, 8 with pharyngitis, 6 with pyelonephritis, 6 with aseptic meningitis, 4 with Gram-negative sepsis, and 3 with encephalitis. The sera from 23 non-fasting patients with gonorrhea were also tested. The serum tNEFA levels were found to be altered, in fact depressed from normal group values, only in patients with pneumonia or tuberculosis. This depression may be related to aberrant pulmonary metabolism during pneumonia.     

Serial measurements of Ca antigen in sera from patients with advanced malignant breast disease

Ca antigen levels in serum samples from three groups of patients were assayed. From a survey of 173 patients with various malignancies, elevated levels were found most consistently in patients with metastatic breast cancer. Spearman rank correlation values of Ca and CEA values on individual serum samples, 0.3009, (n = 194), or individual and serial samples, 0.2406, (n = 264) from a total 194 patients with metastatic breast cancer showed that correlation between Ca and CEA values was poor. For a group of 20 patients within the 194, from whom fortnightly serial samples were available, serum levels for 10/20, measured retrospectively, corroborated clinical observations on the course of their disease, although only 4/20 showed marked elevations during active disease. No correlations between expression of the tumour marker and histological type of the primary tumour, age of the patient, site of recurrence nor aberrant elevation in response to cytotoxic drug could be found to explain the non-correspondence of marker behaviour and disease status in the remaining 10 patients. The indications from this small study are that serial Ca antigen serum measurement could be misleading in 50% of patients with metastatic breast cancer, and that the assay is unsuitable for follow-up of patients with breast cancer.     

A fluorescent artefact resembling BB-creatine kinase in sera of patients with prostatic disease.

A fluorescent zone with mobility towards the anode almost equal to that of human BB-creatine kinase has been detected after electrophoresis on cellulose acetate of sera from each of 28 patients with prostatic carcinoma. The zone is not due to the BB isoenzyme and its appearance does not depend on the presence of substrates of creatine kinase. It therefore appears to be a further example of a fluorescent artefact resembling a creatine kinase ieoenzyme. These observations indicate a need for caution in assessing the possible value of BB-creatine kinase in patients with prostatic disease.     

Anti-idiotype sera raised against surface immunoglobulin of human neoplastic lymphocytes

The idiotypic determinants of surface immunoglobulins on B-cell lymphomas and lymphocytic leukemias represent tumor-specific antigens, individually unique for each tumor. As such they have both diagnostic and therapeutic potential, particularly for those neoplasms with no serum monoclonal immunoglobulin arising from synthesis of the protein for export. We describe the raising in animals of anti-idiotype sera directed against two examples of a nonexporting neoplasm, human chronic lymphocytic leukemia. The procedure involves exposing the cells to papain so as to remove the Fab fragments (containing the idiotypic determinants) from the surface immunoglobulin, recovering the Fab on cellulose immunosorbent particles, and immunizing animals with the immunosorbent-Fab complex.     

Suppression of monocyte dependent lymphocyte stimulation by sera from patients with Hodgkin's disease

The effect of sera from patients with Hodgkin's disease (HD) on monocyte dependent ConA and MLC-activation of normal lymphocytes to DNA synthesis was studied. Lymphocyte stimulation was greatly enhanced in the presence of monocytes at a monocyte : lymphocyte ratio of less than or equal to 8 : 1. Higher ratios were usually suppressive. Some HD sera suppressed monocyte mediated enhancement of ConA and MLC-stimulation efficiently. The degree of inhibition by the individual HD serum remained similar in the absence of monocytes and at various monocyte : lymphocyte ratios. Pretreatment of monocytes or lymphocytes with HD serum had no effect. Inhibition was only noted when serum was present during the whole culture period. It is concluded that HD sera do not hamper the activity of monocytes to augment lymphocyte growth. The effect may be explained by direct effects of serum factors on lymphocytes.     

Increased level of soluble interleukin-2 receptor in sera of patients with Graves' disease.

Soluble interleukin-2 receptor was studied in 20 patients with Graves' disease before and after methimazole treatment. Soluble interleukin-2 receptor level was significantly increased in newly diagnosed Graves' disease compared to controls (667 +/- 270 vs 205 +/- 45 U/ml) (P less than 0.001). In untreated patients' sera the soluble interleukin-2 receptor levels were higher in patients with active ophthalmopathy than in those without eye symptoms. Soluble interleukin-2 receptor levels were normalized in remission induced by methimazole treatment in the majority of patients except those with infiltrative ophthalmopathy. Furthermore, a correlation was found at the hyperthyroid stage of the disease between soluble interleukin-2 receptor level and titre of anti-TSH-receptor antibodies. However, the association with other parameters including anti-eye muscle, anti-thyroid peroxidase, anti-thyroglobulin antibodies was not significant.     

Glycoprotein IIb/IIIa inhibitors in patients with end-stage renal disease

OBJECTIVE: To determine whether glycoprotein IIb/IIIa inhibitors (GPIs) are effective and safe as adjunctive therapy for percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD). DATA SOURCES: MEDLINE (1966-June 2004), EMBASE (1980-June 2004), and International Pharmaceutical Abstracts (1970-June 2004) were searched, in addition to a manual bibliographic search. DATA SYNTHESIS: Even though GPIs have an established role as adjunctive therapy in PCI, little is known about their use in patients with ESRD. We found 3 reports describing experience with abciximab in this population. Based on the limited information from registries and a retrospective chart review, it is difficult to draw definitive conclusions about the utility of GPIs in ESRD. The decision to use abciximab in this population must be made on an individual case basis. CONCLUSIONS: Studies are needed to evaluate the benefit versus risk of GPI therapy in ESRD.     

The prolamin antibody reactivity against hordein polypeptides in sera from patients with coeliac disease

The antibody reactivity against the barley prolamin, hordein, was investigated by an immunoblotting technique, in sera from patients with untreated coeliac disease, patients with other gastrointestinal diseases and healthy controls. No characteristic hordein polypeptide antibody pattern could be connected to coeliac disease, as observed in a similar study using different fractions of the wheat prolamin, gliadin. Gliadin- and hordein-immunoadsorbent column experiments demonstrated that the prolamin reactivity originates from the same population of antibodies. It is speculated that distinct antigenic epitopes characteristic for untreated coeliac disease, might reside within a N-terminal repeat region of gliadin.     

Assays for thyrotropin-receptor binding and thyroid-stimulating antibodies in sera from patients with Graves' disease

We compared the activities of thyroid-stimulating antibodies (TSAb) measured in cultures of human thyrocytes and the values for thyrotropin-receptor antibodies (TRAb) as measured with a commercial kit based on use of radiolabeled receptors. Sera were obtained from patients with Graves' disease before, during, and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). We found a significant correlation between the measurements of these two antibodies in patients: before treatment (r = 0.74, p less than 0.01, n = 44), after three months of treatment (r = 0.76, p less than 0.01, n = 21), and during relapse after the drug was discontinued (r = 0.64, p less than 0.01, n = 19). In all three situations, our TSAb technique was more sensitive than the TRAb method. We conclude that, even though the TRAb technique is simpler and quicker, this commercial kit is too insensitive to replace measurement of TSAb in fresh human thyrocyte cultures for management of drug therapy of patients with Graves' disease.