Showing papers in "Journal of Molecular Medicine in 1982"

Definition and Classification of the Histamine-Release Response to Drugs in Anaesthesia and Surgery: Studies in the Conscious Human Subject* **

Abstract: In 2 clinical studies in 40 conscious human volunteers and 164 orthopedic patients histamine-release responses were diagnosed, defined and classified. Polygeline (Haemaccel) in its now outdated formulation [40] was chosen as a clinical histamine releaser. The main interest was not concentrated on the extreme, the “classical” anaphylactic response, but on theaverage histamine-release response found in clinical experiments with so many drugs in the last 10 years. In human volunteers 600 ng/kg histamine was i. v. injected. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, “metallic taste”, flush, congestion of head, “wet eyes” and tears, hypertension and headache. Following polygeline none of these subjects developed a life-threatening reaction, but 12 showed a systemic response, 11 a cutaneous reaction and 17 were non-responders. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were plasma histamine levels >1 ng/ml, tachycardia, wheals, sensation of heat, narrowness of throat, hypertension, headache and wet eyes or tears. In a prolective, cohort study in the orthopedic patients 3 subjects with life-threatening reactions, 27 with systemic response, 96 with cutaneous reaction and 38 non-responders were included. Indicants with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, erythema and wheals, cough, flush, stuffy nose and facial oedema. With this trial the indicants for diagnosing a systemic histamine release response in volunteers were validated in patients to a large extent. Thus the average histamine-release response was defined by clinical signs such as tachycardia and mild hypertension, scattered hives such as spots of erythema and wheals, respiratory symptoms in the laryngeal and nasal region, such as cough, narrowness in the throat, stuffy nose and sneezingand by pathological plasma histamine levels (>1 ng/ml). In addition histamine-release responses were differentiated as cutaneous responses, systemic responses and life-threatening responses by clinical and operational criteria and by plasma histamine levels. Using clinical trials and medical decision making procedures the incidence of systemic histamine-release responses in patients higher by two orders of magnitude than in other studies reported hitherto.

Fibronectin--mediator between cells and connective tissue.

Abstract: Fibronektin, fruher auch LETS-Protein genannt, ist ein hochmolekularer Eiweiskorper (Mol-Gew. ca. 450 000), welcher im perizellularen Bereich von Fibroblasten und anderen adharenten Zellen aber auch sonst im Bindegewebe in Form dunner Fibrillen auftritt. Eine losliche Form, die mit dem Oberflachenprotein der Zellen immunologisch identisch und chemisch zumindest sehr ahnlich ist, kommt im Blutplasma in einer Konzentration von etwa 300 µg/ml vor. Sie wird auch als Kalte-unlosliches Globulin bezeichnet. Fibronektin besitzt Affinitat zu Zelloberflachen und zu verschiedenen Matrixsubstanzen wie Fibrin und Kollagen und vermittelt dadurch das Anhaften von Zellen an diese Substrate. Es wirkt auserdem als Opsonin fur die Phagozytose gelatinehaltiger Verbindungen und ist vermutlich wichtig fur die Ausschleusung von loslichem Fibrin aus dem Blutkreislauf durch das retikulo-endotheliale System. Auch Bakterienoberflachen werden von Fibronektin erkannt. Eine Umwandlung von loslichem Fibronektin in Fibrillen gelingt mit Heparin, das gleichzeitig die Bindung von loslichem Fibronektin an die Zellen verstarkt. Heparin oder, wie vermutet wird, das an Oberflachen verschiedener Zellen vorhandene Heparansulfat scheinen somit als Cofaktoren fur die Ausbildung der perizellularen Fibrillen wesentlich zu sein. Die mit Heparin abgeschiedenen Fibronektinfibrillen weisen auch eine bessere Affinitat zu nativem Kollagen, besonders zu Typ III, auf als losliches Fibronektin. Als Antagonist wirkt Hyaluronsaure, die in hoheren Konzentrationen die Wechselwirkung der Fibronektinfibrillen mit Kollagen und Zelloberflachen verhindert. Auch sulfatierte Proteoglykane aus Knorpelgewebe maskieren Fibronektinfibrillen. Virus-transformierte Fibroblasten erzeugen weniger Fibronektin und vermogen perizellulare Fibrillen nur schlecht festzuhalten. Eine Erklarung dafur konnte die erhohte Abscheidung von Hyaluronsaure sein. Die transformierten Zellen haften nur schlecht an einer Unterlage und weisen im Gegensatz zu gesunden eine runde Form auf. Dieser Phanotyp kann durch Fibronektin zum grosten Teil korrigiert werden. Es wird vermutet, das Fibronektin auch auf die Bildung von Bindegewebe Einflus nimmt, indem es kollagene Vorstufen an der Oberflache von Fibroblasten akkumuliert und dadurch die Fibrillogenese beeinflust.

The intrarenal renin-angiotensin-system. An immunocytochemical study on the localization of renin, angiotensinogen, converting enzyme and the angiotensins in the kidney of mouse and rat.

Abstract: The localization of renin, converting enzyme (CE) and angiotensin II (ANG II) in the kidneys of rats and mice was investigated with immunocytochemical methods. According to the presence and specific intrarenal localization of these components of the renin-angiotensin-system (RAS) our results suggest that in addition to the well known systemic effects of the RAS, there are interactions of its components inside the kidney. These interactions may lead to the generation of an extra portion of ANG II in the renal blood stream with its target cells determined by the localization of CE at the luminal side of well defined endothelial areas. These intrarenal-intravasal reactions may or may not reinforce the action of “systemic” ANG II, generated prerenally. In addition, the existence of true intrarenal-interstitial interactions, with the different components and actions of this intrarenal RAS restricted entirely to the kidney is suggested by our results, particularly the demonstration of ANG II within epitheloid cells and the dissociation of systemic renin and ANG II from their local concentrations in renal hypertensive rats.

Digoxin-like natriuretic activity in the urine of salt loaded healthy subjects.

Abstract: In previous studies we have demonstrated a natriuretic factor of small molecular weight (<1,000 Daltons) in the serum and urine of salt loaded subjects. This factor isolated from salt loaded animals inhibits the Na-K-ATPase enzyme system. In addition, the natriuretic material isolated from plasma of salt-loaded dogs was shown to bind to specific digoxin antibodies. It was therefore suggested that a digitalis-like endogenous natriuretic factor (endoxin) is released in response to saline loading. In the present study we therefore investigated the presence of such an endogenous natriuretic digitalis-like activity in the urine of healthy volunteers during high salt intake. Using Sephadex G-25 for chromatographic separation of urine a material elutes as a single peak in the natriuretic post-salt fraction IV which is specifically bound to digoxin antiserum complex. Mean peak activity amounted to 1.55±0.48 ng/ml digoxin equivalents. We further purified the natriuretic material by immunoprecipitation with the digoxin antiserum complex. This purification procedure resulted in a more than 10-fold increase in specific natriuretic activity from 2.7±0.4 to 30.4±5.8 µEq Na+·min−1·mg−1. Thus the digitalis-like natriuretic activity previously observed in the plasma of saline loaded dogs is also present in the urine of healthy subjects during high dietary salt intake. Immunoprecipitation may offer a meaningfull tool for further isolation and identification of the natriuretic hormone(s).

Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis

Abstract: Intravenous application of 100 µg synthetic ovine corticotropin releasing factor (CRF) led to stimulation of ACTH-secretion in nine normal controls, with a maximum 30 min after CRF. Cortisol, corticosterone, cortisone and 11-deoxycortisol increased with a maximum at 60 min after CRF, whereas no rise was seen in aldosterone, 11-deoxycorticosterone, 17-α-hydroxyprogesterone, progesterone, DHEA-S and testosterone. The specificity of CRF-stimulation was also shown by unchanged TSH, LH, FSH, hGH, prolactin and thyroid hormone levels, als well as unchanged insulin and gastrin levels. No serious side-effects were observed during the test period and afterwards.

Adverse reactions to intravenous agents in anaesthesia in France.

Abstract: One hundred severe peranesthetic accidents occuring in hospitals in the eastern part of France were tested between 1975 and 1980 at the Immunological Unit of the University Hospital in Nancy Tests were carried out “a posteriori”; mean time: three weeks after the accident (extremes: one week to one year) A second battery of tests was carried out in 35%, and a third one in 8% of the patients

The demonstration of histamine release in clinical conditions: a review of past and present assay procedures.

Abstract: Topics related to the measurement of histamine in human plasma and other body fluids are reviewed. These include (1) an overview of the data obtained by the biological, fluorometric and radioenzymatic assays over the past 45 years; (2) the various modifications of the radioenzymatic isotopic assay of histamine and the development of a single extraction step assay; (3) a compilation of values obtained in our laboratory by the radioenzymatic assay of histamine levels in various body fluids in disease states associated with abnormal histamine production or release; and (4) factors that affect histamine levels in plasma and some experimental considerations for monitoring changes in free histamine levels. The last topic includes a discussion of the halflife of histamine in the circulation, its clearance across various vascular beds, and the fact that capillary endothelial cells are one site of inactivation of circulating histamine.

Dysrhythmias caused by histamine release in guinea pig and human hearts.

Abstract: Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heartin vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heartin vitro.

Cyanide toxicity of sodium nitroprusside in therapeutic use with and without sodium thiosulphate

Abstract: Sodium nitroprusside (SNP) as a mono-infusion was administered to 51 patients for periods of a few hours. A further group of 19 patients received SNP for periods of several days as a combination solution of SNP mixed with sodium thiosulphate. The concentrations of cyanide and of thiocyanate in the blood of all patients were measured. In seven of the patients the level of thiosulphate was also measured. Infusion of SNP on its own at levels exceeding 2 microgram/kg/min led to the rising of cyanide levels in the blood being proportional to dosage. Infusion of SNP mixed with thiosulphate showed no such accumulation of cyanide in any patient, irrespective of dosage level and duration. The efficacy at lowering blood pressure was fully maintained in the mixed infusion. The elimination half-life for thiosulphate was 16.5 min. Pharmacokinetic calculation of the rise in cyanide level showed that mono-infusions of 5-10 micrograms SNP/kg/min could within 5-10 h cause a life-threatening cyanide level in the blood. By contrast, mixed infusion of SNP together with thiosulphate, for which light-opaque syringes and tubing must be used, is a procedure free of danger and should become the technique of choice when therapeutically administering SNP in order to lower blood pressure.

Functional heterogeneity of mast cells from different species and tissues.

Abstract: The systemic responses of different animals to a number of histamine liberators and the effects of these compounds on isolated tissue mast cells in vitro are examined. Mast cells from different species and even from individual tissues within a single animal are shown to vary markedly in their response to given inducers. On this basis, the usefulness of animal models in predicting whether a particular compound may act as a histamine liberator in man is discussed.

Suggested importance of monokines in pathophysiology of endotoxin shock and malaria

Abstract: There are many similarities in the pathophysiology of gram-negative infections and in acute falciparum malaria. Particularly, noteworthy is the detection of circulating inflammatory mediators in animals receiving endotoxin and in animals infected with malarial parasites. These observations have lead to the notion that macrophage derived mediators may be responsible, at least in part, for the pathology observed in malaria.

Cellular mechanism of the furosemide sensitive transport system in the kidney

Abstract: Experiments were performed in the distal tubule of the doubly-perfused kidney of Amphiuma to determine active and passive forces, involved in the transport processes of potassium, sodium and chloride. Ion-sensitive microelectrodes and conventional microelectrodes were applied to estimate intracellular ion activities, cell membrane potentials and net flux of potassium and chloride under control conditions and during inhibition of active transport. Sodium chloride cotransport, located in the luminal cell membrane is postulated, based on the following observations:

Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: Synopsis of three randomized controlled trials

Abstract: To demonstrate the efficacy of a premedication with H1- + H2-receptor antagonists against histamine-release responses in anaesthesia and surgery 3 randomized controlled trials were conducted in patients, volunteers and experimental animals (dogs). Cutaneous anaphylactoid reactions following infusion of polygeline (Haemaccel) in orthopedic patients were successfully abolished by premedication with 0.1 mg/kg dimethpyrindene (Fenistil) and 5 mg/kg cimetidine (Tagamet). Chlorpheniramine (Piriton) was also useful, but dimethpyrindene was more effective in the doses recommended and used. Side-effects of the premedication were not observed when the 2 drugs were slowly administered (2 min each). Systemic anaphylactoid reactions following infusion of polygeline were completely prevented in volunteers by the same premedication (0.1 mg/kg dimethpyrindene and 10 mg/kg cimetidine). Life-threatening reactions could not be tested in human subjects, but were elicited in experimental animals (dogs). In this species which resembles man in its sensitivity against histamine, in plasma histamine levels and in response to polygeline life-threatening reactions were prevented or in especially severe cases diminished to such an extent by the premedication with H1- + H2-blockers that this premedication was finally judged to be very effective against histamine-release responses of any grade of severity. To confirm this clinically very important hypothesis more clinical trials in patients at risk for anaphylactoid reactions to drugs are urgently needed.

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

Abstract: After withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days. Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.

The mesangium and glomerulonephritis

Abstract: The mesangium of the glomerular capillary ultrafilter is a specialized pericapillary tissue. In adult mammals its location is limited to the axial portions of the loop, but it extends peripherally to encircle the capillary in the fetal state and in certain glomerular diseases. It contains predominantly intrinsic mesangial cells, which resemble contractile endocytic capillary pericytes, and which are embedded in the extracellular matrix. In addition, the mesangial space normally harbors few resident Ia-antigen bearing, immune-competent cells and rare transient monocyte-macrophages. Due to its unique location between the fenestrated endothelial lining of the capillary lumen and the glomerular basement membrane, constituting the filtration barrier, the mesangium is prone to deposition of potentially noxious plasma constituents and filtration residues, such as phlogogenic foreign proteins and immune complexes. The determinants of the mesangial entry, uptake and removal of such materials are presently incompletely understood but they are thought to include the amount and nature of the deposit, local hemodynamic factors and the ability of the mesangium to degrade or to eliminate the deposited agent. Histopathologic studies of various human and experimental glomerular diseases reveal that increased mesangial cell proliferation and matrix widening may occur either in direct response to deposits or induced by mediators released from inflammatory cells, such as monocyte-macrophages. While the functional damage to the glomerular filter is usually mild when the reaction is limited to the mesangial space, it is more pronounced when the mesangial abnormalities are secondary to subendothelial deposits of the peripheral capillary wall. Recent experimental data indicate that a mesangial inability in removing deposited material may develop in certain chronic glomerular disorders characterized by marked proteinuria, glomerular hypertension and hyperfiltration or accumulation of matrix material. Such states of mesangial dysfunction may play a critical role in the pathogenesis of progressive glomerular sclerosis. It is concluded that better understanding of the pathophysiology of the mesangium would be valuable for designing more effective diagnostic and therapeutic approaches to patients with glomerular disease.

Measurement of chemiluminescence in freshly drawn human blood. II. Clinical application of zymosan-induced chemiluminescence.

Abstract: Summary. The aim of the present study was to investigate chemiluminescence (CL) of stimulated peripheral phagocytic cells (PC, i.e. granulocytes and monocytes) in patients with malignant disease at various stages. As a first step the zymosan-induced and luminol-amplified CL was determined in diluted whole blood samples from healthy volunteers. A characteristic daytime dependence of the CL activity was observed in six volunteers which had to be taken into account for blood sampling. The detectable CL was demonstrated to depend on the number of erythrocytes in the assay, but correction for this is not neccessary for clinical investigation. The specific CL activity (activity related to 10 3 PC, was significantly but identically increased both in 1) patients with acute inflammatory disease and 2) in patients with carcinoma. The total CL activity (activity/gl whole blood), however, was significantly increased in patients with acute inflammation as compared to the tumour~ group. This greatly reflects the leucocytosis of patients with acute inflammation. In a small number of patients with benign and malignant disease the CL of PC was measured both pre- and postoperatively. Operations in benign disease and palliative operations in malignancy did not influence the CL activity. In contrast, CL activity returned to normal after clinical cure by radical tumour resection.

In vivo microscopic studies of the responses of the liver to endotoxin.

Abstract: In vivo microscopic methods concomitant with electron microscopic and histochemical procedures are being used to explore the sequelae of responses of Kupffer cells and the hepatic microvasculature to endotoxins. To gain further insight into the role of the liver in host defense and nonspecific resistance, the effects of endotoxin also are being studied in animals sensitized to endotoxin (BCG infection) or tolerant to endotoxin (pretreated with detoxified endotoxin, low doses of endotoxin, or in C3H/HeJ mice). The results to date, have demonstrated that endotoxin induces significant alterations in the hepatic microcirculation due to swelling of Kupffer and endothelial cells and the adhesion of leukocytes and platelets to the sinusoid wall. Lymphocytes frequently are associated with the Kupffer cells. Phagocytosis also is affected; following a brief period of stimulation, the rate of phagocytosis by Kupffer cells is depressed. In BCG infected animals all of these responses are exaggerated but can be minimized by pretreatment with detoxified endotoxin or minute concentrations of endotoxin 24 h prior to the challenge dose of endotoxin. The responses are not seen in the endotoxin low-responder, C3H/HeJ mouse which was found to have a deficiency in lysosomal enzymes and a paucity of functional Kupffer cells. The results provide some insight into the sequelae of cellular and microvascular events that occur in the liver during endotoxemia, endotoxin-related host defense mechanisms and non-specific resistance. In addition, support is provided for the central role of Kupffer cells in these events and that lysosomal enzymes participate in the toxic response elicited by endotoxin.

Intracellular sodium and calcium in essential hypertension.

Abstract: Intracellular sodium and calcium activities were measured by ion-selective electrodes in red blood cells of primary hypertensives and of normotensives with and without a familial disposition to hypertension. Intraerythrocytic sodium activity was markedly elevated in patients and normotensives with a familial disposition to hypertension (15.16±2.35 mmol/l in hypertensives and 9.74±1.43 mmol/l in normotensives, respectively, mean value±sD) as compared to the corresponding group without such a history (8.35±2.08 mmol/l in hypertensives and 7.00±1.38 mmol/l in normotensives). Mean intraerythrocytic calcium activity showed the highest values in patients with hypertension (32.8±32.5 µmol/l in patients with and 25.3±19.0 µmol/l in those without a familial disposition to hypertension), whereas in normotensives mean calcium activity was much lower (9.6±9.7 and 4.8±4.5 µmol/l, respectively). Our results document that a disturbed intraerythrocytic sodium metabolism is limited to patients with essential hypertension and a familial disposition to hypertension and, to a lesser extent, to normotensives showing a familial disposition to hypertension. Thus, a genetically determined alteration in intracellular sodium can be assumed. Furthermore, the observation of an enhanced intraerythrocytic calcium in some essential hypertensives with and without a familial disposition suggests additional factors, other than sodium, responsible for the disturbed intracellular calcium balance in these patients.

Lipid A, the lipid component of bacterial lipopolysaccharides: relation of chemical structure to biological activity.

Abstract: Lipopolysaccharides are integral components of the outer membrane of Gram-negative bacteria and they participate in various membrane functions essential for bacterial growth and survival. Lipopolysaccharides also represent the endotoxins of Gram-negative bacteria and possibly play a role for the pathogenesis and manifestations of bacterial infections. These biological activities are mediated mainly by the lipid component of lipopolysaccharides, termed lipid A. Chemically, lipid A consists of a β1,6-linkedD-glucosamine disaccharide which carries substituted phosphoryl groups and a range ofD-3-hydroxy andD-3-acyloxyacyl residues, the latter being arranged in a hexagonal dense packing.

Plasma histamine levels in patients in the course of several standard operations: influence of anaesthesia, surgical trauma and blood transfusion.

Abstract: A prospective controlled clinical trial was conducted on changes in plasma histamine and catecholamine levels during 5 standard operations. This communication, as the first part of the trial, deals only with the feasibility of such a trial and the changes in plasma histamine levels. Elevated histamine concentrations corresponding to histamine-release responses of greater than 1 ng/ml occurred in 8 of 25 operations. In an explorative analysis these responses were associated with distinct phases of anaesthesia or the surgical procedure. Blood transfusion carried the risk of infusion of "free histamine" into the patient--especially when administered under pressure. Since during operations "free histamine" enters the circulation with a rather high incidence and may cause harmful effects, premedication with H1-+H2-receptor antagonists seems worth consideration.

H1-receptor antagonists: comparative pharmacology and clinical use.

Abstract: H1-antihistamines have been used in treatment of allergic disorders for more than 30 years. However, many of them have been employed in a less than systematic fashion. Most of the antihistamines show an apparent dual mechanism of action on isolated organs, consisting of a competitive and a non-competitive component. To induce non-competitive antagonism, higher concentrations are usually required, but for dimethindene the dose ratios for competitive and non-competitive activities differed only by less than one log unit. For therapeutic guidelines it should be considered that some antihistamines loose their effectiveness under long-term treatment and that patients may complain about the sedative side-effects. Thus, for maximum benefit it sometimes appears necessary to change the preparation before a choice for the individual dose is finally made. Under this condition they will cause relief from many allergic symptoms. Nevertheless, the classical antihistamines are without effect in bronchial asthma. The search for new drugs has been successful in this direction, as it has shown the antihistaminic/antiallergic drug Ketotifen to be able to prevent and control bronchial asthma. Many commercial preparations used in the treatment of common cold, vomitus or rhinitis contain an additive in combination with the antihistamines. Some of the additives appear to be of some value since they are used to reduce the side-effects of antihistamines. Secondary pharmacological properties of the antihistamines however provide also additional uses. This holds especially for effects on the CNS. Together with the search for the role played by histamine in the central cell-to-cell communication, new drugs might be found which will inhibit more selectively the action of histamine in the CNS.

Patients' immune response to breast and lung carcinoma-associated Thomsen-Friedenreich (T) specificity.

Abstract: We report here sensitive and specific measurement of immune responses of patients with certain kinds of carcinoma toward the physically and chemically well defined T antigen isolated from healthy human erythrocytes. Over 90% of adenocarcinoma tissues tested possess T-specific immunoreactive structures as determined withhuman antisera, in contrast to healthy tissues and benign lesions. Adenocarcinoma patients recognize the carcinoma-associated T antigen as foreign. Delayed-type skin hypersensitivity reaction to T antigen (DTHR-T) was positive in all 25 lung adenocarcinoma patients tested, in 88% of 101 patients with ductal, in 43% of 30 patients with lobular or tubular breast carcinoma and in 9/9 patients with adenocarcinoma of body cavities. Patients of all Stages reacted positively. All 7 patients with small cell lung carcinoma and 3/5 with malignant melanoma had a positive DTHR-T. None of 17 patients with malignant brain tumors, leukemia or Hodgkin's disease, sarcoma or thyroid carcinoma reacted. The DTHR-T was specific in that all 77 healthy persons and 48/49 with other diseases, including 23/24 with non-cancer lung disease were negative; one patient with organizing interstitial pneumonitis was positive. This points to a possible source of false positive reactions. 91% of 149 patients with histologically benign breast disease had a negative DTHR-T; the histology of some of the positive ones was reexamined, 2 proved to have carcinoma in situ.

Cardiovascular and respiratory mechanisms in anaphylactic and anaphylactoid shock reactions.

Abstract: Different mediators such as histamine, leukotrienes, prostaglandins and bradykinin are involved in different reaction mechanisms such as cytotropic anaphylaxis (CA), immune complex anaphylaxis (ICA), reactions due to direct histamine liberation or activation of the complement system or hyperosmolarity induced anaphylactoid reactions.

Dopamine treatment of human cadaver kidney graft recipients: a prospectively randomized trial.

Abstract: In a prospectively randomized trial, 50 human cadaver kidney graft recipients were tested for the effect of dopamine infusion on kidney function after transplantation. The kidneys were taken from beating-heart donors under optimal conditions. The dopamine infusion did not affect the dialysis frequency in the 1st week after transplantation, in the dopamine group only slightly better creatinine clearances could be detected. However, the diuresis increased significantly when dopamine was given and this resulted in the fact that in the dopamine group 47.4% of the patients were dialyzed although the diuresis amounted to more than 11/day as compared to 15.7% of such patients in the nondopamine group. These findings correspond to experimental data, which showed that the dopamine infusion of the recipient mainly ameliorated renal function in those cases where kidneys were taken after hypotensive injury of the donor.

Phenacetin abuse and malignant tumors

Abstract: The findings presented in this study are based on 29.226 autopsies performed (between 1953 and 1977) at Basel University on adult inhabitants of Basel, from which 409 urinary tract tumors (UTT) and 513 phenacetin abusers (PA) were discovered. There were 44 (8.6%) PA with UTT which, when compared with the control group (1.27%), represents a statistically significant increased incidence. Of the 50 UTT in PA, 52% occurred in the bladder, 6% in the ureter, and 42% in the renal pelvis. The induction time for tumors of the urinary bladder was about 27 years, and for tumors of the renal pelvis about 20 years. The commonest tumors arising in PA were invasive solid and non-invasive papillary urothelial carcinomas. PA with UTT died earlier than nonabusers but had metastases as frequently as nonabusers. Analgesic nephropathy was not always an accompanying disease. The daily dose of g/phenacetin in tumor patients in general, and in patients with tumors of the urinary bladder in particular, was about 1 g lower than in patients with analgesic nephropathy (without tumors) and in those with tumors of the renal pelvis. Thus, for the localization of the tumors, the daily dose seems to be more important than the total dose. Our investigation proved that not only tumors of the renal pelvis, but also of the ureter and the urinary bladder, are significantly more frequent in PA than in nonabusers. It is suspected that despite restriction of the over-the-counter sale of phenacetin-containing analgesics and even after stopping any analgesic abuse, UTT will further increase due to the longer induction time. Routine cytological screening tests of the urine are recommended for all known PA. A prescription for all phenacetin- and paracetamol-containing analgesics is necessary.

Histamine release by neuromuscular blocking agents in man.

Abstract: Several experimental and clinical studies have suggested that histamine is released following the administration of neuromuscular blocking agents, and that the histamine release is an important aspect in the hemodynamic response to the drug. We have measured plasma histamine following the administration of a series of neuromuscular blocking agents in man. Our data suggests that members of this class of drugs can cause a dose dependent release histamine release in man and that this release is hemodynamically significant. We have also evaluated the roles of rate of administration, of pretreatment with H1 and H2 antagonists and alterations in drug design as clinical strategies in attenuating the adverse reactions. The data obtained in humans can be shown to validate the cat model as a means of screening novel neuromuscular blocking agents.

Histamine release with intravenous narcotics: protective effects of H1 and H2-receptor antagonists.

Abstract: High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H1 and H2 antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml−p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m2−p<0.01) and decreases in\(\overline {BP} \) (88±4 to 61±4 torr−p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min−1p<0.01). The prior administration of H1 (dyphenhydramine 1 mg/kg) and H2 (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min−1−p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml−p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml−p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H1 and H2 histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.

Persistent protoporphyrinemia in hereditary porphobilinogen synthase (delta-aminolevulinic acid dehydrase) deficiency under low lead exposure. A new molecular basis for the pathogenesis of lead intoxication.

Abstract: For several years, a 4-12-fold increase of the upper normal limit in erythrocyte protoporphyrin concentrations persisted in two men 34 and 39 years of age who were chronically exposed to lead We are dealing with a zinc protoporphyrinemia in both cases, without lead intoxication or anemia The 34-year-old had been a regular blood donor for 10 years and had already been treated for iron deficiency several times Hemoglobin, red cell counts, hematocrit, and iron were at the lower normal limit The activity of porphobilinogen synthase (PBG-S), uroporphyrinogen-synthase and -decarboxylase as well as urinary porphyrin precursors and porphyrin excretion were normal Protoporphyrinemia was said to be due to a prelatent/latent iron deficiency In the 39-year-old, the activity of PBG-S was lowered to 388 mumol/1 h, as compared to the mean of controls (1,190 +/- 210, x +/- SD, n = 50), in connection with a slightly elevated excretion of delta-aminolevulinic acid and coproporphyrin in the urine and a high-normal blood lead level In his family there was no history of either a protoporphyrinemia or a hematological disturbance Six of eight family members in three generations showed a diminished activity of PBG-S: 600 +/- 160, P less than 0001 compared to controls These family members are heterozygous with regard to the PBG-S deficiency; they are clinically unobtrusive in comparison to homozygotes with an acute prophyria syndrome Activation by zinc and reactivation by dithiothreitol were normal in contrast to PBG-S from patients with lead intoxication The cause of biochemical symptoms of subclinical lead intoxication developed by the propositus is probably due to the hereditary PBG-S deficiency which sensitizes him to low-level lead exposure The determination of red cell PBG-S activity can be recommended as a test detecting heterozygotes The hereditary PBG-S deficiency is recognized as a new molecular basis for the pathogenesis of lead intoxication

Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects

Abstract: Responses of blood pressure and plasma catecholamines to intravenous injection of tyramine at increasing dosage (30, 45, and 60 µg/kg, respectively) were evaluated in 25 normal subjects and 20 patients with mild essential hypertension. Basal plasma norepinephrine and epinephrine concentrations before tyramine injections were similar in the two groups. Following tyramine injection, plasma epinephrine was unchanged. Responses of plasma catecholamines and blood pressure to tyramine were similar in the two groups. Plasma norepinephrine increased significantly 2 min after a dose of 30 µg/kg, but higher tyramine doses failed to produce a further increase in plasma norepinephrine. In contrast, pressor responses to tyramine were dose-dependent. Maximal pressor responses were observed within 2 min after injection. These findings reveal a dissociation between changes in blood pressure and plasma norepinephrine following injection of tyramine. Lack of steady state may limit the value of tyramine bolus injections as a tool for the quantitation of pressor responsiveness to variations in endogenous sympathetic output. Alternatively, it is possible that the pressor effects of tyramine may be mediated at least in part by a norepinephrine independent mechanism.

Interaction of Metoprolol, Propranolol and Atenolol With Concurrent Administration of Cimetidine

Abstract: Pharmacokinetics of metoprolol, propranolol, and atenolol were investigated in six healthy volunteers following 7 days of oral monotherapy with these drugs, and after 7 days concurrent administration of each of these betareceptor antagonists with cimetidine. Application of cimetidine did not lead to any interaction with atenolol, whereas mean peak plasma levels of metoprolol were increased by 70%, and those of propranolol by 95% due to concurrent administration of cimetidine (P<0.05). The plasma level time curve (AUC) of the two above-mentioned beta blockers behaved similarly (P<0.05). Other kinetic parameters of these two drugs were not influenced to a statistically significant extent by cimetidine, despite the tendency for the elimination half-life of metoprolol and propranolol to be prolonged when cimetidine is added. Measurement of exercise-induced tachycardia on the sixth day of administration showed no differences between monotherapy with the beta blockers and combined treatment with each of them together with cimetidine. Apart from one volunteer who complained of anxiety, weakness, and sweating on the sixth day of cimetidine/metoprolol administration, no adverse effects could be observed during the combination therapy with cimetidine and the beta blockers, nor during monotherapy with beta blockers.