Hepatic and cerebral coenzyme A contents after intravenous injection of coenzyme A in rats

Hepatic CoA concentrations and contents were significantly higher in rats having received i.v. CoA injections that in control rats. Maximum hepatic CoA concentrations were found 0.5-1 h after injection. In rat brain, no increase in CoA concentration was detected after i.v. injection of CoA.     

Trauma, dextran 40 and metastasis formation after intravenous tumour cell injection in rats

Dextran 40 did not influence the formation of pulmonary metastases after intravenous tumour cell injection in untraumatized dextran non-sensitive Wistar rats. Trauma significantly increased the formation of metastases and treatment with dextran 40 enhanced this effect of trauma markedly. No definite explanation of the effect of dextran 40 on pulmonary metastasis formation when combined when trauma can be offered, but possible mechanisms are discussed.     

Structural and biochemical changes in lungs of 3-methylindole-treated rats

This study compared co-amoxiclav, vancomycin and teicoplanin with and without netilmicin or amikacin for treating experimental subcutaneous fibrin-clot infection in rabbits due to a clinical beta-lactamase-positive methicillin- and gentamicin-resistant Staphylococcus epidermidis strain (MGRSE). MICs (mg/L) for this strain were: oxacillin 125, gentamicin 32, vancomycin 4, teicoplanin 8, netilmicin 1, amikacin 4, amoxycillin 64 with clavulanate at 2 mg/L. In rabbits treated with a single-dose i.v. regimen (netilmicin 8 mg/kg, amikacin 20 mg/kg, vancomycin 30 mg/kg, teicoplanin 15 mg/kg, co-amoxiclav 150-30 mg/kg), the bacterial count 24 h post-dose was reduced whatever the combination used (ANOVA, P < or = 0.001). Regimens were statistically classified in decreasing order of efficacy as follows: co-amoxiclav combined with netilmicin > vancomycin either alone or combined with either netilmicin or amikacin, teicoplanin with netilmicin > netilmicin and co-amoxiclav alone > teicoplanin or co-amoxiclav combined with amikacin, and teicoplanin alone > amikacin > no drug. From these findings, it is concluded that: co-amoxiclav could be useful for the treatment of beta-lactamase-positive and methicillin-resistant S. epidermidis infection; some enzyme-resistant aminoglycoside could be considered for treating gentamicin-resistant but netilmicin/amikacin-sensitive S. epidermidis infection; the combination of co-amoxiclav with netilmicin was synergistic and more rapidly bactericidal than vancomycin in this animal model.     

Pharmacologic intolerance reaction after intravenous injection of pethidine

We report on anaphylactoid reactions (urticae at the injection site and along the injection vein) after intravenous injections of pethidine in two patients. Skin tests with pethidine were negative, but intravenous challenge showed urticae. These results indicate that the reactions were due to a non-immunological mechanism resembling pharmacological intolerance. Retrospective analysis revealed a 5.6% incidence of pharmacological intolerance reactions to intravenous pethidine in 519 patients.     

Pulmonary chemoreflexes elicited by intravenous injection of lactic acid in anesthetized rats

Experiments were carried out to characterize the cardiorespiratory reflex responses to intravenous injection of lactic acid and to determine the involvement of vagal bronchopulmonary C-fiber afferents in eliciting these responses in anesthetized rats. Bolus injection of lactic acid (0.2 mmol/kg i.v.) immediately elicited apnea, bradycardia, and hypotension, which were then followed by a sustained hyperpnea. The immediate apneic and bradycardiac responses to lactic acid were completely abolished by bilateral vagotomy and were absent when the same dose of lactic acid was injected into the left ventricle. The subsequent hyperpneic response was substantially attenuated by denervation of carotid body chemoreceptors. After a perineural capsaicin treatment of both vagus nerves to block the conduction of C fibers, lactic acid no longer evoked the immediate apnea and bradycardia, whereas the hyperpneic response became more pronounced and sustained, presumably because of the removal of the inhibitory effect on breathing mediated by pulmonary C-fiber activation. Single-unit electrophysiological recording showed that intravenous injection of lactic acid consistently evoked an abrupt and intense burst of discharge from the vagal C-fiber afferent endings in the lungs. In conclusion, the cardiorespiratory depressor responses induced by lactic acid are predominantly elicited by activation of vagal pulmonary C fibers.     

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

We previously developed the "immunogene" approach toward cancer gene therapy using epidermal growth factor receptor (EGFR)-mediated endocytosis. Here, we describe an improved immunogene system, in which the antigen-binding (Fab) fragments of the monoclonal antibody (Ab) B4G7 against the human EGFR were conjugated with poly-L-lysine to form a gene delivery vehicle (designated Fab "immunoporter"). Within 12 hours, the beta-galactosidase beta-gal) gene was transferred via the Fab immunoporter to virtually all of the nuclei of human squamous carcinoma A431 cells that overproduce the EGFR, and the beta-gal enzyme activity was detected within 24 hours and retained for more than 3 days. The beta-gal gene was not transferred into human and mouse cells that were deficient in EGFRs, but it was delivered if those mouse cells were transformed with human EGFR genes. Beta-gal gene transfer via the Fab immunoporter was inhibited by pretreatment with excess amounts of the Fab fragment. The transfer efficiency of the beta-gal gene to A431 cells via the Fab immunoporter was approximately 2%, which is as high as the lipofection method and 20- to 100-fold higher than the whole Ab immunoporter. The transfer of the herpes simplex virus thymidine kinase gene into A431 tumor cells as a form of the thymidine kinase/Fab immunogene was successful, and subsequent treatment with ganciclovir induced remarkable suicide effects which conferred 1000-fold higher drug sensitivity. Thus, the Fab immunogene was substantially improved with regard to the whole Ab immunogene and could be used as a potent gene transfer vehicle for the in vivo targeting of EGFR-hyperproducing tumor cells.     

Metabolic changes of acetaminophen after intravenous administration to rats pretreated with a hepatoprotective agent, YH-439

Sanford et al. (Int. J. Radiat. Biol. 55, 963-981, 1989) have reported that G2-phase cells from many heritable cancer-prone conditions exhibit higher yields of X-ray-induced chromosome damage than those found in the majority of healthy controls. We have applied their protocol to lymphocytes of a group of control and cancer-prone individuals to see if we could confirm these observations. For control donors we observed higher aberration yields, different kinetics and more interexperiment variability than found by Sanford et al. These differences could not be attributed to unavoidable minor variations in procedures (e.g. serum batches, glassware washing methods), but the difference in X-ray qualities used in the two laboratories may have made a small contribution to the discrepancies. We attribute some of our experimental variability to the fact that, to varying extents in different experiments, centrifugation of cells prior to irradiation can slow down the progression of cells into metaphase and that cells can continue to repair during the harvesting procedure (centrifugation and hypotonic treatment). We have applied the assay to cases of ataxia telangiectasia (AT, homozygotes and heterozygotes), xeroderma pigmentosum (homozygotes and heterozygotes), familial adenomatous polyposis and the syndromes Li-Fraumeni, basal cell nevus, Down's and Fanconi's but have been unable to discriminate between these groups and controls except for AT homozygotes. By including a control sample in parallel with samples from cancer-prone groups we found a significant difference in mean aberration yields between controls and AT homozygotes and heterozygotes, but not for the other groups. Since technical features could explain the discrepancies between our laboratories, we have devised our own G2-phase assay which appears to be giving promising results.     

Intestinal zinc absorption after intravenous zinc injection in various amounts and after various time intervals

Beta-hydroxypropionitrile (beta-HPN) was incorporated in the drinking water of rats in order to define the toxicological effects associated with repeated daily exposure to this compound. Parameters evaluated were appearance and demeanor, mortality, body weight, food consumption, water consumption, hematology, terminal organ weights and organ to body weight ratio, and gross and microscopic pathology of tissues. No untoward effects were associated with the ingestion of beta-HPN at the dose levels utilized.     

Functional changes after segmental and lobar resections of the lungs at remote periods of observation

Clinico-roentgenological and functional studies were carried out in 78 patients 2--12 years following segmental (42 patients) and lobar (3) pneumonectomies for tuberculosis. An analysis of the data obtained indicated that partial pneumonectomies within the boundaries of 1-5 segments per se fail to produce significant disorders in the ventilatory and gas metabolism function of the lung. 2-12 years after the operation the patients show considerable ventilatory reserves. Significant respiratory disorders are observed only in patients with postoperative complications and pathological changes in the lung, pleura and bronchi conditioned by tuberculosis and non-specific lung pathology.     

Bupivacaine-induced seizure after accidental intravenous injection, a complication of epidural anesthesia

A technique is presented to eliminate the residual gradient more completely after removing the main pulmonary band at the time of primary repair of ventricular septal defect. The band and underlying pulmonary artery are circumferentially excised, except for a small posterior part, and pulmonary artery is reanastomosed.     

Structural changes in the tissues of white rats after capsaicin administration

Attitudes to health and illness may differ between rural and urban dwellers. Issues that may relate to the provision of health services to rural dwellers are raised for consideration. The response of urban dwellers to illness or disability has often been linked to discomfort caused by pain or cosmetic attractiveness, while for rural dwellers the response to illness or disability is often related to the degree to which the illness or disability affects productivity. Often the rural resident will postpone seeking medical or associated services until it is economically or socially convenient. The notion of exposing their private lives to strangers or acquaintances from the local based services or to undertake the journey to distant services where the cultural or behavioural differences could be misunderstood, may impact on rural dwellers' well-being. Health service providers in rural areas need to understand such differences and difficulties when offering services.     

Accidental administration of racemic adrenaline. Three life-threatening cases after intravenous injection in children

The inhalation of racemic adrenalin is an important part of the treatment of inflammatory airway obstruction in children. In Norway during the last few years there have been several cases of adrenal solutions intended only for inhalation being accidentally administered as intravenous injections. The solution for inhalation contains an adrenalin concentration 110 times greater than the adrenalin intended for emergency use (0.1 mg/ml). The instant consequences of intravenous injections of inhalation adrenalin include arterial hypertension followed by hypotension, cardiac ischemia and cardiac insufficiency, pulmonary oedema, and respiratory failure and the need for artificial ventilation. The clinical picture in the three patients we describe was very dramatic. The injected doses were 0.16-1.1 mg l-adrenalin per kg body weight. All children survived without sequelae. In order to reduce the risk of accidentally administering intravenous injections of adrenalin intended for inhalation a set of guidelines is being proposed.     

Pulmonary function changes after nebulised and intravenous frusemide in ventilated premature infants

AIMS: To compare the effects of a single dose of frusemide administered either intravenously or by nebulisation on pulmonary mechanics in premature infants with evolving chronic lung disease. METHODS: The effect of frusemide on pulmonary mechanics was studied at a median postnatal age of 23 (range 14-52) days in 19 premature infants at 24 to 30 weeks gestational age, who had been dependent on mechanical ventilation since birth. Frusemide (1 mg/kg/body weight) was administered, in random order, intravenously and by nebulisation, on two separate occasions 24 hours apart. Pulmonary function studies were performed before and at 30, 60, and 120 minutes after administration of frusemide. Urine was collected for six hours immediately before and for six hours after administration of frusemide. RESULTS: Nebulised frusemide increased the tidal volume 31 (SE 11.5)% and compliance 34 (SE 12)% after two hours, whereas no change in either was noted for up to two hours after intravenous frusemide administration. Neither intravenous nor nebulised frusemide had any effect on airway resistance. Six hour urine output increased from a mean (SE) of 3.3 (0.4) ml/kg/hour to 5.9 (0.8) ml/kg/hour following intravenous frusemide administration while nebulised frusemide had no effect on urine output. Urinary sodium, potassium, and chloride losses were also significantly higher after intravenous frusemide, whereas nebulised frusemide did not increase urinary electrolyte losses. CONCLUSION: Single dose nebulised frusemide improves pulmonary function in premature infants with evolving chronic lung disease without adverse effects on fluid and electrolyte balance.     

Cardiorespiratory and electrolytic changes in status asthmaticus after intravenous administration of magnesium sulfate

The authors studied cardiorespiratory effects of MgSO4 infusion in 30 randomized patients with status asthmaticus. They found, that after having the drug administered, values of VC, FEV1, FIV1, PaO2 and pH increased, the respiratory and heart rate, diastolic blood pressure reduced. Other ventilation, blood gas and ECG parameters were unchanged. Among the electrolytes, serum Ca2+ level has reduced, both plasma and intracellular Mg2+ concentrations increased. It is apparent from the results, that broncholytical ability of MgSO4 given in therapeutical dose i.v. does not reach the level of beta-stimulating agents. However, this completed with the cardioprotective, sedative effect as well as more advantageous ion-distribution, influences favourably the asthmatic dyspnoea.     

Hematopoietic changes in rats after inescapable and escapable shocks

The key hypothesis of the study was that hospital pharmacies under the pressure of managed care would be more likely to adopt process innovations to assure less costly and more cost-effective provision of care. We conducted a survey of 103 hospitals and analyzed secondary data on cost and staffing. Compared to the size of the reduction in length of stay, changes in the way that a day of care is delivered appear to be minor, even in areas with substantial managed care share. The vast majority of hospitals surveyed had implemented some form of therapeutic interchange and generic substitution. Most hospitals used some drug utilization guidelines, but as of mid 1995 these were not yet important management tools for hospital pharmacies. To our knowledge, ours was the first survey to investigate the link between hospital formularies and use of cost-effectiveness analysis. At most cost-effectiveness was a minor tool in pharmaceutical decision making in hospitals at present. We could determine no differences in use of such analyses by managed care market share in the hospital's market share. One impediment to the use of cost-effectiveness studies was the lack of timeliness of studies. Other stated reasons for not using cost-effectiveness analysis more often were: lack of information on hospitalized patients and hence on the potential cost offsets accruing to the hospital: lack of independent sponsorship, and inadequate expertise in economic evaluation.     

Vascular and glomerular changes in the ageing kidney

Glomerular size, shape and number were examined in 44 human kidneys obtained at necropsy. Intrarenal vascular appearances were assessed histologically and by post-mortem angiography. The mean cross-sectional area of glomeruli varied nearly three-fold and glomerular number varied more than three-fold when kidneys from different adult subjects were compared but kidneys from the same subject resembled one another in glomerular size and number. A significant negative correlation existed in the adult between glomerular number and dimensions. Glomerular numbers in the few immature kidneys studied were similar to those in adult kidneys but glomeruli were smaller. Glomerular numbers tended to decline as age and severity of age-related vascular changes increased but correlation was poor. The possibility remains that glomerular involution in the senescent kidney occurs independently of events in the vessels. In men, but not in women, totally hyalinised glomeruli were observed more frequently with increasing age but their presence did not appear to be related to the degree of vascular change. In the senescent kidney, glomerular lobulations tended to disappear. This, together with glomerular loss, must result in a reduction in the area available for filtration. Assessments of total glomerular surface area should take account of glomerular shape and dimensions as well as numbers.     

Tumor accumulation of poly(vinyl alcohol) of different sizes after intravenous injection

The body distribution and tumor accumulation of polymers were evaluated using poly(vinyl alcohol) (PVA) which has the simplest chemical structure among water-soluble polymers, similar to poly(ethylene glycol). To study the effect of polymer size on the tumor accumulation, we used not only water-soluble PVA with different molecular weights but also PVA microgels prepared through gamma-irradiation of aqueous PVA solutions. The PVA specimens in the aqueous solution were intravenously injected to mice carrying a tumor mass at their footpad. Both types of PVA (water-soluble and microgel) of larger size were retained in the blood circulation for longer time periods and excreted more slowly from the kidney than those of smaller size. The plasma half-life period of PVA became longer with increasing size both for the water-soluble and microgel PVA, indicating that the body fate of PVA is governed only by the size. Both the water-soluble PVA and PVA microgels were accumulated in tumor tissue to a significantly greater extent than in normal tissue. The size dependence of the plasma half-life period and tumor accumulation was similar between the water-soluble PVA and the PVA microgels and the tumor accumulation became maximum around the size of 60 nm both for water-soluble and microgel PVA. A pharmacokinetical study demonstrated that the tumor uptake rate index of PVA decreased with the increase in PVA size. On the other hand, the greater the size, the larger the value of the area under the blood concentration-time curve (AUC). In addition, the PVA around 60 nm in diameter showed the smallest liver clearance. It was concluded that the balance between the uptake rate and the AUC as well as the liver clearance resulted in the maximum accumulation of PVA with the size of 60 nm.