Intravenous Injection Of High Doses Research Articles

Innate immunity to adenovirus: lessons from mice.

Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.

Improved Efficacy and Reduced Toxicity by Ultrasound-Guided Intrahepatic Injections of Helper-Dependent Adenoviral Vector in Gunn Rats

Crigler-Najjar syndrome type I is caused by mutations of the uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) gene resulting in life-threatening increase of serum bilirubin. Life-long correction of hyperbilirubinemia was previously shown with intravenous injection of high doses of a helper-dependent adenoviral (HDAd) vector expressing UGT1A1 in the Gunn rat, the animal model of Crigler-Najjar syndrome. However, such high vector doses can activate an acute and potentially lethal inflammatory response with elevated serum interleukin-6 (IL-6). To overcome this obstacle, we investigated safety and efficacy of direct injections of low HDAd doses delivered directly into the liver parenchyma of Gunn rats. Direct hepatic injections performed by either laparotomy or ultrasound-guided percutaneous injections were compared with the same doses given by intravenous injections. A greater reduction of hyperbilirubinemia and increased conjugated bilirubin in bile were achieved with 1 × 10(11) vp/kg by direct liver injections compared with intravenous injections. In sharp contrast to intravenous injections, direct hepatic injections neither raised serum IL-6 nor resulted in thrombocytopenia. In conclusion, ultrasound-guided percutaneous injection of HDAd vectors into liver parenchyma resulted in improved hepatocyte transduction and reduced toxicity compared with systemic injections and is clinically attractive for liver-directed gene therapy of Crigler-Najjar syndrome.

Effects of High Dose of Anisodamine on the Respiratory Function of Patients with Traumatic Acute Lung Injury

The objective of this study is to observe the effects of high dose of anisodamine in the respiratory function of patients with acute lung injury (ALI) induced by trauma. Fifty cases of patients with complicated ALI after trauma were randomly divided into the anisodamine treatment group (n = 26) and the conventional treatment group (n = 24). Intravenous injection of high dose of anisodamine was administrated in the anisodamine treatment group on the basis of conventional treatment. Acute lung injury scores, oxygenation index, PaO2, respiratory mechanic index, mechanical ventilation time, and the occurrence of adverse reactions in the two groups were observed. Acute lung injury scores and respiratory parameters were all significantly improved in the two groups of patients after the treatment (P < 0.05); compared with the conventional treatment group, the improvements of respiratory function in the anisodamine treatment group were more obvious (P < 0.05), the mechanical ventilation time was shorter (P < 0.05), and there was no significant adverse reaction. In conclusion, high dose of anisodamine contributed to improve the respiratory function of the patients with traumatic ALI.

Megadoses of Ascorbate as a New Chemotherapeutic Approach in Uveal Melanoma: A Preliminary In Vitro Investigation

Background: Despite the more recent advances, there is still no effective systemic therapy for Uveal Melanoma (UM). However, a better understanding of the role of oxidative stress in cancer, has more recently led to a completely new approach to the systemic therapy of cancer, and modulators of the oxidative balance, such as sodium ascorbate (ASC) or arsenic trioxide (ATO), have already entered advanced phases of preclinical and clinical development. Since high doses of ASC have already demonstrated a strong cytotoxic effect on different human cancer cell lines, we have undertaken the present investigation in order to test the sensitivity of OCM1 and C918 uveal melanoma (UM) cell lines to high doses of ASC, in vitro, as compared to ATO, a pro-oxidant drug which has already undergone extensive in vitro and pre-clinical investigation in UM. Methods: Both OCM1 and C918 UM cell lines have been exposed to increasing doses of either ASC or ATO, to build a dose-response curve around the peak plasma concentrations reached by both chemicals. The assessment of cell count and viability was performed with flow cytometry. Results: Both OCM1 and C918 UM cell lines are highly sensitive to ASC in the range of millimolar (mM) concentrations which can be usually reached by the intravenous injection of high doses of the compound. ATO at the dosages used in this study, never reached the LC50. When the exposure to ASC was reduced to two hours, it still had significant effects on survival of both OCM1 and C918 UM cells. Conclusions: This report shows that ASC is highly cytotoxic for both OCM1 and C918 UM cells, when used in high, pro-oxidant doses. To our knowledge, this is the first report showing that UM cells can be efficiently killed, in vitro, with high doses of ASC.

Extracorporeal Albumin Dialysis in Three Cases of Acute Calcium Channel Blocker Poisoning With Life-Threatening Refractory Cardiogenic Shock

We describe 3 patients admitted to the medical-surgical ICU in a university hospital with life-threatening cardiogenic shock after the ingestion of high doses of calcium channel blockers (8.4 g sustained-release diltiazem, 4.2 g sustained-release diltiazem, and 14.4 g slow-release verapamil). Cardiovascular failure and cardiac conduction disturbances were unresponsive to the usual therapy (eg, intravenous injection of high doses of calcium, glucagon, hyperinsulinemia-euglycemia therapy, fluid resuscitation) and to increasing doses of simultaneous infusions of adrenergic agonists. Albumin dialysis with Molecular Adsorbents Recirculating System (MARS) therapy was performed because of its unique ability to selectively remove from circulation protein-bound toxins (and potentially drugs) that are not cleared by conventional hemodialysis. A single procedure was successfully performed in each patient, which was followed by rapid weaning of adrenergic agonist agents and full recovery of the life-threatening cardiovascular failure. At 2-year follow-up, patients were asymptomatic. Albumin dialysis with MARS therapy may be effective when used as a rescue procedure in patients presenting with sustained, life-threatening cardiogenic shock as a result of massive calcium channel blocker poisoning.

Administration of dehydroepiandrosterone reverses the immune suppression induced by high dose antigen in mice.

Several factors including antigen concentration, the route of antigen administration, hormones and cytokines have shown to affect T cells to produce the distinct patterns of lymphokines which exert regulatory and effector functions of immune response. In this study, we asked whether administration of dehydroepiandrosterone (DHEA) to mice which were tolerized by high dose of antigen could modulate T cell functions to restore the suppressed cellular immune response and to produce the distinct lymphokines. An intravenous injection of high dose of sheep red blood cells induced suppression of delayed type hypersensitivity (DTH) and a single subcutaneous injection of the tolerant mice with DHEA restored the suppressed DTH response. Furthermore, in vitro treatment of spleen cells from tolerant mice with DHEA abolished the transfer of tolerance to naive recipients. Lymphocytes from the DHEA-treated tolerant mice produced more IFN-gamma and less IL-4 and IL-6 than the cells from tolerant animals without DHEA treatment. These findings indicate that DHEA could recover antigen-specific immune suppression by differentially affecting T cells to produce the distinct lymphokines.

Infectious hepatitis B virus from cloned DNA of known nucleotide sequence.

The infectivity of cloned hepatitis B viral DNA (HBV) has been tested in chimpanzees to identify a fully functional HBV genome and to assess the risk associated with its handling. Only one of two HBV DNA sequence variants tested was shown to be infectious. "Clone purified" virus of predicted nucleotide sequence was produced from the infectious HBV DNA, and the cloned viral genome was identical in structure with naturally occurring HBV. Infection could be initiated independent of whether circular monomeric or plasmid integrated dimeric forms of the viral genome were inoculated, but the infectivity of the DNA depended on liver cell transfection or intrahepatic injection. Intravenous injection of high doses of infectious HBV DNA did not induce hepatitis, suggesting that there is virtually no risk associated with routine laboratory handling of cloned HBV DNA.

Simultaneous mechanisms on exocrine pancreatic secretion initiated by alcohol in the conscious dog.

Modifications of pancreatic secretion induced by the infusion of alcohol were investigated in seven Thomas fistula dogs. Acute intravenous injections of low doses of alcohol induced a significant increase of all parameters of pancreatic secretion. On the contrary the acute intravenous injection of high doses of alcohol induced a significant decrease of pancreatic secretion. A prolonged-alcohol intravenous infusion producing a stable blood alcohol level provoked at first a decrease of pancreatic secretion, significant only for protein output, followed by a significant increase of all parameters of pancreatic secretion. A spontaneous return to prealcohol values of pancreatic secretion was observed in all cases even if the blood alcohol level remained high and stable and despite four hours of experimentation. Upon the background of a stable blood alcohol level, pentolinium did not suppress alcohol-induced stimulation of water and bicarbonate outputs but did abolish the postalcohol changes in protein secretion. Furthermore, atropine abolished all postalcohol changes in pancreatic secretion. Consequently, there are two responses (inhibition and stimulation) to alcohol which coexist in normal dogs. They are related to the blood alcohol levels and are transitory. These responses involve the vagus nerves. Alcohol appears to stimulate the exocrine pancreas through receptors at different levels of the nervous system.

Feline generalized epilepsy induced by tranexamic acid (AMCA).

Epileptic activities induced by topical application of tranexamic acid (AMCA) and penicillin to the cortex of 12 cats in acute experiments were compared. Both substances when diffusely applied on a wide cortical area of both hemispheres at very low concentration produced an EEG pattern consisting of spike-wave bursts similar to the electrographic manifestations seen in feline generalized epilepsy induced by large parenteral doses of sodium penicillin. These epileptic bursts could be triggered by repetitive stimulation of nucleus centralis medialis. Increased concentrations of both AMCA and penicillin led to the appearance of bilaterally synchronous spikes and poly-spikes which were not further excited by NCM stimulation. Two factors seem to play an important role in eliciting spike-wave bursts in both models: (1) the area of the cortex exposed to the epileptogenic agent and (2) the concentration of the epileptogenic agent used. The similar effects observed in 5 chronic animals either by intravenous injection of high doses of AMCA or by intramuscular injection of sodium penicillin confirm the results obtained in acute experiments and suggest a new way of inducing feline generalized epilepsy.

Cells capable of uptake of horseradish peroxidase in some circumventricular organs of the cat and rat.

The structure of mesenchymal cells distributed in some of the "hypendymal organs" of the circumventricular system in the cat and rat was demonstrated after intravenous injection of high doses of horseradish peroxidase. These cellular elements were observed in the vicinity of blood vessels of the organon vasculosum laminae terminalis, subfornical organ and area postrema. Electron-microscopically, these cells located between the basal laminae of the brain parenchyma and the blood capillaries show long cellular processes encircling fenestrated capillaries. Light- and electron-microscopic examination revealed that this cell type is identical with the "horseradish peroxidase-uptake cells,", previously reported in the vicinity of the hypophysial portal system. Such phagocytic cells may be considered as a cellular component intervening between the brain parenchyma and the blood stream, playing a role in selective barrier functions in the above-mentioned circumventricular organs where a blood-brain barrier in the classical sense of the definition is lacking.

Cefazolin: a valid model of experimental epilepsy?

In various animal species (chicks, rats and rabbits) the intravenous injection of high doses of cefazolin, a cephalosporin not hitherto reported to produce epileptic seizures, was found to produce epileptiform electrocortrical changes similar to those evoked by intravenous benzylpenicillin. Similar phenomena as those reported after systemic injection were also observed after microinjection of cefazolin into the III cerebral ventricle. In fact, both in chicks and rats cefazolin given by the latter route produced wild running crisis, myoclonic jerks of the limbs and in some instances generalized clonic convulsions. Concomitantly, bilateral electrocortical high voltage bursts of spikes were observed, followed during the intercritic period by periodic bilateral or unilateral single spikes.

The influence of prostaglandin metabolites on the uterine response to PGF 2α. A clinical and pharmacokinetic study

Prostaglandin F 2α (PGF 2α) is rapidly metabolized in the human body following exogenous administration. Three main metabolites have been isolated and identified: 15-keto-PGF 2α, 15-keto-13, 14-dihydro-PGF 2α and 13, 14-dihydro-PGF 2α. One of these metabolites, 13, 14-dihydro-PGF 2α, stimulated human uterine contractility during midpregnancy both following intravenous and intra-amniotic administration. The activity approaches that of the parent compound, PGF 2α. Since the concentration of the metabolites in peripheral serum during continuous intravenous infusion of PGF 2α is only slightly lower than that found for PGF 2α, it is likely that 13, 14-dihydro-PGF 2α is of importance for the stimulatory effect of PGF 2α on human uterine activity in vivo. Intravenous injection of high doses of 15-keto-13, 14-dihydro-PGF 2α (2–4 mg) slightly stimulated uterine contractility but most likely this effect was not due to the compound itself but to the formation of its metabolite, 13, 14-dihydro-PGF 2α.

A Low‐Dose Immunization Schedule for the Production of ALG in Rabbits.

ALG was produced in rabbits by intracutaneous injections of small doses (106 cells) of C3H mouse thymocytes suspended in Freund's incomplete adjuvant. The immunosuppressive potency of this ‘low‐dose’ ALG evaluated by allo‐skin graft survival proved to be comparable to that of ALG produced by intravenous injection of high doses of lymphoid cells (ad modum Levey &amp; Medawar). In addition the ‘low‐dose’ method gave rise to negligible amounts of haemagglutinins, lymphagglutinins, and lymphocytotoxic antibodies. The ‘low‐dose’ method may represent a major advantage in overcoming the limiting factor presented by scarcity of available antigen, which is regularly the case in human ALG production.