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M T Marino

Publications and source records attributed to M T Marino.

18 recordsLinked to original sources
PubMed2004

Effect of interleukin 8 and ICAM-1 on calcium-dependent outflow of K+ in erythrocytes from subjects with essential hypertension.

INTRODUCTION: The pathogenic mechanisms underlying the increase in peripheral resistance and the contraction of smooth muscular fibre cells in essential hypertension are not yet clearly understood. However, it is now known that immune system activation plays a role in the pathogenesis of some forms of arterial hypertension, and recent data show that the Ca2+ influx in some cells (i.e. red blood cells, leukocytes, platelets, smooth muscular fibre cells) is increased in subjects with essential hypertension, thus revealing a possible alteration in cellular membrane. The end-points of this study were therefore to ascertain whether red blood cells used as a cellular membrane model have a greater Ca2+ dependent K+ flow (Gardos effect) in hypertensive patients than in normotensive controls, to point out a different regulation of ionic channels, and whether IL-8 and the adhesion molecule ICAM-1 influence the membranous outflow. MATERIAL AND METHODS: The study was conducted on 87 Caucasian subjects. Of these, 50 (25 men, 25 women; mean age 43 +/- 3 years, mean body mass index (BMI) 27 +/- 0.5 and 22.3 +/- 0.3 kg/m(2), respectively) had mild-to-moderate hypertension (mean arterial blood pressure 120 +/- 8 mmHg ). The other 37 (18 men, 19 women; mean age 39 +/- 3 years; BMI 23.8 +/- 0.5 kg/m(2) and 22.8 +/- 0.5 kg/m(2), respectively were normotensive healthy volunteers (mean arterial blood pressure 89 +/- 2 mmHg). All the patients and subjects were untreated for at least 4 weeks before blood sampling. RESULTS: Ca2+-dependent K+ outflow was found to be greater in samples from patients with essential hypertension than in those from normotensive controls. lL-8 and ICAM-1 significantly enhanced the Ca2+-dependent K+ outflow in red blood cells from hypertensive subjects but had an inhibitory effect on cells from controls. In the experimental model, the presence of TMB-8, a membrane calcium antagonist, significantly reduced the Ca2+-dependent K+ efflux. CONCLUSION: Vasoconstriction in subjects with essential hypertension may therefore depend on a different regulation of ionic flow that probably supports an increased Ca2+ inflow in smooth muscle fibre cells. Under certain pathological conditions, some immune system components (i.e. interleukins, adhesion molecules) may directly enhance membrane permeability to Ca2+, thus inducing vasoconstriction in the smooth muscle cells.

Adult↗
PubMed2000

A reproducible nonlethal animal model for studying cyanide poisoning.

Previous studies using bolus intravenous injections of sodium cyanide have been used to model the sudden exposure to high concentrations of cyanide that could occur on the battlefield. This study was designed to develop a model that would simulate the type of exposure to cyanide gas that could happen during actual low-level continuous types of exposure and then compare it with the bolus model. Cardiovascular and respiratory recordings taken from anesthetized dogs have been used previously to characterize the lethal effects of cyanide. The intravenous, bolus injection of 2.5 mg/kg sodium cyanide provides a model in which a greater than lethal concentration is attained. In contrast, our model uses a slow, intravenous infusion of cyanide to titrate each animal to its own inherent end point, which coincides with the amount of cyanide needed to induce death through respiratory arrest. In this model, therapeutic intervention can be used to restore respiration and allow for the complete recovery of the animals. After recovery, the same animal can be given a second infusion of cyanide, followed again by treatment and recovery, providing a reproducible end point. This end point can then be expressed as the total amount of cyanide per body weight (mg/kg) required to kill. In this study, the average dose of sodium cyanide among 12 animals was 1.21 mg/kg, which is approximately half the cyanide used in the bolus model. Thus, titration to respiratory arrest followed by resuscitation provides a repetitive-use animal model that can be used to test the efficacy of various forms of pretreatment and/or therapy without the loss of a single animal.

Acute Disease↗
PubMed1999

Does captopril have a direct pro-apoptotic effect?

The beneficial effect of ACE inhibitors on cardiovascular remodelling from hypertension and ischemic disease may be due to the effect of these drugs on the proliferation/cell death balance. We therefore investigated the effect of the addition of captopril in vitro, on the onset of apoptosis in human vascular myocytes, by using a propidium iodide fluorescence analysis and a morphological analysis using the acridine orange technique. Captopril (0.23 mM) caused an increase in apoptotic phenomena that was more than 3. 5-fold than in controls both at the 24th (7.7 vs. 2%) and the 48th h (10.1 vs. 3.8%). The addition of propranolol strengthened the effect on apoptosis. The induction of apoptotic phenomena may be a mechanism by which ACE inhibitors affect cardiovascular remodelling and it might also explain the favorable effect these drugs have on diseases such as IgA nephropathy and diabetic nephropathy.

Adrenergic beta-Antagonists↗
PubMed1998

High-performance liquid chromatographic determination of N-[2-(hydroxyethyl)-N-(2-(7-guaninyl)ethyl)]methylamine, a reaction product between nitrogen mustard and DNA and its application to biological samples.

Nitrogen mustard (HN2) is a bifunctional alkylating agent which is thought to cause cytotoxicity by covalently binding to DNA. Most studies to date have looked at qualitatively determining the presence of DNA-HN2 adducts from reactions with native DNA. The adduct which is predominately formed in these reactions is N-[2-(hydroxyethyl)-N-(2-(7-guaninyl)ethyl]methylamine (N7G). A simple and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method for the determination of N7G from DNA using ultraviolet detection is described. DNA samples having been exposed to HN2 treatment were hydrolyzed and preseparated from high-molecular-mass material by filtration using a molecular mass cut-off of 3000. The mobile phase consisted of methanol-26 mM ammonium formate, pH 6.5 (24:76, v/v). N7G, as well as the internal standard, methoxyphenol, were separated within 30 min. The recovery of N7G after hydrolysis of the DNA reaction product was quantitative and limits of detection and quantification of 10 and 20 ng/ml, respectively, were calculated. The method was validated in DNA-HN2 dose response experiments. The N7G reaction product appears to be the first reaction product formed at lower ratios of HN2/DNA but its production plateaus at higher ratios of HN2/DNA probably due to increased formation of hitherto unknown adducts. The method is simple and sensitive and for this reason, may be suited for the determination of DNA/HN2 reaction products.

Animals↗
PubMed1998

Population pharmacokinetics and pharmacodynamics of pyridostigmine bromide for prophylaxis against nerve agents in humans.

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3-week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed-effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two-compartment open model with first-order absorption, a lag time, and first-order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition > 10% at the time of the trough.

Acetylcholinesterase↗
PubMed1998

Use of surrogate markers for drugs of military importance.

In the future, U.S. military forces will be faced with opposing forces that have chemical and biological weapon capabilities. Although drugs used against these agents would be an ideal solution to protecting soldiers, the ability to test their efficacy in humans is limited by several ethical and technical problems: (1) the high risk of toxicity to volunteers; (2) the risk of delayed side effects in the volunteers; and (3) the inability to extrapolate effects against sublethal doses to efficacy against lethal doses. The Food and Drug Administration (FDA) relies on safety and efficacy data in humans, making approval for these types of drugs difficult. An alternative approach for regulatory approval would be to use surrogate markers. Surrogate markers are biochemical or physiologic measurements that demonstrate the direct effect of the drug. Surrogate markers, such as CD4 counts and viral RNA levels, have been used recently in the anti-human immunodeficiency virus drug approval process with success. A drug development program using surrogate markers must meet several criteria, including demonstrated efficacy in animal models, correlation between efficacy and the surrogate marker, a link between the surrogate marker and the pathophysiology and toxicologic effects of the agent, and the ability to produce the surrogate marker in humans. This article illustrates the use of drug-induced methemoglobin as a surrogate marker for protection against cyanide intoxication. Safety issues regarding this class of drugs would also have to be pursued aggressively during and after their use by military forces. Demonstrating that the drug satisfies these criteria would be a platform for approval by the FDA. The guidelines mentioned above should be an acceptable approach for FDA approval, scientific researchers, medical practitioners, and the soldiers using these drugs.

Biomarkers↗
PubMed1997

Pharmacokinetics and kinetic-dynamic modelling of aminophenones as methaemoglobin formers.

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations. The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid Emax pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a 'first-pass' activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h. Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.

Administration, Oral↗
PubMed1997

Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h. PATIENTS AND METHODS: 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. RESULTS: At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71). CONCLUSION: Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.

Adult↗
PubMed1996

Mefloquine effect on disposition of halofantrine in the isolated perfused rat liver.

Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine. Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean +/- s.d.) were: volume of distribution (Vd), 7.53 +/- 1.45 mL (g liver)-1; clearance (CL), 0.11 +/- 0.07 mL min-1 (g liver)-1; initial distribution half-life (initial t1/2), 14.62 +/- 2.38 min; terminal half-life (terminal t1/2), 138.7 +/- 178.8 min; AUC 606 +/- 194 mg mL-1 min-1 (g liver)-1; elimination rate constant (Ke), 0.0135 +/- 0.012 min-1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P > 0.05). A single dose, short term (4-6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefloquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 0.05) and biliary clearance (P < 0.05) of halofantrine in mefloquine-pretreated livers. These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.

Animals↗
PubMed1993

High-performance liquid chromatographic method for the determination of a candidate 8-aminoquinoline antimalarial drug (WR 242511) using oxidative electrochemical detection.

WR 242511 (or I) is a new compound of the 8-aminoquinoline class designed to replace primaquine for the treatment of malaria. In order to perform preclinical and clinical testing, an assay was needed to determine drug levels in plasma samples. A simple and reliable reversed-phase high-performance liquid chromatographic (HPLC) method for the measurement of I in plasma using oxidative electrochemical detection is described. A 250-microliters plasma sample containing WR 256408 (or II) as internal standard was extracted with tert.-butyl methyl ether-2-propanol. A 25-microliters aliquot of the extractant was used for HPLC analysis. The mobile phase was 50:50 acetonitrile-sodium acetate (50 mM, pH 6) with 1 mM EDTA. Compounds I and II were separated within 10 min. The limit of detection for I was 10 ng/ml (plasma) with a recovery around 72%. The method was validated in a dog experiment where levels were followed for 48 h. The method is sensitive and robust and can be used for routine drug analysis during pharmacokinetic studies.

Animals↗
PubMed1993

Hypercalcaemia and elevated levels of parathyroid hormone-related protein in cutaneous squamous/basal cell carcinoma.

A patient with mixed squamous/basal cell carcinoma of the skin presented with hypercalcaemia and elevated serum levels of parathyroid hormone-related protein (PTH-rP). The tumour was resected, PTH-rP levels declined and the patient became normocalcaemic. This is the first case to associate squamous cell carcinoma of the skin with hypercalcaemia and significant levels of PTH-rP.

Aged↗
PubMed1990

Mees' lines.

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Aged↗
PubMed1986

Calcium induced potassium efflux in erythrocytes of marine teleosts.

The effect of the calcium-ionophore A23187+ Ca++ on the K+ transport in the intact erythrocytes of sea-water fishes was investigated. A23187+ Ca++ induced a significant increase in the cell-membrane permeability for potassium ion, while A23187+ Mg++ was ineffective. Addition of EGTA to the medium blocked the ionophore+ Ca++ effect. Quinidine inhibited the A23187+ Ca++-induced K+ transport in the nucleated fish red cell. Propranolol is effective in the fish RBC in presence of Ca++ and EGTA. The relationship of the calcium-induced alkali cation transport in nucleated red cell to that in human red cell is discussed.

Animals↗
PubMedDate not supplied

Pharmacokinetics and kinetic-dynamic modeling of an 8-aminoquinoline candidate anticyanide and antimalarial drug (WR242511).

Malaria is a major cause of health problems in a large portion of the world. The 8-aminoquinoline compound, primaquine, is one of the only compounds useful for relapses of Plasmodium vivax and Plasmodium ovale malaria. Primaquine has several toxicities that include methemoglobinemia and hemolytic anemia. The induction of methemoglobinemia is a treatment for cyanide poisoning. We studied the pharmacokinetics and pharmacodynamics (percentage methemoglobin) for WR242511, an 8-aminoquinoline primaquine replacement and potential anticyanide compound. The drug's pharmacokinetics and pharmacodynamics are described for oral and intravenous dosing, and two kinetic-pharmacodynamic models are shown to describe the single dose data. A significant lag occurs between the onset of appearance of drug in the plasma and the onset of methemoglobinemia. Peak drug concentrations occurred within 4 hr for oral dosing, and peak effect (percentage methemoglobin) did not occur for 72-96 hrs for both the oral and intravenous routes. Elimination half-life for the drug was 30 +/- 14 hr. Two kinetic-dynamic models, one with an effect compartment relating drug concentration to effect and one with metabolite causing a first-order conversion of hemoglobin to methemoglobin, are compared as to their ability to predict multiple dose pharmacokinetics and pharmacodynamics. Both models were useful in predicting drug concentrations and methemoglobin levels for multiple-dose experiments.

Administration, Oral↗