RESUMEN
AIM: Non-stent-based immediate release formulations of paclitaxel have been shown to reduce in-stent restenosis in animal experiments and clinical trials. In the porcine overstretch model paclitaxel dissolved in the contrast medium iopromide inhibited neointimal proliferation in a dose-dependent manner after intracoronary injection and was well tolerated. METHODS: As a first step entering clinical development, a phase I trial was performed using four ascending paclitaxel dose/concentration levels: samples of up to 100 mL of the contrast medium (iopromide) containing 10, 50, 100 or 200 µM paclitaxel or iopromide (controls) were randomly administered to patients assigned to bare metal stent implantation for single de novo coronary artery lesions. Safety variables, tolerability and angiographic parameters were assessed. RESULTS: Adverse events, ECG, systolic and diastolic blood pressure, left ventricular ejection fraction, leukocyte count, other hematological or clinical chemistry data did not reveal any trend which could be related to the study medication. Short-lasting serum paclitaxel concentrations remained significantly below those known from cancer therapy. Angiographic late lumen loss was 0.72±0.50 mm (N.=7) in controls versus 0.45±0.65 mm (N.=17) in all paclitaxel-treated patients; binary restenosis rate was 5/7(63%) versus 6/17 (35%) and target lesion revascularization rate was 4/8 (50%) versus 4/24 (17%). CONCLUSION: Intracoronary infusion of paclitaxel dissolved in an X-ray contrast medium was well tolerated. The results show restenosis inhibition, but the number of patients examined was too small to demonstrate a statistically significant inhibition.
Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Medios de Contraste/administración & dosificación , Reestenosis Coronaria/tratamiento farmacológico , Yohexol/análogos & derivados , Paclitaxel/administración & dosificación , Stents , Anciano , Algoritmos , Cateterismo Cardíaco/métodos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/terapia , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/terapia , Método Doble Ciego , Femenino , Alemania , Humanos , Inyecciones Intraarteriales , Yohexol/administración & dosificación , Masculino , Persona de Mediana Edad , Proyectos Piloto , Recurrencia , Stents/efectos adversos , Resultado del TratamientoRESUMEN
The use of drug-coated balloons (DCB) for preventing restenosis in both coronary and peripheral arteries has received increasing attention. The first successful clinical outcomes in inhibiting restenosis have been reported for paclitaxel-coated balloons. Paclitaxel is a lipophilic substance characterized by rapid intracellular uptake and irreversible binding to microtubules. In this way, paclitaxel alters the cell structure, ultimately reducing proliferation, migration, and signaling. These properties make paclitaxel a very potent antiproliferative drug. Paclitaxel admixed to a small amount of the hydrophilic X-ray contrast medium iopromide (Ultravist™) emerged as a very effective coating matrix from numerous in vitro and in vivo experiments and has been denoted as Paccocath™. The randomized controlled ISR I/II-, Thunder- and FEMPAC studies have been conducted using Paccocath™ balloons. Late lumen loss as the primary endpoint at 6 months proved to be statistically significantly reduced in the coated balloon groups in coronary and peripheral arteries. The slightly modified coating on the SeQuent™ Please balloons (B.Braun, Melsungen, Germany) has been clinically studied in the PEPCAD (Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease) clinical trial program. Cotavance™ balloons (MEDRAD Inc, Minneapolis, USA) are also coated with the Paccocath™ formulation. In this review we first outline the development of Paccocath™ balloons to then provide an overview of the clinical results obtained with the modified coating. Furthermore we examine possible mechanism of action by which single administration of an antiproliferative drug dose using paclitaxel-coated balloons inhibits restenosis.
Asunto(s)
Arteriopatías Oclusivas/terapia , Cateterismo/instrumentación , Estenosis Coronaria/terapia , Paclitaxel/administración & dosificación , Constricción Patológica/terapia , Diseño de Equipo , HumanosRESUMEN
During the last decades considerable advances have been made in intravascular interventions for the treatment of coronary and peripheral arterial disease. However, long-term outcome remains an area of concern in many applications. Restenosis is still a challenge in endovascular medicine and has thus been referred to as the Achilles' heel of percutaneous intervention. Therefore, novel strategies have been developed to overcome this problem. These include drug-eluting stents, though still associated with stent thrombosis and in-stent restenosis, and the more recently introduced non-stent based local drug delivery systems, especially the paclitaxel-eluting balloon. Results of several preclinical and clinical studies indicate that short-term exposure of injured arteries to paclitaxel eluted from regular PTA and PTCA balloons may be sufficient to reduce late lumen loss and restenosis rates during a critical period of time after angioplasty of diseased coronary and peripheral arteries. Although the number of published trials and patients treated is still limited, available data seem to prove that restenosis inhibition by immediate drug release is feasible. This article reviews the rationale for the use of paclitaxel-coated balloons, data from preclinical and clinical studies, and the perspective of drug-coated balloons in peripheral arterial disease.
Asunto(s)
Angioplastia Coronaria con Balón/instrumentación , Angioplastia de Balón/instrumentación , Arteriopatías Oclusivas/terapia , Materiales Biocompatibles Revestidos , Estenosis Coronaria/terapia , Portadores de Fármacos , Angioplastia de Balón/efectos adversos , Angioplastia Coronaria con Balón/efectos adversos , Animales , Arteriopatías Oclusivas/diagnóstico por imagen , Constricción Patológica , Reestenosis Coronaria/etiología , Reestenosis Coronaria/prevención & control , Estenosis Coronaria/diagnóstico por imagen , Diseño de Equipo , Humanos , Radiografía , Prevención Secundaria , Resultado del TratamientoRESUMEN
This article addresses current pacing practices and issues. Pacing, sensing, sensing amplifiers, and pacing leads are discussed. Cardiac resynchronization is reviewed. Issues of ventricular pacing avoidance, pacemaker lead infections, ionizing radiation effects on pacing and pacing issues after deterioration and expiration of the patient are considered.
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Estimulación Cardíaca Artificial/métodos , Marcapaso Artificial , Bradicardia/fisiopatología , Bradicardia/terapia , Estimulación Cardíaca Artificial/efectos adversos , Terapia de Resincronización Cardíaca , Electrocardiografía , Electrodos Implantados , Diseño de Equipo , Sistema de Conducción Cardíaco/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Marcapaso Artificial/efectos adversos , Calidad de Vida , Resultado del Tratamiento , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/terapiaRESUMEN
Restenosis following interventions in the coronary or peripheral arteries develops over weeks to months. In coronary arteries the restenosis rate has been markedly reduced since the advent of drug-eluting stents. Non-stent-based methods for local drug delivery enable restenosis inhibition without the need for stent implantation, does not permanently change the structure of the vessel, are repeatable, and seems to be applicable where drug-eluting stents provide insufficient protection. Preclinical data indicate that short exposure of the vessel wall to a lipophilic inhibitor of cell proliferation is sufficient for preventing restenosis. Initial evidence to this effect emerged from an investigation of paclitaxel embedded in a matrix that enhances the solubility and release of the agent from the balloon coating as well as its transfer to the vessel wall. Further corroborating data from preclinical and clinical studies demonstrating a reduction in late lumen loss and lower restenosis rates led to the market introduction of a variety of paclitaxel-coated angioplasty balloons. The effectiveness of restenosis inhibition is not determined by the active agent alone. Other factors that are crucial for the effectiveness and safety of drug-coated angioplasty balloons are the formulation containing the agent and the coating technique. In this review we first outline the development of paclitaxel-coated balloons to then provide an overview of the preclinical results obtained with different paclitaxel-coated balloons and finally compare these with the outcome in patients. The article concludes with a short outlook on initial results with a zotarolimus-coated angioplasty balloon.
Asunto(s)
Angioplastia Coronaria con Balón , Reestenosis Coronaria/prevención & control , Stents Liberadores de Fármacos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Sirolimus/uso terapéuticoRESUMEN
Randomized clinical trials investigating the treatment of coronary in-stent restenosis with paclitaxel iopromide coated balloon catheters have shown favorable results. The aim of the present clinical investigation was to assess the efficacy of a novel paclitaxel urea coated angioplasty balloon in the treatment of coronary in-stent restenosis. A total of 26 restenotic bare metal stents in 23 patients with a lesion length of 22.8 ± 11.1 mm and a reference vessel diameter of 2.64 ± 0.31 mm were treated. Up to six months and including the six-month angiographic control, only one target lesion revascularization was necessary; in total, the rate of major adverse cardiovascular events until six-month follow-up was 4.3 %. In-stent late lumen loss was 0.07 ± 0.37 mm, in-segment late lumen loss 0.02 ± 0.50 mm. Binary restenosis was present in one patient (4.3%). The results of this first-in-human series with a paclitaxel urea coated balloon are comparable to paclitaxel iopromide coated balloon catheters. Randomized, controlled clinical trials are warranted to further evaluate this promising approach.
Asunto(s)
Angioplastia Coronaria con Balón/instrumentación , Reestenosis Coronaria/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Anciano , Catéteres , Angiografía Coronaria , Stents Liberadores de Fármacos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Stents , Urea/químicaRESUMEN
PURPOSE: To survey contrast media (CM)-induced alterations of complement factors. MATERIAL AND METHODS: In 31 adult patients, who received either an iotrolan (n = 19) or iopromide (n = 12) i. v. injection for CT examination, complement factors C1 q, C3, C4, C5 a, and C1-esterase inhibitor in serum/plasma samples were analyzed. The samples were obtained prior to and 5 min., 30 min., 1 hr., 6 hrs. and 24 hrs. after CM injection. RESULTS: 5 patients (16.1 %) developed a CM reaction. 4 of these were patients who received iotrolan. Other than minimal data, we neither found a significant influence of the CM on complement activation nor a difference between the analyzed CM. In detail, 5 min. after CM administration, we found the tendency to be for the values to decrease and then to return to the basic value. The changes induced by iotrolan were more pronounced than those induced by iopromide; nevertheless the differences were not statistically significant. A more pronounced decrease of C3 and C4 after iotrolan injection indicates the activation of the classic way, while this could not been observed after iopromide injection. One patient who experienced an unwanted reaction towards iotrolan showed shifts of C1 q, C1 INH, C3 and C4. CONCLUSION: The presented data shows different influences of CM injection on the analyzed complement factors after 5 min. that were commonly no longer present 30 min. after CM injection. The dimeric iotrolan induced a significantly increased frequency of unwanted CM reactions than the monomeric iopromide. The question of whether iotrolan is possibly able to activate the classic way of the complement cascade should be analyzed in the future in a greater patient group.
Asunto(s)
Activación de Complemento/efectos de los fármacos , Proteínas del Sistema Complemento/análisis , Medios de Contraste , Yohexol/análogos & derivados , Tomografía Computarizada por Rayos X , Ácidos Triyodobenzoicos , Adulto , Anciano , Complemento C2/análisis , Complemento C3/análisis , Complemento C4/análisis , Medios de Contraste/administración & dosificación , Medios de Contraste/efectos adversos , Interpretación Estadística de Datos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hipersensibilidad/diagnóstico , Inmunodifusión , Inyecciones Intravenosas , Yohexol/administración & dosificación , Masculino , Persona de Mediana Edad , Factores de Tiempo , Ácidos Triyodobenzoicos/administración & dosificación , Ácidos Triyodobenzoicos/efectos adversosRESUMEN
BACKGROUND: According to current understanding the drug-coated balloon carries a sufficient dose of an effective antineoplastic agent, i.e. paclitaxel, to the target lesion. METHODS: Literature review and report on experimental studies simulating the access of coated balloons to the treatment site and studies in pigs. RESULTS: The drug adheres to the balloon membrane and is partially hidden below the folds which are wrapped around the shaft. Upon inflation solid paclitaxel particles are pushed into the vessel wall. Premature loss of paclitaxel and transfer to the vessel wall is controlled by the formulation including an inactive additive. Particles in the tissue dissolve slowly resulting in a terminal half-life of almost 2 months. Premature loss of the drug, dissolution, elimination, efficacy and tolerance are limited by the very low solubility of paclitaxel. From exemplary DCB approximately 10% of drug is lost before the target lesion is reached, 5-20% is transferred into the vessel wall and 10% remain on the balloon after withdrawal. The difference is distributed in the general circulation. Inhibition of neointimal proliferation in animal models is reliable and as persistent as with drug-eluting stents. Histology reveals slight to moderate dose-dependent downstream effects without functional or clinical symptoms. CONCLUSION: For the time being paclitaxel remains the drug of choice, the dose varies between 2 and 3.5 µg/mm² balloon surface. Neither in animal experiments nor in clinical trials problems have been detected in vessel segments treated with overlapping balloons. Future developments are expected improving efficacy in additional disease conditions (e.g., calcified vessels) and vessel territories.
RESUMEN
Hypertonic and hypotonic contrast media and/or solutions were injected intracerebrally and into the subarachnoid space of rats, and the effects on the central nervous system (CNS) were investigated. Additionally, rabbits were injected intracisternally with nonionic contrast media that were either isotonic or hypertonic to the cerebrospinal fluid, and their behavior was observed. Both hypertonic and hypotonic contrast media and/or control solutions caused CNS depression, but not excitation. Even slight hypertonicity affected motor coordination. The sedating effect of nonionic contrast media, when given in the large doses customary in in vivo experiments, can mask their inherent epileptogenicity and give a false impression of a high safety margin.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Medios de Contraste/toxicidad , Manitol/toxicidad , Sorbitol/toxicidad , Animales , Femenino , Masculino , Concentración Osmolar , Conejos , RatasRESUMEN
Groups of 5 fasting male and female patients aged 32-83 years were each given 3 gm of the cholecystographic contrast medium iosumetic acid in micronized form (particle size less than 20 mum); Group I with 150 ml tea (standard administration); Group II with 500 ml tea; Group III with 150 ml tea plus 10 mg metoclopramide (Paspertin) 5 min p. admin. i.v.; and Group IV with 150 ml tea and 3 gm sodium bicarbonate. Blood samples were taken in the period up to 6 hours after administration in order to determine the iodine concentration according to the method of Juegst and Stauch. In Groups I and II maximum blood levels were reached 2.1 +/- 0.4 or 2.0 +/- 0.4 h p. admin. respectively, in Group III 1.6 +/- 0.2 h p. admin (in comparison to Group I: p less than 0.05) and in Group IV the maximum level was reached after only 0.9 +/- 0.2 h p. admin. The difference between Group IV and the other three groups is statistically significant (p less than 0.01). A half-life of 0.3 +/- 0.1 h was calculated for absorption in Group IV.
Asunto(s)
Colecistografía , Medios de Contraste/metabolismo , Absorción Intestinal , Yodobencenos/metabolismo , Administración Oral , Adulto , Anciano , Bicarbonatos , Femenino , Jugo Gástrico/metabolismo , Humanos , Masculino , Metoclopramida , Persona de Mediana Edad , TéRESUMEN
Pain caused by x-ray contrast media in peripheral arteriography was assessed by behavioral changes of nonanesthetized, unrestrained rats. All ionic monomeric contrast media caused severe pain in a concentration of 300 mg I/ml. Dilution of contrast media markedly reduced pain. Sodium salt solutions were considerably more painful than meglumine salt solutions. The intravenous cholegraphic agent iodipamide did not cause vascular pain in a concentration of 300 mg I/ml, although its systemic toxicity is high. Pain in arteriography was attributable primarily to the high osmotic pressure of contrast media solutions rather than to their chemotoxicity.
Asunto(s)
Angiografía , Medios de Contraste/efectos adversos , Dolor/inducido químicamente , Animales , Relación Dosis-Respuesta a Droga , Presión Osmótica , Ratas , Tecnología FarmacéuticaRESUMEN
RATIONALE AND OBJECTIVES: The feasibility of targeting iodinated contrast agents to the exocrine pancreas was investigated. Iodinated weak organic acids including succinic acid-mono-3-amino-2,4,6-triiodo- N-ethylanilide (compound I), the ethanolamine salt of N-ethylsuccinic acid-(2,4,6-triiodo-3-methylamino anilide) (compound II), and the sodium salt of 2,4,6-triiodo-3-N-ethylacetylamino-phenylpropionic acid (compound III) were studied as potential contrast agents for computed tomography (CT) of the pancreas. METHODS: An ex vivo perfusion system was used to compare pancreatic uptake of the three compounds. In vivo CT studies were conducted using domestic pigs to study potential enhancement of the pancreas after intravenous injection of the compound. RESULTS: Ex vivo perfusion studies with isolated rat pancreas demonstrated nearly identical extraction ratios of approximately 0.6 for all three compounds tested. Average iodine concentrations measured in pancreas at the end of the perfusion studies was 0.27 mg/g +/- 0.20 for compound I, 0.18 mg/g +/- 0.06 for compound II, and 0.16 mg/g +/- 0.09 for compound III. Differences in iodine concentrations retained were not statistically significant. Computed tomography studies in domestic pigs demonstrated up to 30% enhancement of the pancreas after intravenous injection of 75 and 150 mg/kg of compound II at 45 minutes. Whereas ex vivo perfusion studies indicated increasing extraction of the three compounds with increasing doses/concentrations in the perfusate, no improved contrast enhancement was observed at the higher dose level compared with the lower dose in CT. CONCLUSION: Both ex vivo perfusion studies and dose-independent enhancement levels achieved seem to indicate a transport maximum in the pancreas for the iodinated weak organic acids studied.
Asunto(s)
Medios de Contraste/farmacocinética , Páncreas/diagnóstico por imagen , Páncreas/metabolismo , Tomografía Computarizada por Rayos X , Anilidas/administración & dosificación , Anilidas/farmacocinética , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacocinética , Animales , Disponibilidad Biológica , Arteria Celíaca , Medios de Contraste/administración & dosificación , Femenino , Inyecciones Intraarteriales , Inyecciones Intravenosas , Yodo/análisis , Yodo/farmacocinética , Masculino , Páncreas/química , Fenilpropionatos/administración & dosificación , Fenilpropionatos/farmacocinética , Intensificación de Imagen Radiográfica/métodos , Ratas , Ratas Wistar , Succinatos/administración & dosificación , Succinatos/farmacocinética , PorcinosRESUMEN
Nonionic dimers enable us for the first time to produce highly concentrated, blood isotonic contrast media. If the toxicity of contrast media is dependent on molar quantity, molar concentration, or the motility of small molecules, nonionic dimers could have advantages over the monomeric contrast media. Their higher viscosity is a basic disadvantage. Solutions of the nonionic dimers with an iodine concentration of up to 400 mg/ml often have an osmotic pressure that is lower than that of blood. THe new contrast media are extremely hydrophilic, show no binding to protein, and lead to complement activation only in extremely high concentrations. They do not cause the deformation of the erythrocytes that is known to occur with other contrast media. The LD50 after fast intravenous injection in the rat is higher that with all other known contrast media. In peripheral arteriography, the nonionic dimers are tolerated painlessly by rats, and in carotid angiography they cause as few side effects as metrizamide. The neural tolerance is better than that of metrizamide. In circulatory investigations no drop in blood pressure was found after intravenous injection. Elimination is almost exclusively renal. As with other nonionic contrast media, properties of the dimers that appear to be problematic are formation of supersaturated solutions and nephrotoxicity after extremely high doses.
Asunto(s)
Angiografía , Medios de Contraste/farmacología , Animales , Activación de Complemento/efectos de los fármacos , Medios de Contraste/efectos adversos , Medios de Contraste/síntesis química , Eritrocitos/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Soluciones Isotónicas , Riñón/metabolismo , Dosificación Letal Mediana , Ratones , Presión Osmótica , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A new zwitterionic iodinated molecule, 2-[3-(N-ethyl-2-hydroxyethyl) amino-acetamido-2, 4, 6-triiodobenzyl]-butyric acid (RCK-136) was synthesized, and its potential as an oral cholecystopaque was tested. In rats, 15 minutes following intravenous injection, RCK-136 reached maximum biliary concentration; 84% of the dose was excreted into bile. Biliary excretion of RCK-136 elicited a strong choleresis (44 ml of bile flow per mmol compound). Intravenous LD50 in rats averaged 390 mgI/kg. ED50 in rats, intradiencephalic, averaged 1.98 mgI/kg. The average densities of cholecystograms produced in three dogs with iosumetic acid and/or RCK-136 were comparable.
Asunto(s)
Colecistografía , Medios de Contraste/metabolismo , Yodobencenos/metabolismo , Animales , Bilis/metabolismo , Medios de Contraste/toxicidad , Perros , Masculino , Ratones , RatasRESUMEN
Iopromide (Schering, Berlin) is a new nonionic, monomeric contrast medium containing three different substituents on the triiodinated benzene ring. Iopromide exhibits low osmolality and viscosity in aqueous solutions of high concentrations. It has been shown to have a remarkably low intravenous toxicity in mice and rats. Neural tolerance was found to be equal to or better than that of metrizamide when injected in rats intracisternally and intracerebrally, respectively. The effects of iopromide after selective peripheral and cerebral arterial injections in rats were demonstrated to be very moderate at high dosages. The interaction of iopromide with proteins and membranes was found to be considerably low due to its hydrophilicity. Excretion of iopromide is fast and predominantly by the renal route. On the basis of the preclinical profile iopromide is a very promising contrast agent, being most suitable for all angiographic indications, including digital subtraction angiography, urography, and computed tomography.
Asunto(s)
Medios de Contraste/efectos adversos , Yodobenzoatos/efectos adversos , Yohexol/análogos & derivados , Ácidos Triyodobenzoicos/efectos adversos , Animales , Proteínas Sanguíneas/metabolismo , Encéfalo/efectos de los fármacos , Medios de Contraste/metabolismo , Tolerancia a Medicamentos , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Yopamidol , Ácido Yotalámico/efectos adversos , Ácido Yotalámico/análogos & derivados , Ácido Yotalámico/metabolismo , Masculino , Metrizamida/efectos adversos , Metrizamida/metabolismo , Ratones , Ratas , Ratas Endogámicas , Ácidos Triyodobenzoicos/metabolismoRESUMEN
The pharmacodynamics of polylysine-(Gd-DTPA) (Schering, Berlin, Germany), a new blood pooling contrast agent for MRI, were studied in the rabbit and the rat. Polylysine-(Gd-DTPA) is a compound with high LD50. Due to its high molecular weight (50.000) and physico-chemical properties, it remains in the vascular system; during the first hour, the plasma level is three times higher than for Gd-DTPA. MRI was performed at 1.5 T using a SE sequence with TR/TE = 300/15 or 20 msec. Signal intensities of muscle, liver and kidney were measured before and after intravenous injection of the contrast agent (0.1 mmol/kg) during 8 hours in the rat (n = 3) and up to 2 wk in the rabbit (n = 3). A dose response study in three additional rabbits confirmed that the 0.1 mmol/kg dose was optimal. The pharmacodynamics results show that the effects of polylysine-(Gd-DTPA) are similar in both the rabbit and the rat. The liver signal is enhanced by about 60% immediately after injection in both species. This enhanced signal decays to half its maximal value in about one hour, which makes the contrast agent useful for clinical applications at a dose of 0.1 mmol/kg. In the kidney medulla and cortex the signals are enhanced by much larger factors (about 3 to 4); it takes at least one day for the kidney to clear the contrast agent in both species.
Asunto(s)
Gadolinio DTPA , Espectroscopía de Resonancia Magnética , Compuestos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Polilisina/farmacocinética , Animales , Medios de Contraste , Femenino , Gadolinio/farmacología , Riñón/anatomía & histología , Riñón/metabolismo , Hígado/anatomía & histología , Hígado/metabolismo , Músculos/anatomía & histología , Músculos/metabolismo , Conejos , Ratas , Ratas EndogámicasRESUMEN
Norethisterone, levonorgestrel, cyproterone acetate and gestodene have been used for a long time in oral contraception and other indications, or are in the process of development for such indications. However, very little is known concerning the bioavailability and plasma levels of unmetabolized gestagens in the animal species used for chronic toxicity testing and pharmacological investigation. In this study the gestagens were administered intravenously, subcutaneously and orally to rats, beagles and rhesus monkeys. The drug plasma levels were determined by specific radioimmunoassay. The half-life of the terminal disposition phase was calculated following intravenous administration, and the extent of bioavailability was determined from the area under the drug level curves following subcutaneous and oral administration. The terminal half-lives of a particular compound in different animal species differed considerably. Furthermore, comparison of the different gestagens showed large variations in this parameter in all the animal species. In addition, inter-animal species comparison of a particular substance, and comparison of different substances in a single species, also showed great differences in bioavailability. The results are compared with the corresponding parameters in man. This investigation illustrates the fundamental problems inherent in the extrapolation of the results of toxicity studies and pharmacological investigations in animals, to man. The best tolerance and the lowest degree of pharmacological effect seem to occur where the bioavailability of a gestagen is poor and its terminal half-life short.
Asunto(s)
Ciproterona/análogos & derivados , Noretindrona/sangre , Norgestrel/sangre , Norpregnenos/sangre , Administración Oral , Animales , Disponibilidad Biológica , Ciproterona/sangre , Acetato de Ciproterona , Perros , Semivida , Inyecciones Intravenosas , Inyecciones Subcutáneas , Cinética , Levonorgestrel , Macaca mulatta , Ratas , Especificidad de la Especie , EstereoisomerismoRESUMEN
The aim of the investigations was to develop a long-acting depot contraceptive on the basis of norethisterone or levonorgestrel. Disappointing results with levonorgestrel nonanoate and levonorgestrel undecylate showed that elongation of the fatty acid, esterified with the steroid, decreased the bioavailability of the latter due to incomplete hydrolysis of the ester. Therefore, several new compounds were synthesized which contained a bifunctional molecule between the steroid and the fatty acid. In vivo studies showed an increase in hydrolysis when glycolic acid was taken as the "bridge", compared to the hitherto known esters. Due to the new principle of the steroid-fatty acid connection, in the case of norethisterone, it was possible to introduce tridecanoic acid as lipophilic release controlling substituent without a loss of bioavailability in the baboon. This compound (called: "norethisterone glycotridecanoate") and the corresponding levonorgestral derivative were chosen for a pharmacokinetic-clinical study in women.
Asunto(s)
Anticonceptivos/administración & dosificación , Animales , Ácidos Grasos/sangre , Femenino , Glicolatos/sangre , Haplorrinos , Inyecciones Intravenosas , Macaca mulatta , Noretindrona/administración & dosificación , Norgestrel/administración & dosificación , Norgestrel/sangre , PapioRESUMEN
Ethinyloestradiol-3H was given intravenously and orally to four and three women, respectively, in a dose of 60 micrograms and 3 mg. To another three female volunteers, 100 micrograms of ethinyloestradiol was administered by both routes in succession. Drug concentration in plasma and total radioactivity in plasma, urine and faeces were measured for different periods of time. Intraindividual comparison of the area under the drug level vs. time curve after intravenous and oral administration of 100 micrograms showed that ethinyloestradiol is subject to an about 60% first-pass effect in women. The time course of ethinyloestradiol concentration in plasma can be described by a 3-compartment model after intravenous injection and by a 2-compartment model after oral administration, because an early disposition phase with a half-life of about 15 minutes only becomes visible after i.v. injection. On an average, the terminal half-life of unchanged ethinyloestradiol level and total radioactivity was calculated to be about 1 day. However, a high variability was found with this parameter as well as with the rate and degree of elimination in urine.
PIP: Investigations of pharmacokinetics of ethinyl estradiol (EE) to specific consideration of a possible 1st-pass effect in women are reported. Tritiated EE was given intravenously and orally to 4 and 3 women, respectively, in a dose of 60 mcg and 3 mg. 3 female volunteers received 100 mcg of EE by both routes in succession. EE concentration in plasma and total radioactivity in plasma, urine, and feces were measured for different periods of time. Intraindividual comparison of the area under the drug level vs time curve following iv and oral administration of 100 mcg showed that EE is subject to about 60% 1st-pass effect in women. The time course of EE concentration in plasma can be described by a 3-compartment model after iv injection and by a 2-compartment model after oral administration, because an early disposition phase with a 1/2-life of about 15 only became visible after iv injection. The terminal 1/2-life of unchanged EE level and total radioactivity was calculated to be about 1 day.
Asunto(s)
Etinilestradiol/metabolismo , Absorción , Adulto , Etinilestradiol/sangre , Etinilestradiol/farmacología , Etinilestradiol/orina , Estudios de Evaluación como Asunto , Femenino , Humanos , Cinética , Radioinmunoensayo , Factores de TiempoRESUMEN
PIP: Bioavailability and pharmacokinetics of carbon-14-cyproterone acetate-methylene (2 mg) and tritiated ethinyl estradiol (50 mg) after oral administration as a coated tablet (SH B 209 AB) were investigated. 8 women received the compounds, and carbon-14 and tritium activity in plasma, urine, and feces was determined up to 7 or 10 days postadministration. Cyproterone acetate was completely absorbed. The maximum plasma level was reached in 30 minutes to 3 hours, when 2.2% of the dose was found in total plasma corresponding to 24 ng eq/ml. The plasma level decreased with a 1/2-life of 7.9 hours (distribution and elimination) and later with a 1/2-life of 2.5 days (elimination). Elimination via urine was 37% and up to Day 10 postadministration 91% of the dose was found in urine and feces. Ethinyl estradiol was adsorbed very rapidly and almost completely with the maximum plasma level reached in 60 minutes. At this time 10% of the dose was found in the plasma corresponding to 2.1 ng eq/ml. The plasma level dropped up to about 8 hours postadministration with a 1/2-life of 5.1 hours and later with a 1/2-life of 27 hours. Ethinyl estradiol was eliminated in urine and feces in the ratio of 4:6 and 91% of the dose was recovered.^ieng