RESUMEN
An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Adulto , Factores de Edad , Anciano , Área Bajo la Curva , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/sangre , Estimulantes del Sistema Nervioso Central/efectos adversos , Femenino , Fiebre/inducido químicamente , Cefalea/inducido químicamente , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modafinilo , Faringitis/inducido químicamente , Factores Sexuales , ComprimidosRESUMEN
A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Adolescente , Adulto , Ansiedad/inducido químicamente , Área Bajo la Curva , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/química , Estimulantes del Sistema Nervioso Central/efectos adversos , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Cefalea/inducido químicamente , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modafinilo , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Estereoisomerismo , Comprimidos , Taquicardia/inducido químicamenteRESUMEN
An open-label, randomized, crossover study was performed in healthy male volunteers to evaluate the potential pharmacokinetic and pharmacodynamic interactions and tolerability of single oral doses of modafinil (200 mg) and dextroamphetamine (10 mg). Blood samples were collected for determination of plasma levels of modafinil, the acid and sulfone metabolites of modafinil, and dextroamphetamine at intervals through 48 hours after administration for each treatment. Vital signs (blood pressure and pulse rate) were measured through 48 hours, and electrocardiograms were measured through 24 hours after administration. Pharmacokinetic parameters were determined using noncompartmental methods. The data collected in this study of 24 healthy volunteers suggest that concomitant administration of single oral doses of modafinil and dextroamphetamine has no clinically significant effects on the pharmacokinetic profile of either agent. Although there was a slightly greater incidence of adverse events when modafinil and dextroamphetamine were administered together, the concomitant administration of the two drugs was well tolerated.
Asunto(s)
Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/farmacocinética , Dextroanfetamina/administración & dosificación , Dextroanfetamina/farmacocinética , Adulto , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Intervalos de Confianza , Estudios Cruzados , Quimioterapia Combinada , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Modafinilo , Estadísticas no ParamétricasRESUMEN
Modafinil is a novel wake-promoting agent being developed for treatment of excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin square, randomized, cross-over study was performed in healthy males to compare the pharmacokinetics of single-dose oral modafinil (200 mg) and methylphenidate (40 mg) administered alone or in combination. Blood samples were obtained for analysis of d- and l-threo-methylphenidate and modafinil and its acid and sulfone metabolites. Pharmacokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels that were close to the assay quantitation limit. Although sporadic differences in plasma concentrations were observed between treatments, coadministration of modafinil and methylphenidate did not significantly alter the plasma concentrations of modafinil, modafinil acid, modafinil sulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half-life (t1/2), maximum concentration (Cmax), area under the concentration-time curve (AUC0-infinity), total clearance (Cl/F), and apparent volume of distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0-infinity for modafinil acid were not affected by concomitant administration of methylphenidate. Small but statistically significant increases in time to Cmax (tmax) were observed for modafinil and modafinil acid after methylphenidate coadministration compared with modafinil alone. Modafinil coadministration did not significantly alter the pharmacokinetics of d- or l-threo-methylphenidate, except for a small decrease in Vd/F of l-threo-methylphenidate. Concomitant methylphenidate may cause a delay in the oral absorption of modafinil, but this delay might not be relevant clinically. Coadministration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between modafinil and methylphenidate would be unlikely.
Asunto(s)
Adrenérgicos/farmacocinética , Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Metilfenidato/farmacocinética , Adolescente , Adrenérgicos/administración & dosificación , Adrenérgicos/efectos adversos , Adrenérgicos/farmacología , Adulto , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Estimulantes del Sistema Nervioso Central/farmacología , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Humanos , Masculino , Metilfenidato/administración & dosificación , Metilfenidato/efectos adversos , Metilfenidato/farmacología , Persona de Mediana Edad , ModafiniloRESUMEN
Motor neuronal disorders, such as the loss of spinal cord motor neurons in amyotrophic lateral sclerosis or the degeneration of spinal cord motor neuron axons in certain peripheral neuropathies, present a unique opportunity for therapeutic intervention with neurotrophic proteins. Normally, such proteins do not cross the blood-brain barrier, but spinal cord motor neuron axons and nerve terminals lie outside the barrier and thus may be targeted by systemic administration of protein growth factors. Insulin-like growth factor-I (IGF-I) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Enfermedad de la Neurona Motora/tratamiento farmacológico , Secuencia de Aminoácidos , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Supervivencia Celular , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Modelos Biológicos , Datos de Secuencia Molecular , Enfermedad de la Neurona Motora/fisiopatología , Neuronas Motoras/citología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Sistema Nervioso/efectos de los fármacos , Fenómenos Fisiológicos del Sistema Nervioso , Receptor IGF Tipo 1/fisiologíaAsunto(s)
Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Enfermedades Neuromusculares/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Animales , Muerte Celular/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Compresión Nerviosa , Neuronas/citología , Neuronas/efectos de los fármacos , Nervios Periféricos/citología , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
A new orally active inotropic agent, 6-[3,4-dihydro-3-methyl-(2H)-2-oxoquinozolinyl)]-4,5-dihydro-3- (2H)-pyridazinone (I), is currently under investigation. In support of clinical studies, a HPLC assay for the analysis of compound I in human plasma has been developed. The method involved a solid-phase extraction using C18 cartridge columns washed with methanol-water (20:80) and eluted with acetonitrile-water (70:30). The eluate was then extracted with dichloromethane. A reversed-phase alkylphenyl-bonded column was used as the analytical column. The mobile phase was a mixture of methanol, acetonitrile, 2-propanol and phosphate buffer (pH 4.6). A wavelength of 311 nm was used for detection. The limit of detection of the assay was 2 ng/ml, and the limit of quantitation was 5 ng/ml. A linear calibration range of 5 ng/ml to 1200 ng/ml was obtained with a correlation coefficient less than 0.99. The precision and accuracy were evaluated by analyzing samples of three different concentrations (n = 5), 40, 200 and 800 ng/ml in plasma. The coefficients of variation and the differences from nominal values were less than 10%. The average recovery for 5, 50 and 100 ng/ml of analyte in plasma was about 90%. This assay has been applied to clinical studies with satisfactory performance and to plasma of different species in preclinical studies.
Asunto(s)
Cardiotónicos/sangre , Piridazinas/sangre , Quinazolinas/sangre , Cromatografía Líquida de Alta Presión , Humanos , Espectrofotometría UltravioletaRESUMEN
Celiprolol HC1 is a new cardioselective beta-blocker with properties which may make it the next advance in the evolution of this class of compounds. Its cardioselectivity has been demonstrated both in vitro and in vivo, with an intravenous potency equivalent to atenolol. The compound is devoid of a membrane stabilizing effect which is reflected in anesthetized dogs by a lack of myocardial electrophysiological effects. The compound induces a vasodilator effect in anesthetized dogs which is partially attenuated by propranolol, suggesting a weak beta 2-agonist activity. This beta 2-agonist property is also manifested in other peripheral tissues and undergoes down-regulation with repeat exposure. In contrast to other beta-blockers, celiprolol produces a bronchodilation in anesthetized cats which is propranolol-resistant. Isolated tissue studies suggest that a weak alpha 2-blocking effect contributes to this bronchodilation, although another unknown mechanism participates as well. Celiprolol induces a cardiac stimulation in anesthetized dogs which is inhibited by propranolol. The mechanism for this effect appears to be due to adrenergic interaction. These unique properties of celiprolol convey salutary effects in the clinical use of celiprolol.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Propanolaminas/farmacología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Atenolol/farmacología , Bronquios/efectos de los fármacos , Celiprolol , Corazón/efectos de los fármacos , Propranolol/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Renal impairment can affect the disposition of metabolites, as well as unchanged drug, especially when there is significant renal clearance of metabolites. The pharmacokinetics of indapamide, a highly metabolized drug, and total indapamide equivalents (as an indicator of metabolites plus unchanged drug) were determined in the anephric dog. An intravenous dose of 14C-indapamide was administered to dogs first after a sham-operation, and then following bilateral nephrectomy. The disposition of total indapamide equivalents, calculated from total radioactivity, was not substantially different after nephrectomy as compared to after sham-operation, with an increase after nephrectomy in the area under the blood level curve (+26.2%), and decreases in the elimination rate constant (-6.9%), volume of distribution (-12.7%) and total blood clearance (-21.9%). The only statistically significant change was the decrease in the volume of distribution. The elimination kinetics of unchanged drug were also qualitatively similar in both cases. After nephrectomy, a decrease was seen in the elimination rate constant (-10.9%) and the volume of distribution (-16.3%) while slight increases in the total blood clearance (+1.9%) and the area under the blood level curve (+4.8%) were noted. These findings could have important implications for advantageous use of indapamide in treatment of hypertensive patients with renal failure since these data suggest that metabolites as well as unchanged drug could still be effectively eliminated by an alternate, non-renal route, thus minimizing accumulation of these compounds.
Asunto(s)
Diuréticos/metabolismo , Indapamida/metabolismo , Nefrectomía , Animales , Bilis/metabolismo , Radioisótopos de Carbono , Perros , Riñón/metabolismo , Cinética , MasculinoRESUMEN
Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 microgram-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly shorter time of maximum blood concentration (2.3 vs 3.5). Cmax(333ng/ml) and tmax (0.7h) values for the solution were significantly higher than either tablet. The average half-life (beta-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.
Asunto(s)
Antihipertensivos/metabolismo , Diuréticos/metabolismo , Indapamida/metabolismo , Adolescente , Adulto , Disponibilidad Biológica , Esquema de Medicación , Humanos , Indapamida/administración & dosificación , Cinética , Masculino , Persona de Mediana EdadRESUMEN
Four beagle dogs received both an oral and intravenous dose (1 mg/kg) of indapamide in a crossover design. The blood levels and urinary excretion of intact indapamide were measured, and the pharmacokinetic parameters of the drug were defined. The results indicate that indapamide is completely bioavailable after an oral dose and does not undergo first-pass metabolism. Excretion of unchanged drug from the kidney accounted for only a small percentage of the drug's clearance. While the dog is very similar to the human in its handling of indapamide, the dogs clears indapamide approximately twice as fast as humans.
Asunto(s)
Diuréticos/metabolismo , Indapamida/metabolismo , Administración Oral , Animales , Perros , Indapamida/administración & dosificación , Inyecciones Intravenosas , Cinética , MasculinoRESUMEN
The pharmacodynamic profile of bucainide dimaleate (RHC G-233) in dogs has been studied. The first observed pharmacologic effect was a change in the ECG pattern (T-wave duration and amplitude) that occurred after an average intravenous dose of 2.7 mg/kg. The average plasma concentration of bucainide was approximately 350 ng/ml. Analysis of data from dogs that received a dual infusion of bucainide indicated that bucainide has an extensive volume of distribution, with an average value of approximately 26 l/kg. An average terminal half-life of 89 minutes was observed. Studies with the radiolabeled drug in rats and dogs also demonstrated the drug's large volume of distribution, and its initial rapid disappearance from the blood. Tissue distribution studies in the rat after administration of the radiolabeled drug showed that bucainide is rapidly taken up by the tissues.
Asunto(s)
Antiarrítmicos/metabolismo , Corazón/efectos de los fármacos , Piperazinas/metabolismo , Animales , Antiarrítmicos/sangre , Antiarrítmicos/farmacología , Perros , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Cinética , Masculino , Piperazinas/sangre , Piperazinas/farmacología , Ratas , Distribución TisularRESUMEN
A sensitive fluorescence procedure for the determination of indapamide in plasma and whole blood was developed. The procedure requires preextraction of the biological sample followed by continuous-flow analysis. The assay is sensitive to indapamide levels of 25 ng/ml in plasma and blood. A linear response from 25 to 200 ng/ml is observed. The procedure also can be used to measure urinary levels of indapamide. The assay has been used to obtain whole blood and plasma level curves from subjects receiving 2.5 mg of indapamide.
Asunto(s)
Diuréticos/sangre , Indapamida/sangre , Autoanálisis , Fluorometría , HumanosRESUMEN
Indapamide, an antihypertensive agent, is an aryl sulfonamide that inhibits carbonic anhydrase in vitro but not in vivo. An assay was developed for indapamide in drug-rodent food mixtures that utilizes this inhibitory effect. Indapamide was extracted from the mixtures with methanol, and an aqueous dilution of the extract was sampled by a continuous-flow system. In the system, the drug was extracted with butanol and then back-extracted into alkali. This solution was neutralized, buffered, and mixed with bovine erythrocyte carbonic anhydrase. The substrate, p-nitrophenyl acetate, was added, the solution was incubated, and the amount of p-nitrophenol formed was measured. The assay was sensitive to 20 micrograms of indapamide/g of food, and 20 unknown samples could be analyzed per hour on the continuous-flow system. It is possible that the method could be extended to the analysis of other toxicological test substances that inhibit carbonic anhydrase in vitro.
Asunto(s)
Alimentación Animal/análisis , Diuréticos/análisis , Indapamida/análisis , Animales , Autoanálisis/métodos , Anhidrasas Carbónicas/metabolismo , RoedoresAsunto(s)
Líquido Ascítico/metabolismo , Tuftsina/aislamiento & purificación , gammaglobulinas/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Cromatografía en Capa Delgada , Perros , Electroforesis en Papel , Femenino , Cobayas , Humanos , Técnicas In Vitro , Masculino , Peso Molecular , Péptido Hidrolasas , Conejos , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Tuftsina/biosíntesis , Tuftsina/farmacologíaRESUMEN
The leukokinin-leukokininogen system is a pathological kinin generating system which is catalyzed by acid proteases present in neoplastic cells, white cells and even normal tissues. The components of the human system including leukokinin-H and leukokininogen have now been isolated and characterized. Very specific protease inhibitors of the system such as pepstatin have been found and are now known to prevent "in vivo" the formation of pathological fluids such as neoplastic ascites. Strong evidence has been previously published and additional evidence has been presented here which indicates that pepstatin's actions are related to the inhibition of cathepsin-D in vivo and the inhibition of leukokinin formation. Both leukokinins and leukokininogens have been clearly defined and shown to differ from bradykinin and human bradykininogens. This clearly demonstrates the presence in pathological systems of a kinin-generating system which is separate and distinct from the bradykinin generating system. The importance of the leukokinin-leukokininogen system in disease would seem to be very great. The finding that pepstatin can inhibit the system in vivo opens the way for studies of pepstatin and related protease inhibitors as therapeutic agents in neoplastic disease and protease mediated inflammatory disorders.
Asunto(s)
Ascitis/metabolismo , Precursores de Proteínas , Tuftsina , gammaglobulinas , Aminoácidos/análisis , Animales , Bioensayo , Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Femenino , Cobayas , Humanos , Íleon/efectos de los fármacos , Macrófagos/análisis , Sarcoma de Mastocitos/análisis , Ratones , Peso Molecular , Neutrófilos/análisis , Neoplasias Ováricas/análisis , Precursores de Proteínas/fisiología , Ratas , Tuftsina/farmacología , Tuftsina/fisiología , Útero/efectos de los fármacos , gammaglobulinas/fisiologíaRESUMEN
A sensitive fluorescence method for the determination of indapamide was developed. Reaction of indapamide with sodium hydroxide at 100 degrees yielded a fluorescent product, and addition of formaldehyde to the fluorescent product increased its fluorescence intensity by a factor of three. The assay is sensitive to levels of indapamide of 0.025 microgram/ml in an aqueous solution, and a linear response between 0.025 and 2.0 microgram/ml was observed. The procedure was adapted to the analysis of intact indapamide in urine. Concentrations of indapamide of 0.05 microgram/ml can be detected in dogs given 20 mg of the drug.
Asunto(s)
Diuréticos/orina , Indapamida/orina , Animales , Cromatografía en Capa Delgada , Perros , Estabilidad de Medicamentos , Estudios de Evaluación como Asunto , Masculino , Métodos , Espectrometría de FluorescenciaRESUMEN
Ascites fluid accumulation accompanying a mastocytoma or L1210 murine tumor is significantly retarded following the i.p. or s.c. injection of moderate quantities of pepstatin, a known acid protease inhibitor. No effect on cell count was noted by pepstatin treatment. The probable mechanism by which pepstatin acts is by inhigiting the enzymatic formation of chemical mediators known as leukokinins. These are pharmoacologically active peptiedes having potent permeability characteristics previously described by this laboratory. Leukokinins are formed by cathepsin D-like enzymes present in the invading cells and in the ascites fluid acting on a protein substrate, leukokininogen. present in the ascites fluid. Pestatin inhibits the action of these leukokinin-forming enzymes invitro but has no effect on kallikreins (bradykinin-forming enzymes) in vitro. Human ascites fluid from a patient with ovarian carcioma was found to have a paepstatin-inhibited, leukokinin-generating system, as does the mouse. A 'chemical mediator' theory is proposed for ascites fromation which broadens the previously held theory of lymphatic blockage (Holm-Nielsen) and may explain the recent findings of Hirabayashi and Graham of increased plasma-ascites exchange in peritoneal carcionmatosis. Pepstatin inhibition of chemical mediator formation may represent a new therapeutic approach to ascites fluid accumulation in neoplastic disease.