Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs.

The non-clinical pharmacokinetics (PK) of TAK-357, a highly lipophilic (clogP>6) potential agent for the amelioration of Alzheimer's disease, was investigated in rats and dogs. A long half-life (t1/2) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t1/2. The absorption, distribution, metabolism and excretion (ADME) studies using radiolabeled TAK-357 revealed that the total radioactivity was highly distributed to the adipose tissues and sustained with high concentration for over 4 weeks after oral administration. The metabolite analysis also revealed that the main component in the plasma and adipose tissues was unchanged TAK-357. The major elimination route of absorbed TAK-357 was suggested to be by metabolism. An ADME study indicated that the adipose tissue is the main depot of remaining TAK-357 in the body and slow release from the adipose tissues contributes to the long t1/2. The PK of highly lipophilic compounds have a tendency to be affected by body weight changes especially changes in the adipose tissues. Therefore, it is considered that the relationship between the plasma levels of TAK-357 and the body weight should be evaluated carefully during the clinical trials.

Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.

Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.

Synthesis of glycosyl-trehaloses by cyclomaltodextrin glucanotransferase through the transglycosylation reaction.

Cyclomaltodextrin glucanotransferase from Bacillus stearothermophilus produced a series of glycosyl-trehaloses through the transglycosylation reaction with cyclomaltohexaose as the glycosyl donor and trehalose as its acceptor. After beta-amylase treatment, five species of glycosyl-trehaloses were isolated by column chromatography. After chemical and enzymatic analyses, it was concluded that these oligosaccharides were alpha-maltosyl alpha-D-glucopyranoside, alpha-maltotriosyl alpha-D-glucopyranoside, alpha-maltosyl alpha-maltoside, alpha-maltotriosyl alpha-maltoside, and alpha-maltotriosyl alpha-maltotrioside. These were not hydrolyzed by salivary amylase, artificial gastric juice, or pancreatic amylase, however they were hydrolyzed by enzymes of the small intestine.

The crystal structure and physicochemical properties of L-ascorbic acid 2-glucoside.

The stable L-ascorbic acid glucoside produced by the action of the cyclomaltodextrin glucanotransferase (CGTase, EC 2.4.1.19) from Bacillus stearothermophilus was crystallized from an aqueous solution. Determination of the molecular structure by single crystal X-ray analysis showed the compound to be 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G). The crystals are orthorhombic, space group P2(1)2(1)2(1), with unit-cell dimensions a = 11.929 A, b = 24.351 A, and c = 4.864 A. The D-glucopyranose residue has the 4C1 conformation. These conclusions are in good agreement with those based on the 13C-NMR spectrum. The general physicochemical properties of crystalline AA-2G are reported.

Vascular responsiveness to angiotensin II and phenylephrine, the tubular function and the prostaglandin, renin-angiotensin system in a patient with Bartter's syndrome.

In a 39-yr-old female patient with Bartter's syndrome, vascular responsiveness to angiotensin II and phenylephrine was studied. Pressor responses to angiotensin II and to phenylephrine were markedly decreased prior to treatment and were improved by administration of indomethacin, dextran, KCl, captopril, propranolol or pindolol. Moreover, the responses of total peripheral vascular resistance to angiotensin II and phenylephrine were markedly decreased before treatment and were improved by the treatment. A relatively low fractional distal chloride reabsorption was found, and that was not changed after the administration of KCl or indomethacin. The results of this patient were compatible with the primary cause of Bartter's syndrome, defective chloride reabsorption at the loop of Henle, but the possibility of an abnormality in the vascular wall could not be denied.

[Relation of mass screening blood pressure to usual 24-hour working day blood pressure variation and left ventricular hypertrophy].

Fifty-three regularly employed hypertensive men (HT group) aged 38 to 68 years, whose blood pressure measured at a health evaluation clinic was systolic blood pressure (SBP) greater than or equal to 160 mmHg and/or diastolic pressure (DBP) greater than or equal to 95, and 21 age-matched normal controls (NC group), whose SBP was less than 140 and DBP was less than 90 had their blood pressure monitored over 24 hours during a usual working day. Age and clinical pressure were 53.1 +/- 7.1 years (mean +/- SD) and 147 +/- 18/97 +/- 10 mmHg (SBP/DBP) in the HT group, and 52.7 +/- 8.9 and 117 +/- 8/78 +/- 7 in the NC group. In the HT group, blood pressure during work (146/96 mmHg) was similar to clinical blood pressure, while blood pressure at home (135/89 mmHg) was considerably lower than clinic measured values. In contrast, blood pressure variabilities in the NC group during non-sleep hours were less, and clinical measurement was lower than that at home (122/80 mmHg), and during work (126/82 mmHg). For those examined by echocardiogram (46 in HT and 21 in NC), end-diastolic left ventricular wall thickness (LVT), and left ventricular mass index (LVMI) correlated most strongly with pressure during work by partial correlation analysis with age as a covariant (LVT:: SBP: r = 0.47, DBP: r = 0.53 both p less than 0.001, and LVMI:: SBP: r = 0.29, DBP: r = 0.25 both p less than 0.25). Clinical blood pressure as well as blood pressure at home and during sleep correlated significantly with LVT. These findings suggest that the blood pressure measurements obtained at a mass screening clinic, although infrequent, have important implications in relation to cardiac organ damage and for providing an estimate of blood pressure during work for hypertensives.

Quality of life of patients receiving antihypertensive treatment.

Ninety-four hypertensive patients, 52 females and 42 males, 38 to 79 years old, were investigated for quality of life under antihypertensive treatment, using a self-administered questionnaire. Their social situation, work and leisure activities and hypertension-related symptoms were evaluated when first diagnosed and after treatment with antihypertensive drugs. Of the 94 patients, 85 (90%) felt uneasiness due to hypertension, 21 (22%) felt their work was limited, and 27 (29%) reported restricted leisure activities due to hypertension. Eighteen patients (19%) had sexual problems. Females who were severely hypertensive at first visit (mean BP greater than or equal to 120 mmHg), those who were well-controlled by treatment (mean BP at last visit less than 105 mmHg), and those whose mean BP decreased markedly (decrease in mean BP greater than or equal to 20 mmHg) showed significant improvement in hypertension-related symptoms. Side effects varied depending on the antihypertensive drug used. It is recommended that the quality of life of patients be taken into consideration when choosing antihypertensive drugs.

The effect of reduced alcohol consumption on blood pressure: a randomised, controlled, single blind study.

A randomised, controlled, single blind trial was conducted in office workers with mild hypertension (systolic blood pressure (SBP) 140 to 180 mmHg, diastolic blood pressure (DBP) 90 to 110 mmHg) to determine the effect of decreasing alcohol consumption. After a baseline examination, 50 male volunteers aged 30 to 59 were randomised to two groups. Group A were told to abstain from or reduce alcohol consumption for two weeks, while group B were instructed to maintain their usual alcohol consumption. Complete records were obtained on 49 subjects. The daily alcohol consumption of groups A and B at baseline was similar, i.e. 71.9 ml and 72.5 ml of ethanol, respectively, and changed to 16.1 ml and 62.9 ml, respectively, during the experiment. After two weeks, group A were asked to resume their normal consumption whilst group B were asked to reduce or abstain (phase II). However in view of a treatment period interaction, statistical analysis was confined to phase I. During phase I, group A, whose alcohol consumption had reduced, showed decreases of 5.8 and 7.1 mmHg in SBP during the the first and second weeks, respectively. In group B, these decreases were only 0.6 and 1.9 mmHg, respectively. The difference between the falls in SBP in groups A and B was significant (P = 0.005) as judged by analysis of variance. The DBP also decreased, but there was no significant difference between the decreases in the two groups. Changes in gamma-glutamyl-transpeptidase, a biochemical marker of alcohol consumption, from the initial values to the end of phase I were significantly different in groups A and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of two angiotensin II analogues on blood pressure, plasma aldosterone concentration, plasma renin activity and creatinine clearance in normal subjects on different sodium intakes.

Two angiotensin II analogues (AIIA), 1-sarcosine, 8-isoleucine angiotensin II ([Sar, Ile]-AII) and 1-sarcosine, 8-alanine angiotensin II ([Sar, Ala]-AII), were infused in six normal volunteers on high, regular and low sodium diets. The agonist and antagonist activities of these AIIA on blood pressure (BP), plasma aldosterone concentration (PAC), creatinine clearance and plasma renin activity were examined. Both AIIA had agonistic pressor activities in subjects on high and regular sodium diets, [Sar, Ile]-AII being more potent than [Sar, Ala]-AII. Both AIIA caused similar elevation of PAC in subjects on high and regular sodium diets, and an equally fall in PAC in subjects on a low sodium diet. Both AIIA strongly antagonized the rise in BP, the increase in PAC and the reduction of Ccr induced by AII administration in subjects on all three sodium diets. The results indicate that both AIIA can be used to examine the activity of the renin-angiotensin system in patients with hypertension, and they also suggest that AII interaction with its receptors differs in different target tissues.

Urinary catecholamine response to glucagon in young and elderly patients with essential hypertension.

The role of the sympathetic nervous system (SNS) in essential hypertension was evaluated by examining the response of urinary catecholamines to the intramuscular injection of glucagon in both young and elderly normal subjects (total 16) and in both young and elderly patients with essential hypertension (total 16). Urine was collected for 2 hours before glucagon injection and for 2 and 4 hours after injection, for determination of adrenaline and noradrenaline. The increments of urinary adrenaline and noradrenaline after glucagon injection were significantly higher in young hypertensive than in young normotensive subjects or in normotensive and hypertensive elderly subjects. The observation that the reactivity of the SNS is increased in young patients with essential hypertension lends support to the hypothesis that the SNS is more important in the maintenance of hypertension in the young than in the elderly.

Studies on the renin-angiotensin-aldosterone system in elderly hypertensive patients with an angiotensin II antagonist.

1. To characterize the renin-angiotensin-aldosterone system in elderly hypertensive patients, an angiotensin II antagonist, [Sar1,Ile8]angiotensin II, was infused into individuals 60 years old and older with and without hypertension. 2. After infusion of [Sar1,Ile8]angiotensin II in all of the elderly patients and subjects an agonistic pressor response was observed that was greater than in middle-aged hypertensive patients. 3. Pre-infusion plasma renin activity and plasma aldosterone concentration in hypertensive and normotensive elderly groups were suppressed in comparison with those in middle-aged hypertensive subjects. The increased agonistic effects of [Sar1,Ile8]angiotensin II infusion on blood pressure in the elderly are presumably due to their hyporeninaemia. 4. The angiotensin-aldosterone system in elderly essential hypertensive patients is suppressed and is presumably not responsible for their elevated blood pressures.

Simple method for the simultaneous determination of noradrenaline, dopamine and serotonin by stepwise elution from a short column of weak cation-exchange resin.

A simple method for the simultaneous determination of noradrenaline, dopamine and serotonin using a short column of Amberlite CG-50 is described. Noradrenaline and dopamine were eluted from the column with phosphate buffers containing 1.5 and 4.0% boric acid, respectively, and then serotonin was eluted with 1.0 N HCl. Catecholamines were determined by a modification of the ethylenediamine condensation method using potassium ferricyanide as oxidant and isobutanol for extraction of the fluorophores. Serotonin was measured by the acidic o-phthalaldehyde method. The method was applied to the simultaneous determination of noradrenaline, dopamine and serotonin in discrete regions of rat brain.

Blood pressure response to [1-sarcosine, 8-isoleucine] angiotensin II in patients with liver cirrhosis and ascites.

[1-Sarcosine, 8-Isoleucine] angiotensin II was given to 8 patients with cirrhosis and ascites and 7 cirrhotic patients without ascites on a regular diet. The 3 ascitic patients with high plasma renin activity (PRA) gave a depressor response, but the other ascite patients with normal or low PRA gave a pressor response or no response. All the non-ascitic patients gave a pressor response. There was an inverse correlation between the PRA before infusion and the change in blood pressure induced by this compound. In the patient with the highest PRA, who had ascites of a few days' duration, a marked reduction in blood pressure was observed on infusion of this compound. These results suggest that the renin-angiotensin system might be involved in maintenance of a normal blood pressure in some patients with cirrhosis and ascites, whose ascites is presumably in an early stage.

[A study on the pathophysiology and diagnosis of adrenocortical insufficiency using angiotensin II blocker (author's transl)].

Angiotensin II analogue (AIIA), 1-sarcosine, 8-isoleucine angiotensin II (Sar1, Ile8-AII), was given in a graded dose to patients with adrenal hypofunction of various etiologies, and the blood pressure response to AIIA was observed to investigate the role of the renin-angiotensin system for the maintenance of blood pressure in the state of adrenal insufficiency. An agonistic pressor response to AIIA was observed in the control subjects without adrenal hypofunction. In contrast with this, patients with Addison's disease showed a blood pressure fall to AIIA. When the test was repeated on the same patients after hydrocortisone replacement, these patients showed a neutral or pressor response. Three patients with adrenalectomy and hydrocortisone replacement showed a pressor response to AIIA in a supine position. When these patients were tilted, fall in blood pressure to AIIA was observed in two of them who had been on a regular diet, whereas one patient who had been on a high sodium diet showed no fall in blood pressure with this procedure. We concluded that the renin-angiotensin system plays an important role in the maintenance of normal or subnormal blood pressure in Addison's disease and in the postural change of adrenalectomized patients on hydrocortisone and regular salt intake. The response of blood pressure to AIIA may be a clue for the diagnosis of Addison's disease and the evaluation of the adequacy of replacement therapy with regard to these patients.

Comparison of two angiotensin II analogues in normal subjects and hypertensive patients.

Two angiotensin II analogues, i.e., 1-sarcosine, 8-isoleucine angiotensin II (Sar1, Ile8-AII) and 1-sarcosine, 8-alanine angiotensin II (Sar1, Ala8-AII), are now available in the clinical study. Comparative studies of the antagonistic potency and the agonistic effect of these two AII analogues were made in normal subjects on three sodium balances and in hypertensive patients with various etiologies on sodium depletion. Both AII analogues had an agonistic pressor effect in normal subjects. This effect changed with different sodium balances. In the low sodium state, this agonistic action was minimized. The agonistic pressor effect of Sar1, Ile8-AII was greater than that of Sar1, Ala8-AII in all sodium states. There was found an agonistic activity of both AII analogues not only on blood pressure, but also on renin and aldosterone secretion, and renal vasculature in normal subjects on a regular diet. The antagonistic depressor potency of both compounds was also varied by changing sodium balance, being greatest in the low sodium state. In hypertensive patients on sodium depletion, the blood pressure responses of individual patients to these two AII analogues were significantly correlated (r = 0.8, n = 20). These results indicate taht pretreatment of sodium depletion is necessary to prevent the side effect caused by the agonistic pressor action of AII analogue, and also to predict renin depency in hypertensive patients efficiently.