Effect of aprotinin on the rectal delivery of insulin.
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Biomedical subjects
Publications and source records attributed to T Higuchi.
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The secretory profile of prolactin and oxytocin in response to suckling stimuli by litters was studied in unanesthetized and urethane-anesthetized lactating rats. Serum prolactin levels were determined by radioimmunoassay. Oxytocin released at milk-ejection reflex was monitored by the changes in the intramammary pressure and/or the characteristic pup's reaction associated with the milk ejection. Serum prolactin concentrations began to rise earlier than the first milk ejection in unanesthetized rats, but they were never elevated without the appearance of milk ejections in urethane-anesthetized rats. Pulsatile fluctuation in serum prolactin levels at 6-15 min intervals was observed in the nursing period when 10 pups were suckling continually. The intermittent milk-ejection reflex occurred not always but preponderantly (64-91%) when the serum prolactin levels were at the nadir of the fluctuation. Injection of an estimated dose of oxytocin released at each milk ejection (1 mU) did not change the serum prolactin levels. These results indicate that the mechanism for prolactin release may be more susceptible to the effects of anesthesia than that for oxytocin release in response to the suckling stimuli and that the release of both the hormones is pulsatile in nature and be influenced by a common biological clock during the nursing period.
The effect of an increase in plasma osmolality on the milk-ejection reflex of rats was studied. The lactating rats, at day 8-12 of lactation, were anesthetized with urethane (1.1 g/kg, i.p.) and 8-11 pups which had been separated from their mother 16-18 h were put to the nipples to suckle. In 21 of 47 rats studied an intermittent pattern of milk ejection was recorded with a latency of 15-74 min (group-I rats). The mean interval between recurring milk ejections was 8.3 +/- 0.6 (S.E.M.) min and the mean amount of oxytocin released at each milk ejection estimated in 11 of them was 0.26 +/- 0.04 mU. The remaining 26 rats showed no milk ejection throughout the nursing period of more than 90 min (group-II rats). The intraperitoneal injection of 1.5 M NaCl (1 ml) had no effect on the interval between milk ejections but increased the amount of oxytocin released at each milk ejection by 2.4 times in group-I rats, as the plasma osmolality changed from 297.9 +/- 2.7 mOsm/kg to 310.4 +/- 3.6 mOsm/kg. On the other hand, the 1.5 M NaCl injection induced recurring reflex milk-ejections in all of the group-II rats, while the plasma osmolality increased from 307 +/- 2.8 mOsm/kg to 320 +/- 3.1 mOsm/kg. The mean interval was not significantly different from that observed in the group-I rats. The sensitivity of the mammary gland to oxytocin was not altered by the 1.5 M NaCl injection. The injection of isotonic NaCl had no effect on the milk-ejection reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
The authors report a case of giant aneurysm in which extravasation of contrast medium was demonstrated during cerebral angiography and confirmed by computed tomography. A 33-year-old man suddenly lost consciousness and vomited frequently. Three hours later, he was admitted to our hospital in semicomatose state with left hemiplegia. Within two hours after admission, plain CT scan, enhanced CT scan, left carotid angiography and post-angiographic CT scan were performed. CT scan showed marked subarachnoid hemorrhage, left temporal intracerebral hematoma and oval mass which was remarkably enhanced in the left Sylvian fissure. First left carotid angiogram demonstrated a giant aneurysm of the middle cerebral artery which was measured 4.5 cm in maximum diameter. Second left carotid angiogram demonstrated an extravasation of contrast medium around the aneurysm. The patient immediately underwent CT scan, which showed enlargement of intracerebral hematoma and intraventricular high density area as added lesion. By regulation of window level, the presence of contrast medium due to intra-angiographic rupture of the aneurysm was confirmed. The patient expired fifteen hours after admission. At autopsy, the thrombus in the aneurysmal sac was hardly present and the wall of the sac was made mainly of collagen fibers. From the following two points this case was very interesting. However this aneurysm was very large, the thrombus in the aneurysmal sac was hardly present. Extravasation of contrast medium was clearly demonstrated during cerebral angiography with confirmation by computed tomography in the giant aneurysm.
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Dihydroxyacetone synthase, present in methanol-grown Candida boidinii (Kloeckera sp.) No. 2201, catalyzes the transfer of the glycolaldehyde group from xylulose 5-phosphate to formaldehyde to form glyceraldehyde 3-phosphate and dihydroxyacetone. This enzyme was purified to electrophoretic homogeneity and found to be a new type of transketolase. The molecular weight of the enzyme was estimated to be 190,000 by gel filtration. The enzyme appeared to be composed of four identical subunits (Mr, 55,000). Thiamin pyrophosphate and Mg2+ were required for the activity. The optimum pH was found to be 7.0. With xylulose 5-phosphate as the ketol-donor, aliphatic aldehydes (C1-C7), glycolaldehyde and glyceraldehyde were better acceptors than ribose 5-phosphate. The kinetic data were consistent with a ping-pong bi-bi mechanism. The Km values obtained were as follows: xylulose 5-phosphate, 1.0 mM; formaldehyde, 0.43 mM; glyceraldehyde 3-phosphate, 0.42 mM; and dihydroxyacetone, 0.52 mM.
The absorption-promoting effect of sodium 5-methoxysalicylate was studied in the rat with respect to rectal delivery of pentagastrin and gastrin. Rectal bioavailability was quantitated by direct comparison of pharmacological effect with intravenous dose response. Coadministration of the absorption adjuvant greatly enhanced the rectal bioavailability of the model polypeptides. Sodium 5-methoxysalicylate, therefore, is representative of a new type of absorption promoter which appears to facilitate rectal absorption of polypeptide drug entities.
The kinetics and mechanism of hydrolysis of N-(4-hydroxy-3,5-dimethylbenzyl)pyridinium bromide and similar quaternary derivatives of niacinamide, N,N-dimethylaniline, and trimethylamine were investigated. pH-Rate profiles at 25 degrees for formation of tertiary amine and 4-hydroxymethyl-2,6-dimethylphenol indicated that the zwitterionic quaternary phenoxide was the reactive species in alkaline solution. The apparent rate of hydrolysis was strongly inhibited by addition of small amounts of product tertiary amine, which is consistent with the presence of an intermediate in the reaction pathway. A mechanism was proposed for the hydrolysis and methanolysis of these compounds involving the reversible formation of the quinone methide, 4-methylene,-2,6-dimethyl-2,5-cyclohexadien-1-one, followed by a trapping reaction with solvent or nucleophiles. Replacement of the phenolic hydrogen with methyl or acetyl groups greatly stabilized the molecule which is in agreement with the proposed mechanism. For the ester, the rate of amine release was limited by specific base catalyzed hydrolysis of the ester group. Compounds of this type may be useful in prodrug design for tertiary amines. The possibility of quinone methine intermediates in the degradation of structurally similar drugs, such as epinephrine, was discussed.
Ten potential adjuvants for rectal absorption which are structurally similar to salicylate have been examined using an in situ perfusion of the rat rectum technique as well as an in vivo absorption method from microenemas. All of the adjuvants studied readily disappeared from the perfusate at pH 4.5; however, several were not absorbed well at pH 7.4. Only those that were lost rapidly from the perfusate at pH 7.4 were effective in enhancing the disappearance of the drugs (theophylline, lidocaine, cefmetazole, and levodopa) at either a pH of 4.5 or 7.4. The compounds that were effective in promoting the disappearance of drugs from the rectal perfusate all had hydroxy and carboxy groups. Those substances lacking a hydroxy group were not effective. The binding of these potential adjuvants and salicylates to rat rectum tissue was studied by equilibrium dialysis. Those adjuvants with relatively high binding to rat rectal tissue were better absorbed themselves and promoted the disappearance of drugs more than those substances exhibiting little binding. Thus, adjuvant binding to some feature of the rectal membrane appears to be important in the enhanced absorption of drugs from the rectum under the conditions of this study.
Salicylic acid and sodium salicylate have been found to enhance the absorption of lidocaine, levodopa, and cefmetazole after rectal administration to rats. These drugs represent a base (lidocaine), an acid (cefmetazole), and a substance (levodopa) which exists as a zwitterion in solution. The rectal absorption of each type of drug, as well as theophylline, a neutral compound, was enhanced by salicylate, particularly at pH values where the substances exist primarily in their ionic form. A requirement for the observed enhancement is that salicylate be present in the rectal membrane. The loss of drug from the perfusing solution was greater from solutions having an ionic strength of 0.75 than from those with mu = 0.15.
The impact of self-association on mass transport was studied. The model system chosen was the diffusion of phenol through an immobilized layer of isooctane. In the theoretical development, self-associated phenol contributed to diffusion, with the fluxes being interdependent because of the self-association equilibrium. Predictions from theory were then compared with experimental results. It was shown that self-association can significantly affect flux of diffusing species.
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Antimicrobial activity of the following four new N-chloramine compounds was evaluated: two chlorinated simple amino acids, a chlorinated half-ester of succinic acid, and a chlorinated half-ester of glutaric acid. For comparison, the known bactericidal agents 3-chloro-4,4-dimethyl-2-oxazolidinone and chlorhexidine were evaluated by the same procedure. The contact germicidal efficiency screen was used to examine the in vitro bactericidal activity of all six compounds in the absence and presence of 5% horse serum or 5% Triton X-100. The four new compounds were found to have greater germicidal activity than the other compounds tested and to exhibit low toxicity and skin irritation values. The in vivo bactericidal activity was evaluated in two studies. In the occlusion test, three of the four new compounds plus chlorhexidine diacetate were tested. The N-chloramines were significantly superior to chlorhexidine in preventing the expansion of the normal flora under occlusion. In the scrub test, a gloved-hand wash method was used to compare the antimicrobial effect of a 1% solution of the chlorinated half-ester of succinic acid in triacetin with that of a commercial germicidal hand wash containing 4% chlorhexidine gluconate. The two preparations exhibited essentially the same hand-degerming activity.
Ovariectomized rats with neural deafferentation at the level of the posterior border of the anterior hypothalamic area (AC rats) were used to re-evaluate the direct feedback effect of oestrogen on the regulation of LH secretion by the pituitary gland. Synthetic LH releasing hormone (LH-RH; 300 ng/kg), injected at 30 min intervals into AC rats with undetectable basal LH, induced pulsatile increase of serum LH concentrations. Oestradiol-7Beta (5 micrograms), administered i.v. just before the first LH-RH injection, significantly decreased the LH response to a second injection of LH-RH given 30 min later and to subsequent injections. Maximal inhibition was 58%. Oestradiol 17 beta (5 micrograms) given i.v. to control ovariectomized rats decreased serum LH concentrations 40 min after administration; the maximum reduction being 52%. An s.c. injection of oestradiol benzoate (5 micrograms) increased pituitary responsiveness to LH-RH by the next day in AC rats but decreased serum LH levels in control ovariectomized rats. These results indicate that acute inhibitory and chronic facilitatory effects of oestrogen on LH secretion are exerted at the pituitary gland, without a change in LH-RH secretion. The prolonged inhibitory effect of oestrogen is at the level of the hypothalamus and causes a reduction in LH-RH secretion.
In order to characterize the nature of the LH response to exogenous LH releasing hormone (LH-RH) in female rats during the oestrous cycle and after ovariectomy with or without oestrogen treatment, serum LH levels were determined after repeated LH-RH injections (300 ng/kg body wt, six times with 30-min intervals). The LH response to the first LH-RH stimulation was greatest on the days of pro-oestrus and oestrus followed by dioestrus 2 and dioestrus 1. Second and subsequent LH-RH challenges enhanced the LH response only on pro-oestrus and dioestrus 2. Larger doses of LH-RH (3 microgram/kg body wt) induced a small self-priming effect on dioestrus 1 and oestrus. The LH response to the first LH-RH administration increased with time up to 30 days after ovariectomy and then reached a plateau. A small self-priming effect was present in rats ovariectomized for 30 and 60 days, but absent in rats ovariectomized for 5, 10 and 120 days. Oestrogen treatment increased the self-priming effect in rats ovariectomized for 5 days, with little sensitization of the pituitary gland to the first LH-RH injection on the next day. In rats ovariectomized for 120 days, oestrogen treatment enhanced responsiveness to the first and successive LH-RH stimulations on the next day, and further enhancement to the first response only was induced 3 days after oestrogen treatment.
Changes in the characteristics of LH secretory pulses in female rats were determined in different hormonal conditions; during the oestrous cycle and after ovariectomy and oestrogen treatment. The frequency and amplitude of the LH pulses were stable during the oestrous cycle except at oestrus when a pattern could not be discerned because of low LH concentrations. These were significantly lower than those measured during other stages of the cycle. Mean LH concentrations and LH pulse amplitudes increased with time up to 30 days after ovariectomy. The frequency of the LH pulse was unchanged 4 days after ovariectomy when mean LH levels had already increased. The frequency increased 10 days after ovariectomy and then remained stable in spite of a further increase in mean serum LH concentrations. Oestradiol-17 beta injected into ovariectomized rats caused a decrease in LH pulse amplitude but no change in pulse frequency. One day after treatment with oestradiol benzoate no LH pulse was detectable, probably because the amplitude was too small. A generator of pulsatile LH release is postulated and an oestrogen effect on its function is discussed.
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