Nonsteroidal antiinflammatory agents. 3. Synthesis of the positional isomers of 4'-chloro-5-methoxy-3-biphenylylacetic acid and their antiinflammatory and analgesic activities.

The positional isomers 3a-i of 4'-chloro-5-methoxy-3-biphenylylacetic acid [1 (DKA-9), R = 4-ClPh; R' = MeO] which is a newly developed nonsteroidal antiinflammatory agent, have been prepared and evaluated for antiinflammatory and analgesic activities using both the carrageenan-induced rat paw edema and AcOH writhing assays. The 3- and 4-biphenylylacetic acids 3a,d, which closely resemble 1 (R = 4-ClPh, R' = MeO) structurally, showed, by far, excellent activities compared with the other isomers in these assays. However, none of the compounds tested was more active than 1 (R = 4-ClPh; R' = MeO). In this series of compounds, structural requirements for good antiinflammatory activity seemed to be parallel to those for analgesic activity.

Nonsteroidal antiinflammatory agents. 2. Synthesis of 4',5-disubstituted 3-biphenylylacetic acids and their derivatives with antiinflammatory and analgesic activities.

A series of 5',5-disubstituted 3-biphenylylacetic acids (5a-n) and several alpha-methyl derivatives (5o-v) were prepared as analogues of a newly developed nonsteroidal antiinflammatory agent, 5'-chloro-5-methoxy-3-biphenylylacetic acid [1 (DKA-9), R = 4-C1Ph; R' = Me], and evaluated for antiinflammatory and analgesic activities using both carrageenan rat paw edema and AcOH writhing assays. Among them, 5-fluoro-3-biphenylylacetic acid (5m) showed the highest antiinflammatory activity, while 2-(3-biphenylyl)propionic acid (5o) showed the highest analgesic activity. However, they were less potent than 1 (R = 4-C1Ph; R' = Me) in these assays.

Influence of repeated cocaine exposure on the endocrine and behavioral responses to stress in rats.

Previous studies have determined that chronic cocaine exposure inhibits the serotonergic stimulation of hormone secretion. The present experiments were conducted to determine whether the endocrine responses to stress could be a useful approach to assess the influence of cocaine exposure on neuronal function. Male rats received twice daily injections of cocaine (1-15 mg/kg, IP) for 7 days. Animals were subsequently exposed to different stressors, i.e. conditioned emotional stress utilizing a low (0.5 mA) or high (1.5 mA) intensity footshock during training, or to immobilization stress. Immediately after the stress procedures, blood samples were collected for radioimmunoassay of plasma corticosterone, prolactin, and renin concentrations. Repeated cocaine exposure attenuated the stress-induced elevations of corticosterone and prolactin secretion, and attenuated some of the behavioral effects of the low intensity conditioned emotional stress. When exposed to the high intensity conditioned emotional stress, cocaine did not alter the endocrine or behavioral effects of stress. Finally, repeated cocaine exposure modified the immobilization stress-induced elevation of renin secretion; low doses of cocaine (1 or 5 mg/kg) attenuated, while higher doses (10 mg/kg) potentiated the renin response to immobilization stress. Thus, the influence of repeated cocaine exposure on the endocrine and behavioral responses to stress appears to depend upon the type and intensity of the stressor. Compared with previous studies which found altered neuroendocrine responses to serotonin releasers and agonists following cocaine exposure, the hormonal responses to stress are less consistently modified by cocaine.

Cytoarchitectonic subdivisions of the parabrachial nucleus in the Japanese monkey (Macacus fuscatus) with special reference to spinoparabrachial fiber terminals.

The cytoarchitectonic subnuclear organization of the parabrachial nucleus (PB) surrounding the brachium conjunctivum (BC) in the monkey was examined using the Nissl method and the anterograde axonal flow method. PB of the monkey could be divided into the following subnuclei: the dorsal area (DPBM) along the medial surface of the medial three-fourths of BC in the caudal half of medial PB (PBM), the ventral area (VPBM) along the medial surface of the lateral one-fourth of BC in the rostral two-thirds of PB, the ventrolateral part of lateral PB (PBL) lateral to BC throughout PB (EL), the ventral part of the rostral half of PBL ventral to EL (EXL), the medial part of middle PBL along the dorsal surface of BC (VL), the dorsal and lateral marginal part of PBL in the rostral two-thirds of PB (DL), the cell cluster in the dorsomedial part of the rostral half of PBL between VL and DL (CL), the dorsocentral part appearing at the level of root exit of the trochlear nerve between DL and CL and extending to the rostral end of PBL (IL), the area between DL and IL in the rostral one-seventh of PBL (SL), and Kölliker-Fuse nucleus (KF) ventral to EL and BC in the middle one-third of PB and lateral to the lateral pontine tegmentum. After the injection of biotinylated dextran amine into the upper cervical segments, labeled fibers terminated in each subdivision of PB with different densities; most heavily in IL, more heavily in DL and KF, moderately in EL and VPBM, and scarcely in the rest of PB. The present study demonstrated for the first time the subdivisions of PB in the monkey, which were essentially common to those of the rat based on the cytoarchictecture of PB and spinal fiber terminals in it.

Role of midbrain raphe in stress-induced renin and prolactin secretion.

Stress-induced changes in renin and prolactin secretion were studied using a conditioned emotional response paradigm. Three minutes after being placed in a chamber, the stressed animals received a brief electric shock (1.0 mA for 10 s through the grid floor), then were returned to their home cage. This procedure was repeated for 3 consecutive days. On the fourth day, the rats were placed in the chamber for 3 min, but instead of receiving shock, they were removed and sacrificed. Control animals were treated in the same manner, except that they never received foot shock. The sham-operated stressed rats evidenced significant elevations in plasma renin activity (270%) and prolactin level (550%). Electrolytic lesions in the dorsal raphe nucleus blocked the stress-induced increase in plasma renin activity but did not affect the stress-induced increase in prolactin secretion. Electrolytic lesions in the median raphe nucleus did not affect prolactin levels in either control or stressed animals. However, median raphe lesions led to a significant increase in plasma renin activity in non-stressed rats and potentiated the stress-induced elevation in plasma renin activity. These results suggest that neurons within the dorsal and median raphe nuclei are involved in the regulation of renin but not prolactin secretion during stress. The results also suggest that median raphe neurons play a role in basal renin secretion.

Cocaine-induced suppression of renin secretion is mediated in the brain: investigation of cardiovascular and local anesthetic mechanisms.

Acute cocaine reduces renin secretion. To determine a peripheral versus central site of action, intracerebroventricular (ICV) versus intraperitoneal (IP) injections of cocaine were compared. Cocaine was more potent reducing plasma renin activity (PRA) and concentration (PRC) when injected ICV (0.050 mg/kg) than IP (5 mg/kg), suggesting a central site of action. Furthermore, addition of cocaine (10(-4) M) to kidney slices in vitro did not influence renin release, indicating that cocaine does not suppress renin secretion by acting directly in the kidney. We also investigated whether the hypertensive or local anesthetic properties of cocaine mediate its inhibition of renin secretion. Therefore, we compared the cardiovascular and endocrine effects of cocaine with those of the local anesthetic drug procaine. Both cocaine and procaine (500 micrograms/kg, ICV) produced rapid and short-term increases in blood pressure, but cocaine decreased PRC whereas procaine increased PRC. Intra-arterial (IA) and IP injections of cocaine also reduced PRC whereas procaine had no effect (IA) or elevated PRC (IP). Together, the data suggest that cocaine decreases renin secretion by acting in the brain. It is not likely that the cardiovascular or local anesthetic actions of cocaine are the main cause of its suppressive effect on renin secretion.

Significance of different levels of the Edinburgh 2 coma scale calculated from the outcome of neurosurgical patients.

In the management of patients with acute cerebral disturbances, it is essential to determine precisely the degree of impaired consciousness. In order to secure the accuracy of observations, one must use a reliable coma scale. We have evaluated the Edinburgh 2 coma scale (E2CS) and explored the relationship between levels of the E2CS and the final outcome. Case notes and observation charts of the past 7 years were reviewed, covering neurosurgical operations on 406 patients, in each of whom the postoperative course was evaluated periodically by the E2CS and the outcome was determined by the Glasgow outcome scale. By matching the outcome with each level of impaired consciousness, about 22,000 pairs of data were obtained. In order to quantify the morbidity rate, different stages of the Glasgow outcome scale were rated from 100 through 0, arbitrarily. It was proved that levels of the E2CS were arranged in the correct order in respect to both mortality and morbidity rates. It was shown at the same time that each level has different prognostic significance and that the distance between each level is not identical. The recommendation is made to separate the levels on a chart not by an ordinal number but by the distance calculated on the basis of either mortality or morbidity rates. This will make it possible to get a rough estimate of the patients' prognoses by simply looking at a daily clinical chart.

ICV injection of the serotonin 5-HT1B agonist CP-93,129 increases the secretion of ACTH, prolactin, and renin and increases blood pressure by nonserotonergic mechanisms.

This study tested whether a new serotonin (5-HT1B) agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxy-pyrrolo[3,2-b]pyridine (CP-93,129), could be used to study the potential role of 5-HT1B receptors in the secretion of adrenocorticotropic hormone (ACTH), prolactin, and renin. CP-93,129 has a high affinity for 5-HT1B receptors but low affinity for other 5-HT receptor subtypes. In addition, CP-93,129 does not readily cross the blood-brain barrier. The secretion of ACTH, prolactin, and renin is known to be increased after activation of 5-HT receptors. ICV injections of CP-93,129 (100 micrograms/kg) increased the plasma concentrations of ACTH, prolactin, and renin. CP-93,129 also increased blood pressure and reduced heart rate. To determine whether these effects of CP-93,129 are centrally mediated, we compared them with IP injection of the same dose of CP-93,129. IP-injected CP-93,129 did not alter blood pressure or heart rate and did not elevate plasma prolactin and renin concentrations. To determine whether 5-HT1B receptors mediate the central effects of CP-93,129, rats were pretreated with the 5-HT antagonists l-propranolol or metergoline prior to ICV injections of doses of CP-93,129 (0-100 micrograms/kg). The 5-HT1A/1B/2A/2C antagonist metergoline (0.5 mg/kg, IP) failed to inhibit the CP-93,129-induced elevation of ACTH, prolactin, or renin concentrations. In contrast, the 5-HT1A/1B/beta antagonist l-propranolol (20 micrograms/kg, ICV) inhibited the renin but not the ACTH or prolactin responses to ICV CP-93,129.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative vibrational and NMR study of cis-cinnamic acid polymorphs and trans-cinnamic acid.

The IR and Raman spectra of the two polymorphic forms (58 degree- and 68 degree-forms) of cis-cinnamic acid were measured, and the spectral differences discussed on the basis of the crystal structures of the two forms. The IR bands related to the COOH group differ in the frequencies and band shape, reflecting differences in the hydrogen bonding between the two modifications. These spectra were compared with those of trans-cinnamic acid. The IR, Raman, and NMR spectra of the isotopic compounds, including the deuterated and 13C analogs of the cis and trans acids, were also recorded in the solid state and in solution to confirm the spectral assignments.

Molecular structure and vibrational spectra of phenolphthalein and its dianion.

Infrared (IR) and Raman spectra of phenolphthalein (PP) and its dianion form (sodium and potassium salts) were studied both in the solid state and in aqueous solution. Band assignments were carried out on the basis of the isotope shifts of the ring deuterated and 13C-substituted derivatives. Spectral analyses reveal that the PP dianion exists as mixtures of the benzenoid form (colorless) and the quinonoid form (colored) in the solid state and in aqueous solution, while the neutral PP solely takes the gamma-lactone form. This work provides the first vibrational spectroscopic evidence for the coexistence of the two species in the PP dianions.

[Estimation of prognosis in patients with putaminal hematoma].

In order to determine the factors affecting the functional prognosis of operated putaminal hematoma patients, the relationship between the final outcome and the acute stage clinical factors were analyzed by the use of multimodality analysis method (Hayashi's Qualification Type 2). Forty-five consecutive cases who admitted to and operated on during the last two years were included in this study (30 male and 15 female patients, the distribution of age was 40 to 75 years old). Clinical factors just prior to surgery were collected from the case record and categorized to calculate the Pearson's product moment correlation coefficient against the Glasgow Outcome Scale. Five clinical factors with the correlation coefficient above 0.5 (Edinbugh 2 coma scale (0.85), light reflex (0.67), respiratory status (0.61), age (0.58) and the side of the lesion (0.50) were used to apply the Hayashi's Qualification Type 2 analysis. By this method, each categories are given scores so that the different outcome separate maximally. The correct estimation ratio for outcome was 100% for good recovery, 30% for moderately disabled, 50% for severely disabled and 88% for death, over all correct estimation ratio being 69%. The mean scores for each outcome were 1 +/- 0.01 for good recovery (9 cases), 0.74 +/- 0.32 for moderately disabled (10 cases), 0.6 +/- 0.36 for severely disabled (10 cases) and -0.16 +/- 0.37 for dead (16 cases). There were statistical significance (p less than 0.01) between each outcome except for moderately disabled and severely disabled.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct maxacalcitol injection into hyperplastic parathyroids improves skeletal changes in secondary hyperparathyroidism.

Direct maxacalcitol (OCT) injection into a parathyroid gland (PTG) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism (s-HPT): the upregulations of vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis. In this study, we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s-HPT. Five/six nephrectomized Sprague-Dawley rats were fed a high-phosphorus and low-calcium diet for 8 weeks. These rats were divided into four treatment groups: (1) basic uremic (at the baseline), (2) direct OCT single injection into PTGs (DI-OCT) followed by OCT intravenous administration for 4 weeks (IV-OCT), (3) direct vehicle injection and IV-OCT, and (4) no treatment for an additional 4 weeks. The effects of these treatments on serum intact-parathyroid hormone (PTH) level, PTG weight, VDR and CaSR expression levels in PTGs, and bone histomorphometric parameters were investigated. In the DI-OCT+IV-OCT group, the significant decrease in serum intact-PTH level was maintained by the following IV-OCT. A significant decrease in PTG weight and the upregulations of VDR and CaSR expression levels in PTGs were also observed. Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones. However, these findings were not observed in the other groups. These results suggest that osteitis fibrosa caused by advanced s-HPT can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI-OCT+IV-OCT.

[Potential obstetrical application of prostaglandins].

PIP: The potential obstetrical application of prostaglandins (PGs), in particular PG F2-alpha (PGF2a), PGE2, and PGE1 is discussed. Much of the research discussed is based upon experiments performed either on human females or on rats and sheep. Some important applications of PGs (particularly PGE2) are for inducing labor, regulating uterine contractions during delivery, and making uterine walls more flexible. PGE1 (or preglandin, as it is commercially known) is widely used to induce abortion in the intermediate stages and bring about uterine contractions. PGF2a can be used to stop bleeding caused by uterine relaxation and to treat puerperium bladder paralysis. PGE1 application for intrauterine growth retardation is also mentioned. PGs can also be used to treat patent ductus arteriosus. Some general methods for administering PGs are also discussed.^ieng

Effect of castration on the appearance of diabetes in NOD mouse.

To examine the influence of sex hormones on the appearance of overt diabetes in NOD mice, oophorectomy and orchiectomy were performed. Castrated males showed a high incidence of diabetes. The time course of onset was similar to that of the intact females. On the other hand, castrated females showed a intact-male pattern of onset with a low incidence. Clinical determinations demonstrated a close similarity between spontaneous and castration-induced diabetes. These data suggest that sex hormones modulate the expression of overt diabetes in NOD mouse, i. e. androgens have at least a suppressive effect.