[Long-term evolution of a patient diagnosed of small lung cancer with extension to the central nervous system]. / Larga evolución de un paciente diagnosticado de cáncer microcítico de pulmón con afectación del sistema nervioso central.

Cell lung cancer is the principal cause of cancer death in men and women. We report the case of a man diagnosed with small cell lung cancer, metastatic from the outset. The disease is stable at present, forty-seven months from dia-gnosis, after receiving different treatment modalities.

Larga evolución de un paciente diagnosticado de cáncer microcítico de pulmón con afectación del sistema nervioso central / Long-term evolution of a patient diagnosed of small lung cancer with extension to the central nervous system

El cáncer de pulmón es la principal causa de muerte por cáncer en hombres y mujeres. Presentamos el caso de un varón diagnosticado de un carcinoma microcítico de pulmón metastásico desde el inicio, con enfermedad estable en la actualidad, cuarenta y siete meses después del diagnóstico, tras recibir diferentes modalidades de tratamiento (AU)

Cell lung cancer is the principal cause of cancer death in men and women. We report the case of a man diagnosed with small cell lung cancer, metastatic from the outset. The disease is stable at present, fortyseven months from diagnosis, after receiving different treatment modalities (AU)

Melatonin concentration before and during testosterone replacement in primary hypogonadic men.

OBJECTIVE: To study circadian levels of melatonin in primary hypogonadic adult men before and after testosterone treatment. DESIGN AND METHODS: Circadian serum melatonin profiles were studied in six men with primary hypogonadism before and during testosterone substitution and compared with an age-matched control group (n = 6). RESULTS: Hypogonadal patients had higher plasma melatonin concentrations than the control group during day time (34.2 +/- 8.8 compared with 5.4 +/- 0.5 ng/l, means +/- SD; P < 0.005) and night-time (74.8 +/- 34.5 compared with 30.8 +/- 3.2 ng/l). A 3 months course of testosterone replacement treatment in the hypogonadal group was followed by a diminution of the amplified melatonin circadian rhythm, with lower mean values both during the day (34.2.8 +/- 8 compared with 12.7 +/- 2.45 ng/l, P < 0.001) and at night (74.8 +/- 34.5 compared with 41.5 +/- 13.5 ng/l, P < 0.01), and a decrease in the total area under the curve (958 +/- 318 compared with 475.5 +/- 222.9, P = 0.046). There was a significant negative correlation between melatonin (r = -0.69) and testosterone concentrations. CONCLUSIONS: These data indicate that diminished testosterone in male primary hypogonadism is associated with enhanced plasma levels of melatonin, and that testosterone substitution treatment induces a deamplification of the circadian rhythm of melatonin values in humans.

Flow cytometry analysis of pituitary adenomas.

UNLABELLED: Using flow cytometry, DNA content and index, and/or proliferative capacity (measuring proliferating cell nuclear antigen PCNA) in operated pituitary tumors, control pituitaries obtained at necropsy, and experimental pituitary hyperplasia induced in rats were analyzed. Simultaneous measurement of cell ploidy and proliferation differentiated normal pituitary (diploid DNA index and negative PCNA) from pituitary hyperplasia (diploid DNA index with intensely positive PCNA, between 30 and 72% of cells). In the tumors 83% (19/ 23) were positive for PCNA (between 3 and 84%) and 73% (17/23) aneuploid; only 1 tumor was diploid and negative for PCNA. CONCLUSIONS: Differentiation between normal and abnormal (neoplastic or hyperplastic) pituitary is possible by flow cytometry, but in the adenomas no correlation with postoperative clinical outcome was observed.

In vivo and in vitro flow cytometry comparative analysis of somatostatin-positive cells in the pineal gland of the neonatal rat.

Flow cytometry was used for comparative in vivo and in vitro analysis of cell populations staining positively for somatostatin. Experiments were carried out with pineals obtained from neonatal, 8- and 15-day-old rats. Pineal cells were obtained by dispersion with collagenase and then processed in a flow cytometer or maintained in culture for 1 or 2 weeks. Identification of somatostatin-immunopositive cell populations was performed using a polyclonal somatostatin antibody and confirmed by indirect immunostaining of cytospun smears with the avidin-biotin-peroxidase method. In vivo, the percentage of somatostatin-positive cells was 60.6 +/- 4% in neonatal pineals and declined to 22.2 +/- 11% in 15-day-old animals (p < 0.04). The density of peptide immunostaining decreased in 8-day-old animals but recovered to the neonate levels in 15 day-old animals; homogeneity in the immunopositive population increased with age. Maintenance in culture for 1 week resulted in an increase in positive somatostatin staining in animals of 8 and 15 days with no changes in neonates; however, after 2 weeks of culture, the percent of immunopositive cells decreased from 53.3 +/- 6 to 12.2 +/- 4% in the older animals and remained unchanged in neonates. We conclude that somatostatin is found in pinealocytes and shows a declining pattern during the perinatal period; this probably implies that the peptide plays a paracrine role important for cell differentiation in these young animals, since maximal cellularity and a high mitotic index occur within the first 3 days of life, and pineal cell differentiation is completed before the end of the third week of extrauterine life.

Expression of somatostatin in rat pineal cells in culture.

The expression of somatostatin mRNA was investigated in rat pineal cells after 1 week in culture, using reverse transcription of mRNA into cDNA and the polymerase chain reaction. The positive expression in cultured pineal cells demonstrates the capacity of this gland to synthesize somatostatin in denervated cells. Thus, apart from the neural origin of pineal somatostatin, which has been described in detail in the bovine species, a parenchymal source is demonstrated.

MK-927: a topically active ocular hypotensive carbonic anhydrase inhibitor.

MK-927 (dl-5,6-dihydro-4-(2-methylpropylamino)-4H-thieno(2,3b)thiopyra n-2-sulfonamide-7,7-dioxide hydrochloride) is a water soluble, carbonic anhydrase inhibitor (CAI) possessing a Ki of 12.0 nM against purified human carbonic anhydrase II in vitro. The acute instillation of one drop (50 microliters) of 0.5%, 1% and 2% solutions of MK-927 maximally decreased the intraocular pressure (IOP) of ocular hypertensive, cynomolgus monkeys by 4.7, 5.9 and 9.6 mm Hg, respectively. The decline of 9.6 mm Hg represented a reduction of 27% from the corresponding vehicle-treated value of 35.3 mm Hg. Peak reductions in IOP were present at 2 to 4 hr after the instillation of the three doses and the ocular hypotensive effect was waning at 6 hr. The IOP of normotensive, monkey eyes was significantly lowered by 1% and 2% solutions of MK-927 with the effect being more transient in these eyes than in hypertensive eyes. The elevated IOP of alpha-chymotrypsinized rabbits was dose-dependently decreased by 0.01%, 0.1% and 0.5% solutions of MK-927. MK-927 modestly bound to rabbit ocular pigment in vitro and the concentrations of MK-927 in the iris + ciliary body of pigmented rabbits were higher than those in the same tissue of albino rabbits after dosing with 0.5% MK-927. The ocular hypotensive effect of 2% MK-927 was greater in magnitude and longer in duration in normal pigmented than in albino rabbits. The IOP lowering action of MK-927 was local as evidenced by results of ocular distribution studies and the observation that the unilateral instillation of 0.5% MK-927 into the contralateral eye was devoid of effect on the untreated, hypertensive eye of alpha-chymotrypsinized rabbits. MK-927 has been selected for topical evaluation in glaucoma patients.

Immunoreactive somatostatin diurnal rhythms in rat pineal, retina and harderian gland: effects of sex, season, continuous darkness and estrous cycle.

Diurnal profiles of the content of immunoreactive somatostatin (IRS) in the male and female rat pineal, Harderian gland and retina have been studied. Supplementary experiments have been performed to elucidate a possible effect of infradian cycles, namely estrous and seasonal cycles, and continuous dark on IRS concentration. Results demonstrate that the IRS content in the rat pineal gland, Harderian gland and retina is submitted to diurnal variations, but not under all studied conditions. A sexual dimorphism exists between male and female animals: male rats showed higher IRS content in pineal (103.8 +/- 4.7 vs 32.3 +/- 1.8 pg IRS/gland), but lower in retina (1,362.1 +/- 82.7 vs 2,176 +/- 102.2 +/- pg IRS/mg of protein) and Harderian gland (10.3 +/- 0.8 vs 30.6 +/- 3.5 pg IRS/mg of protein). Additionally, seasonal differences appeared: in male and female animals pineal IRS content was lower in spring than in November. This decrease also appeared in female retina IRS concentration. Estrous cycle did not seem to change IRS content in the three studied tissues. Finally, pineal IRS rhythm persisted after continuous dark for a week. These results demonstrate, in the rat, sexual differences in the IRS content of the various tissues studied and suggest a physiological role for somatostatin, possibly related to seasonal adaptation.

Regional distribution of immunoreactive somatostatin in the bovine pineal gland.

Regional distribution of immunoreactive somatostatin (IRS) and melatonin were investigated in the bovine pineal gland. The total IRS and melatonin content ranged from 0.26 to 2.28 pmol, and from 19.4 to 42.7 pmol, respectively, per bovine pineal. Reverse phase liquid chromatography of pineal extracts demonstrated that more than 90% of IRS coeluted with synthetic somatostatin-14 and somatostatin-28. While the IRS content was shown to vary considerably throughout the gland, with a constant and marked maximal concentration at the proximal end of the pineal, the maximal melatonin concentration appeared in the central part of the gland, coinciding with the total protein distribution. The existence of the highest levels of pineal IRS near the habenular commissure, where the afferent fibers of the central pinealopetal innervation enter the gland, suggests that pineal somatostatin may be, at least in part, of neural origin.

Identification of immunoreactive somatostatin in the rat harderian gland: regulation of its content by growth hormone, beta-adrenergic agonists and calcium channel blockers.

Immunoreactive somatostatin (IRS) was identified in the male rat Harderian gland (HG) by radioimmunoassay. Tissue was extracted and a displacement curve performed; there were no significant differences between values obtained with serial dilutions of extracted tissue and those from purified somatostatin standard used in the radioimmunoassay. Basal values of HG-IRS were found to be in the nanomolar range (10.8 +/- 3.5 ng IRS/mg protein). Hypophysectomy did not change the HG-IRS but, in vivo growth hormone (GH) treatment led to a dramatic increase (6-7-fold) in the levels of IRS in the HG. Isoproterenol, a beta-adrenergic agonist, when administered in vivo significantly decreased the HG-IRS content. The effect of two different calcium channel blockers on the isoproterenol-induced decrease of HG-IRS was studied; no changes were observed with nifedipine but verapamil, injected one hour after isoproterenol administration, prevented the drop in HG-IRS levels. These data demonstrate the existence of IRS in a new location, the rat Harderian gland, and support a classical endocrine regulation for its tissue concentration.

L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.

L-653,328 is the acetate ester of L-652,698 ((S)-3-tert-butylamino-1-[4-[2(hydroxy)ethyl]phenoxy]2-propanol). The penetration of L-652,698 into the albino rabbit eye was enhanced when the compound was instilled as its prodrug acetate ester. The instillation (one drop of 50 microliter) of 0.01, 0.05 and 0.1% solutions of L-653,328 significantly decreased in a dose-dependent manner the elevated intraocular pressure (IOP) of alpha-chymotrypsinized rabbits by 3.2, 4.7 and 6.1 mm Hg, respectively. A 0.01% solution of L-652,698 failed to significantly lower IOP, whereas this dose of timolol (3.8 mm Hg) and betaxolol (3.3 mm Hg) was effective. L-652,698 was active at 0.05% and 0.1%. Extraocular beta-adrenoceptor blockade was quantified in ganglion-blocked, conscious rabbits by determining effects on heart rate and blood pressure changes to i.v. isoproterenol (0.5 microgram/kg). Doses of timolol blocking isoproterenol-induced hypotension and tachycardia by 50% were 0.0065% and 0.03%, respectively. The corresponding doses for betaxolol were greater than 3% (43% inhibition) and 0.3%. Heart rate and blood pressure changes to isoproterenol were blocked by 18 and 36%, respectively, after the instillation of a 3% solution of L-653,328. The reduced propensity of L-653,328 for extraocular beta-adrenoceptor blockade stems from the modest affinity of L-652,698, its active moiety, for beta-adrenoceptors. The Ki values of L-652,698 for displacement of 125I-iodocyanopindolol binding to beta 1-(left ventricle) and beta 2-binding sites (iris + ciliary body) in the rabbit were 5.7 microM and 7.3 microM, respectively. In marked contrast, the corresponding values for timolol were 12 nM and 1.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhythms in pineal immunoreactive somatostatin in the Syrian hamster, mouse, and gerbil.

Immunoreactive somatostatin (IRS) has been previously demonstrated in the pineal gland of different rodent species, and we observed a 24-hr rhythm in rats. Recent data suggest that the peptide may represent a neurotransmitter in the so-called peptidergic nerves of the central, pinealopetal innervation of the epiphysis, which may modulate the activity and secretion of the gland. We investigated whether 24-hr changes of pineal IRS content occurred in Syrian hamsters, gerbils, and mice. Adult males, kept in a 14:10 LD photoperiod, were decapitated at 4-hr intervals throughout a 24-hr period. Pineals and median eminences were analyzed for IRS by radioimmunoassay. No significant changes in the median eminence content of IRS with time was observed. As previously described in rats, a statistically significant rhythm of IRS was observed in the pineal of hamsters and mice, with a peak at 2000 hr (mice 51.7 +/- 5 pg/pineal; hamsters 26.3 +/- 4.6) and a nadir at 2400 hr (mice 30.8 +/- 1.4) or 0400 hr (hamsters 8.6 +/- 1). However, in the gerbil pineal IRS content remained unchanged throughout the period of study. Since the three species examined have very different melatonin cycles, it is suggested that the melatonin and IRS rhythms are unrelated and independently regulated events within the pineal gland.

On the pharmacology of L-645,151: a topically effective ocular hypotensive carbonic anhydrase inhibitor.

L-645,151 [(2-sulfamoyl-6-benzothiazolyl)-2,2-dimethylpropionate] is the O-pivaloyl ester of L-643,799 (6-hydroxybenzothiazole-2-sulfonamide), topically administered L-645,151 being a substrate for ocular esterases with the resultant liberation of the active moiety, L-643,799, during penetration of the ocular surface. The minimum concentrations of topically administered suspensions (1 drop of 50 microliters into both eyes) of L-645,151, L-643,799, dichlorphenamide and methazolamide significantly lowering the elevated intraocular pressure (IOP) of the alpha-chymotrypsinized rabbit eye were 0.25, 2, 10 and 5%, respectively. IOP was not significantly decreased by 10% suspensions of acetazolamide or ethoxzolamide. The IOP lowering action of L-645,151 was local as the unilateral instillation of L-645,151 (0.25%) into the contralateral eye was devoid of effect in alpha-chymotrypsinized rabbits. L-645,151 (2%) decreased aqueous humor inflow in both the conscious rabbit and the anesthetized dog. Outflow facility in the conscious rabbit was unaltered by a 10% suspension of L-645,151. Low peak levels (0.52 microgram/g) of L-643,799 were present in rabbit renal cortex after the instillation of L-645,151 (2%) into both eyes; this treatment did not induce diuresis in the conscious rabbit. The corresponding maximum concentration in the iris + ciliary body was 4.01 micrograms/g. These preclinical studies reveal that L-645,151 is the most potent, topically effective ocular hypotensive carbonic anhydrase inhibitor described to date.

A study on the ocular and extraocular pharmacology of metipranolol.

Metipranolol (Betamann) is a clinically efficacious ocular hypotensive drug and preclinical experiments were undertaken to characterize this beta-adrenoceptor antagonist. In vitro beta1- and beta2-adrenoceptor antagonism was evaluated using the guinea pig atrium and the rat uterus, respectively. The respective pA2 values were 8.3 and 8.4. Topical metipranolol, 0.3% and 0.6%, blocked both the hypotension (beta2-mediated) and the tachycardia (beta1-mediated) elicited in ganglion-blocked, conscious rabbits by isoproterenol, 0.5 microgram/kg, i.v. The Ki for displacement of 3H-dihydroalprenolol binding to rabbit iris + ciliary body homogenates was 34 nM. The effect of metipranolol, 0.3% and 0.6%, was not particularly striking on the intraocular pressure (IOP) of conscious, normotensive rabbits. However, the elevated IOP of the alpha-chymotrypsinized rabbit eye was significantly decreased (maximum reduction of 5.8 mm Hg) following the instillation of metipranolol, 0.3%. IOP recovery in conscious rabbits following hyperosmotic challenge (i.v. infusion of a 20% NaCl solution) was not decreased by a 1-h pretreatment with a 0.3% solution. In contrast, a significant reduction of 41% was elicited by a 0.6% solution. Hence, the ocular hypotensive effect of metipranolol may result from decreased aqueous humor inflow. Metipranolol, 0.6%, was devoid of effect on rabbit pupil diameter. However, corneal local anesthesia was elicited in the rabbit by both 0.3% and 0.6% solutions of the drug, the effect being more marked with the higher concentration.