[Study of the comorbidities in hospitalized patients due to decompensated chronic obstructive pulmonary disease attended in the Internal Medicine Services. ECCO Study]. / Estudio de las comorbilidades en pacientes hospitalizados por descompensación de la enfermedad pulmonar obstructiva crónica atendidos en los servicios de Medicina Interna. Estudio ECCO.

OBJECTIVE: Evaluate comorbidity in patients hospitalized due to COPD in the Internal Medicine services. METHODS: An observational, prospective and multicenter study. The Charlson index and a specific questionnaire were used. RESULTS: A total of 398 patients, 353 men (89%), with mean age of 73.7 years (8.9) and mean FEV(1) of 43.2% (12.5), were included. The most frequent comorbidities were: arterial hypertension (55%), arrhythmias (27%) and diabetes mellitus (26%). A total of 27% suffered heart failure, 17% coronary disease and 9% previous myocardial infarction. The number of associated chronic diseases was 3.6 (1,8). Score on Charlson index was 2.72 (2). CONCLUSIONS: The patients hospitalized due to decompensated COPD had an elevated comorbidity.

Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil.

Gemfibrozil, a novel hypolipidemic agent identified chemically as 2,2-dimethyl-5-(2,5-xylyoxy) valeric acid, was evaluated for mutagenic potential in in vitro assays with Salmonella typhimurium. For evaluation of tumorigenic potential, gemfibrozil was administered in the diet (0.30, and 300 mg gemfibrozil/kg) to groups of noninbred CD-1 mice (72/sex) and noninbred CD rats (50/sex) for 78 and 104 weeks, respectively. In the bacterial mutagenesis assays, between 100 and 2,500 microgram gemfibrozil/plate failed to induce a significant increase in revertant bacterial colonies. Neither was a mutagenic response in bacterial assays induced at concentrations up to 300 microgram of five in vivo metabolites of gemifibrozil isolated from rat urine/plate. In mice, gemfibrozil did not significantly increase the frequency or the mean latency period of tumors. In rats, the statistically significant increases in hepatocellular tumors and interstitial cell tumors of the testes were dose related. Adrenal medullary and pancreatic acinar tumors were increased in male rats but were inversely dose related. Under the conditions of this assay, gemfibrozil did not elicit a tumorigenic potential in mice and female rats. In male rats and related to the hepatocellular tumor response, the peroxisome proliferation seen did not occur in humans chronically administered hypolipidemics.

[Method for the study of pulmonary function in laryngectomized patients]. / Método para el estudio de la función pulmonar en los laringectomizados.

OBJECTIVE: The aim of the study is to develop a instrumental method capable to achieve pulmonary air function test (spirometry) by assembling the spirometer mouthpiece to the laryngectomized patient's stoma. MATERIAL AND METHOD: Our study was carried out in 33 laryngectomized patients (all male). The spirometer tests were done with a Datospir 92 by Sibelmed equipment, which consists of a dry Fleish pneumotacographer with flow and volume chart register. We have made a stoma-spirometer adapter with a cardboard tube, an adhesive and silicone disc. RESULTS: The whole sample achieved excellent outcome with the stoma-spirometer adapter. Nor air leak neither high resistence were measured while spirometry was performed. CONCLUSIONS: We consider that the facts studied may enable us to add, pragmatically, new resources to the more effective understanding of the respiratory handicap in the laryngectomized population.

[Qualitative spectral evaluation of oesophagic voice]. / Evaluación espectral cualitativa de la voz esofágica.

OBJECTIVES: The aim of the study is to determine the accuracy of acoustic spectrography as an outstanding tool in the characterization and monitoring of esophageal voice. MATERIAL AND METHODS: Our subjects were comprised of 33 laryngectomized patients (all male) that underwent qualitative acoustic (spectrography of vowel /a/ and a sentence), quantitative acoustic (phonation time, fundamental frequency, maximun intensity sound level, speech rate) and perceptual protocol. RESULTS: There is a significant statistical relationship among Yanagihara-like spectrographic chart classification, psycho-acoustical perception and quantitative acoustic parameters. CONCLUSION: We consider that acoustic spectrography is an easy, effective method for studying esophageal voice, seeking for improving oral communication skills and rehabilitation in the laryngectomee population.

[Amyloidosis in the ORL field]. / La amiloidosis en el area otorrinolaringológica.

OBJECTIVES: To review the clinical and pathological characteristics of upper aerodigestive tract amyloidosis with particular attention to laryngeal amyloidosis. Amyloidosis of the upper aerodigestive tract is relatively rare. The larynx is the most common site of involvement in head and neck isolated amyloidosis and the supraglottic region represents the major site of involvement. MATERIAL AND METHODS: Retrospective review of 6 patients diagnosed with upper aerodigestive tract amyloidosis. Hoarseness and airway compromise were the main presenting symptoms. RESULTS: Laryngeal CO2 laser microsurgery was performed and then we refered the patients to the Medical Deparment seeking for systemic involvement and ENT Clinic follow up. CONCLUSIONS: In our experience, laryngeal CO2 laser microsurgery is a succesfull way to treat isolated laryngeal amyloidosis with clinical improvement and low recurrence rates.

[Acoustic and aerodynamic characteristics of the oesophageal voice]. / Caracterización acústica y aerodinámica de la voz esofágica.

OBJECTIVE: The aim of the study is to determine the physiology and pathophisiology of esophageal voice according to objective aerodynamic and acoustic parameters (quantitative and qualitative parameters). MATERIAL AND METHODS: Our subjects were comprised of 33 laryngectomized patients (all male) that underwent aerodynamic, acoustic and perceptual protocol. RESULTS: There is a statistical association between acoustic and aerodynamic qualitative parameters (phonation flow chart type, sound spectrum, perceptual analysis) among quantitative parameters (neoglotic pressure, phonation flow, phonation time, fundamental frequency, maximum intensity sound level, speech rate). CONCLUSION: Nevertheles, not always such observations bring practical resources to clinical practice. We consider that the facts studied may enable us to add, pragmatically, new resources to the more effective vocal rehabilitation to these patients. The physiology of esophageal voice is well understood by the method we have applied, also seeking for rehabilitation, improving oral communication skills in the laryngectomee population.

Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment.

The effects of long-term gemfibrozil (Lopid) therapy on human liver structure are not known. Studies of this nature are becoming essential in determining the risk/benefit ratio since gemfibrozil is an effective agent for the control of hyperlipoproteinemia types IIa, IIb, and IV. Particularly, gemfibrozil is effective when dietary management or available therapeutic control fail to reduce serum cholesterol and triglycerides as well as normalizing the lipoprotein pattern. Percutaneous liver biopsies of 9 patients on long-term gemfibrozil therapy were evaluated by light microscopy, interference contrast optics and transmission electron microscopy. The distribution of patients according to lipoprotein phenotype was 3 Type IIa, 3 Type IIb, and 3 Type IV. Their lipoprotein patterns approached normal and the serum lipids were controlled during gemfibrozil therapy. By light microscopy, the lobular architecture and other parameters were within normal limits. Varying degrees of fatty change were found as would be expected. No preferential lobular disposition of the fat globules was evident. Coalescence of fat droplets, nuclear displacement and fatty cysts were noted. Differential interference contrast microscopy revealed several degrees of contrast amplitude in these droplets suggesting a heterogeneous lipid deposition in hepatocytes. The subcellular analysis revealed a moderate degree of glycogen deposition, absence of nuclear abnormalities and unremarkable mitochondria; the rough endoplasmic reticulum was not significantly altered and smooth surfaced membranes appeared proliferated. Detailed analysis of the peroxisome population showed matrix rarefaction, marginal plate formation and spurious densities though no significant proliferation occurred. Distribution of peroxisomes in hepatocytes varied widely from cell to cell and in different lobular areas. This study confirmed the association of hepatic fatty change with hyperlipoproteinemia irrespective of the pattern observed in circulating lipoproteins. Peroxisome proliferation, as seen in rodents when receiving gemfibrozil, did not occur and the structure of these subcellular organelles was not compromised. It was concluded that the long-term administration of this compound did not show adverse effects on the hepatocyte in hyperlipoproteinemia.

Preclinical toxicology of pirmenol hydrochloride.

Pirmenol hydrochloride, a novel pyridinemethanol derivative, is a long-acting class Ia antiarrhythmic agent. Preclinical toxicology data were obtained in rat, mouse, dog and rabbit. In acute toxicity studies by oral and intravenous routes, no pathologic changes were observed in surviving mice, rats and dogs. In repeated dose toxicity studies, no drug-related pathologic changes were evident; dryness of the oral mucosa in dogs and body weight gain reductions in rodents were the only significant clinical signs. In a chronic (52 week) toxicity study in rats, pirmenol given in the diet was tolerated clinically at doses up to 100 mg/kg/day. No drug-related aberrations in clinical laboratory parameters or ophthalmic or pathologic findings were evident. In a similar study in beagle dogs, pirmenol was tolerated clinically at a dosage up to 30 mg/kg/day. No significant changes in biochemical, hematologic, urinary or bone marrow determinations were found in either species. In reproductive toxicology studies in rats, pirmenol had no significant effect on litter size or embryonic viability. In rabbits pirmenol had no effect on average litter size, embryonic viability or fetal wastage. Given to male rats, pirmenol had no overt effects on fertility. Pirmenol failed to elicit deoxyribonucleic acid damage or induce cytogenetic alterations. Pirmenol appears to be without significant limiting toxicologic properties.

Gabapentin-induced mitogenic activity in rat pancreatic acinar cells.

Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays.

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.

Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa.

Among chromosome defects in colon cancer, deletions in 1p, 17p, and 18q have been reported as frequent events. To verify this, we investigated 1p, 17p, and 18q aneusomy in 60 colorectal cancers and their surrounding mucosa by means of fluorescence in situ hybridization (FISH). We also evaluated ERBB2 gene (alias HER-2/neu) amplification in a subset of tumors. The genetic picture in tumors was correlated with chromosomal alterations in normal colonic mucosae, as well with clinicopathologic variables. A population of cells in morphologically normal epithelium possesses genetic aberrations common to those in colon cancer, although in different percentages. No significant difference emerged in terms of fraction of nuclei with 17p monosomy between primary tumors and distal mucosal samples. Of tumor samples aneusomic for the three chromosomes, 58.3% also showed aneusomy in related normal colonic mucosa. In neoplastic samples, significant correlation existed between 1p aneusomy and mucosal component (P<0.007), between 17p aneusomy and increased depth of invasion (T3-T4) (P<0.05), and between 18q aneusomy and tumor site (P<0.03). None of the evaluated samples, neoplastic or normal, showed ERBB2 gene amplification.

Effect of amphetamine on the hepatic endoplasmic reticulum of the pregnant rat.

Search for the elucidation of the mode of action of amphetamines has revealed that this drug brought about changes in the activity of some enzymes bound to the hepatic endoplasmic reticulum of the pregnant and non-pregnant rat. Amphetamine administration caused loss of appetite and changes in enzyme activity due to starvation, however, its effects were assessed applying pair-feeding conditions. Drug-metabolizing activity was increased by amphetamine as measured by coumarin 3-hydroxylase and aminopyrine N-demethylase in both pregnant and non-pregnant animals; aniline hydroxylase was elevated only in pregnant rats. These changes were associated with the enhanced synthesis of microsomal phospholipids as indicated by the increased activity of [14C-Me]S-adenosyl-L-methionine : microsomal phospholipid methyl transferase, de novo synthesis and levels of microsomal phospholipids. These effects were mainly manifest in phosphatidylethanolamine and phosphatidylcholine fractions. Glucose-6-phosphatase activity remained unaltered by amphetamine. Pregnancy alone brought about a reduction of all these microsomal parameters. The rise of hepatic drug metabolism following the administration of amphetamine indicated a compensatory mechanism by means of stimulating enzyme induction processes.

Cynomolgus monkeys (Macaca fascicularis) in preclinical immune function safety testing: development of a delayed-type hypersensitivity procedure.

A delayed-type hypersensitivity (DTH) test commonly used for humans was adapted for use with cynomolgus monkeys (Macaca fascicularis). Pilot experiments showed naive animals had poor response rates and inconsistent reactivity to the antigens. In an exploratory phase, it was determined that monkeys could be experimentally sensitized by immunization with commercially available antigens. Animals were then sensitized with various concentrations of diphtheria and tetanus toxoids, Candida, and Trichophyton in the dose-response phase. Antigens were injected intradermally (i.d.) 3 times over a 7-day period and monkeys were tested 14 days after the last injection. Responses were measured 24, 48, and 72 h post-challenge, with skin biopsies taken from two animals per group at the 24 h interval. Optimal concentrations were 1.2 Lf diphtheria, 6 Lf tetanus, 1000 PNU Candida, and 1000 PNU Trichophyton. These concentrations produced the best balance between DTH responses, homogeneity of dermal mononuclear cell infiltrate and lowest frequency of undesirable skin reactions. Positive responses were seen at 24 and 48 h post-challenge and were waning by 72 h. DTH responses were inhibited by topical corticosteroids. The final phase of these studies assessed whether sensitization of naive animals could be achieved using subcutaneous (s.c.) administration of the optimal antigen concentrations. Comparable responses to i.d. sensitization were obtained and skin sores did not develop at injection sites. These studies show that the DTH test adapted to monkeys was reproducible, minimally invasive, did not require sacrifice of the test animal, allowed repeated measurements and paralleled the reactions observed in humans.

Rodent carcinogenesis bioassay with oxisuran, a selective immunosuppressive agent.

The carcinogenic potential of oxisuran, a synthetic immunosuppressive agent, was studied for 80 weeks and 104 weeks in mice and rats, respectively. Groups of 50 mice and 70 rats of each sex received oxisuran at doses of 600, 240, and 40 mg/kg/day as dietary admixtures over the entire experimental period. Adequate survival rates allowed accurate statistical analysis of diagnosed neoplasia. Increased susceptibility to tumor development was not clearly demonstrated. In mice the only statistically significant increase in the incidence of malignancy was lung carcinomas in high dose females (P less than 0.05). However, lung carcinoma incidence was significantly decreased in mid- and low-dose male mice when compared to spontaneous control rates (P less than 0.01). Although not confirmed statistically, there was an increased incidence of lung carcinomas and liver cell adenomas in high dose male mice, and increased lymphoid tumors in all female treated groups. In rats, the incidence of liver cell adenomas in high dose animals of both sexes was increased, although confirmed statistically in males only (P less than 0.01). In high dose females, significantly decreased incidences of mammary fibroadenomas, pituitary chromophobe adenomas, and thyroid parafollicular cell tumors (P less than 0.01) contributed to an overall decrease in both benign tumors and in the combined benign and malignant tumor rates.

Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure.

Gabapentin, an anticonvulsant agent designated chemically as 1-(aminomethyl)-cyclohexaneacetic acid, was evaluated in a 2-year tumor bioassay in male Wistar rats. Three groups of 50 rats were fed gabapentin at 250, 1000 and 2000 mg/kg in the diet for 104 weeks. A fourth group was fed diet without drug. All rats were subjected to full histopathological evaluation. Body weight gain suppression occurred at 1000 and 2000 mg/kg. Survival was comparable across all groups. There was a treatment-related increase in the number of pancreatic acinar cell carcinomas; 0, 4, 3 and 8 of these carcinomas were observed in the control, 250, 1000 and 2000 mg/kg groups, respectively. There were no other increases in other tumor types, and there were no tumor increases in female rats. The frequency of pancreatic acinar cell hyperplasia was similar in treated and control groups. Biologically, the pancreatic carcinomas were not invasive, did not metastasize, were of late onset and did not compromise survival. Thus, gabapentin was a carcinogen in male Wistar rats. However, the tumorigenic response was of low-grade because it constituted a late tumor response which required very high doses. We reported recently that mice treated with gabapentin had no increase in pancreatic tumors. Therefore, neoplastic development was confined to the pancreas in a single sex and species of rodent. Consequently, gabapentin at therapeutic doses poses a low carcinogenic risk to humans.

Coumarin and 4-methylcoumarin induced changes in the hepatic endoplasmic reticulum studied by quantitiative sterelogy.

Coumarin and 4-methylcoumarin constitue chemicals widely available in foodstuffs and coumarin-induced hepatotoxicity has been characterized in laboratory animals. The present studies were undertaken to analyze the effects of these compounds on the structure of endoplasmic reticulum membranes. The liver of rats treated for seven days with 1 mmole/kg of either coumarin or 4-methylcoumarin were subjected to quantitative sterologic analysis and various morphometric parameters were determined. Coumarin induced cytoplasmic enlargement while 4-methylcoumarin produced changes in the endoplasmic reticulum and Golgi aratus (GOL) without altering cell size. Both compounds caused a significant overall reduction of smooth-surfaced (SER) membranes. Since 4-methylcoumarin stimulates drug metabolism, this indicates that conformational changes must have taken place in the membrane arrangement. On the other hand, the reduction of membranes by coumarin is accompanied by reduced enzyme activity and phospholipid metabolism, suggesting an impairment of membrane synthesis mircosopical examinations provides a useful and sensitive tool to study the effects of foreign compounds in the liver.

Influence of oral contraceptives on the acute effect of amphetamine on the hepatic endoplasmic reticulum of the rat.

The interaction between amphetamine and synthetic oral contraceptive steroids have been studied in the female rat. A progestational agent, quingestanol acetate, and a standard combination contraceptive (quingestanol acetate/ethynyl estradiol) were given with and without the concurrent administration of amphetamine. Steroid treatments increased the activity of some drug-metabolizing enzymes (aminopyrine N-demethylase, coumarin 3- hydroxylase, hexobarbital oxidase). Other parameters measured remained unaltered (glucose-6-phosphatase, aniline hydroxylase, cytochrome c reductase, cytochrome P 450, microsomal protein and phospholipid contents). Amphetamine treatment alone raised some drug-metabolizing enzymes (coumarin 3-hydroxylase, hexobarbital oxidase), increased microsomal phospholipid content and de novo synthesis, but elicited no effect on other enzymes measured. Amphetamine and quingestanol acetate given together significantly increased some drug metabolizing enzymes while the simultaneous treatment with combined steroids and amphetamine showed the most pronounced action. These experiments thus revealed that at least in the liver of the female rat, amphetamine elicited no overt hepatotoxicity, rather, brought about a weak inductive action of drug metabolizing enzymes. The application of steroid hormones also raised drug metabolism and the interaction between amphetamine and contraceptive steroids showed additive effects.

Effect of drugs on progesterone metabolism in the female rat.

Various drugs brought about a reduction of serum progesterone level irrespective of whether or not a potent inducer (phenobarbital, 4-methyl-coumarin) or a hepatotoxin (carbon tetrachloride, alpha-naphthylisothiocyanate, coumarin) has been administered. The decrease by hepatotoxins was highly significant during the estrus phase of the cycle. These treatments affected the hepatic level of progesterone and altered the uptake of [4-14C]progesterone in vivo. The serum level of progesterone was significantly decreased by phenobarbital and carbon tetrachloride; however, the incorporation into the liver was enhanced by phenobarbital and reduced by carbon tetrachloride. This opposing hepatic action showed selectivity; phenobarbital increased the oxidative pathway of progesterone metabolism (formation of 6 beta-, 16 alpha-, 20 alpha-hydroxyprogesterone) but the reductive pathway remained unaltered (formation of pregnanediol, pregnanolone). Conversely, carbon tetrachloride diminished oxidation and raised reduction of progesterone. These results have been confirmed by measurements of progesterone metabolism in vitro using isolated microsomes. Phenobarbital brought about an induction of progesterone 16 alpha-, 6 beta- and 20 alpha-hydroxylase, did not affect progesterone delta 4-5 alpha-dehydrogenase, whereas carbon tetrachloride inhibited hydroxylase and raised dehydrogenase activities. The action of these test compounds on serum and liver levels of progesterone and on the variation of progesterone metabolism seemed to be related to changes manifest in the function of the hepatic endoplasmic reticulum. Similar changes might be associated with the development of mild hepatic lesions induced by various steroids.