Parsalmide: a new anti-inflammatory agent. V. Pharmacokinetic and metabolic aspects in the rabbit

The bacterial mutation psuA1, known as (suA) a polarity suppressor, partially relieves all N defects in bacteriophage lambda growth. No evidence is found that psuA1 relieves Q defects in lambda growth. Specific mechanisms of action by the N and Q gene products are discussed. The psuA1 mutation was also found to suppress IS1 type but not IS2 type insertion mutations in lambda.     

Parsalmide: a new anti-inflammatory agent. III. Study of the analgesic and anti-inflammatory activity

When human chorionic gonadotropin (hCG) was treated with a 20-fold molar excess of N-acetylimidazole in aqueous solution, two tyrosyls were acetylated, resulting in a 50% reduction in in vivo biological activity. With increased quantities of reagent, the number of tyrosyls acetylated increased but with no further decrease in the biological activity. In vitro biological activity (binding to hCG receptors) of the hormone was not affected at all. Acetylation in urea increased tyrosyl modification, accompanied by acetylation of some lysyls, yielding a product in which all seven tyrosyls were acetylated and both in vivo and in in vitro biological activities were completely abolished. Deacylation with hydroxylamine partially restored biological activity of some but not all of the modified products. When individual hCG subunits were treated with the same reagent, the number of tyrosyls acetylated in each subunit again increased with increasing amounts of reagent, up to three in the alpha subunit and two in the beta subunit in the absence of urea. The tyrosyls in the beta subunit appeared less reactive to the reagent than those in the alpha subunit. Subunits modified to these extents retained ability to recombine as examined by gel electrophoresis, but the recombined products varied considerably in both in vivo and in vitro biological activities. A completely tyrosyl-acetylated product of hCG-alpha did not combine with intact hCG-beta, while fully modified hCG-beta did with intact hCG-alpha.     

Interaction between enoxacin, a new antimicrobial, and nimesulide, a new non-steroidal anti-inflammatory agent in mice

Convulsions induced by the combination of enoxacin, a new antimicrobial, and nonsteroidal anti-inflammatory drugs including nimesulide, ketoprofen, pranoprofen and loxoprofen sodium, were investigated in mice. The oral administration of nimesulide alone induced clonic convulsions at more than 300 mg/kg. The oral administration of ketoprofen, pranoprofen or loxoprofen sodium induced no convulsion up to 1000 mg/kg, 500 mg/kg and 600 mg/kg, respectively, and that of enoxacin induced no convulsion at more than 5000 mg/kg. The combination of nimesulide at 200 mg/kg and enoxacin at 400 mg/kg induced no convulsion. In contrast, the combination of enoxacin at 100 mg/kg and either ketoprofen at 125 mg/kg or pranoprofen at 500 mg/kg induced clonic convulsions, while that of enoxacin at 400 mg/kg and loxoprofen sodium at 600 mg/kg induced no convulsion. These results suggest that the combination of nimesulide and enoxacin may possibly induce few or less convulsions in the clinical setting.     

GLC and NMR analysis of isomeric impurities in the new anti-inflammatory agent benoxaprofen

GLC and NMR methods are described for the determination of four possible isomeric impurities in the novel anti-inflammatory agent benoxaprofen. The 2- and 3-chlorophenyl isomers were determined by GLC after alkaline hydrolysis and subsequent methylation. A rapid NMR procedure, using the lanthanide shift reagent tris- (1, 1, 1, 2, 2, 3, 3-heptafluoro- 7, 7-dimethyl- 4, 6-octanedionato)-europium, was developed for the 6- and 7- (alpha-methylacetic acid) isomers. Similar methodolology, with tris-(3-heptafluorobutyryl-d-camphorato)europium, enabled the determination of the enantiomer ratio for benoxaprofen. For the positional isomers, the limits of detection were 0.05% by GLC and 0.2% by NMR.     

Pharmacokinetic aspects of measurement of glomerular filtration rate in the dog: a review

Oxidative insults, whether over-excitation, excessive release of glutamate or ATP caused by stroke, ischemia or inflammation, exposure to ionizing radiation, heavy-metal ions or oxidized lipoproteins may initiate various signaling cascades leading to apoptotic cell death and neurodegenerative disorders. Among the various reactive oxygen species (ROS) generated in the living organism, hydroxyl and peroxynitrite are the most potent and can damage proteins, lipids and nucleic acids. It appears that some natural antioxidants (tocopherol, ascorbic acid and glutathione) and defense enzyme systems (superoxide dismutase, catalase and glutathione peroxidase) may provide some protection against oxidative damage. Recent findings indicate several polyphenols and antioxidant drugs (probucol, seligilline) are effective in protecting the cells from ROS attack. Further development of these antioxidant molecules may be of value in preventing the development of neurodegenerative diseases.     

The positive aspects of being a lesbian or gay man.

The need to provide culturally competent training for counseling gay men and lesbians (as well as other sexual minorities) is limited by the relative scarcity of research. Extant research has focused on psychopathologies and negative life experiences with little attention to the positive aspects of the lives of gay men and lesbians. An online survey collected data on perceptions of the positive aspects of being a gay man or lesbian (N = 553). Qualitative analyses revealed 3 domains with 11 themes. The positive aspects of gay or lesbian identity were belonging to a community, creating families of choice, forging strong connections with others, serving as positive role models, developing empathy and compassion, living authentically and honestly, gaining personal insight and sense of self, involvement in social justice and activism, freedom from gender-specific roles, exploring sexuality and relationships, and enjoying egalitarian relationships (lesbian participants only). These findings are discussed in light of recent literature on positive psychology and strength-based therapeutic approaches. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacokinetic aspects of digoxin in patients with terminal renal failure. II. On hemodialysis

Pharmacokinetics of digoxin was studied in 9 patients during hemodialysis. All patients were treated with a short-dialysis schedule, using Gambro Lundia Major dialysers for 5 patients and Gambro Lundia Nova dialysers for 4 patients. Clearances of the dialysers and half-lives were calculated from plasma digoxin levels in blood samples taken simultaneously from arterial and venous blood lines during hemodialysis. The mean clearances of the Major and Nova were 28.3 and 21.8 ml/min respectively. During hemodialysis the mean plasma half-life was 13.8 hours with the Major and 19.1 hours with the Nova. The mean net lowering effect of hemodialysis on the plasma concentration decay line was 9.5 and 6.5% for the Major and Nova respectively. Post-dialysis plasma concentration data suggest that the rate at which digoxin returns to plasma from body tissues is the rate-controlling factor in the elimination of digoxin by the artificial kidney.     

The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man

The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.     

4-nitro-2-phenoxymethanesulfonanilide (R-805): a chemically novel anti-inflammatory agent

The anti-inflammatory activity of the sulfonanilide, 4-nitro-2-phenoxymethanesulfonanilide (R-805) has been demonstrated in conventional models (carrageenan-induced edema of the rat's paw, UV-induced erythema of guinea-pig skin, adjuvant-induced arthritis of the rat). R-805 differs from most currently available acidic anti-inflammatory drugs in that its functional acidic group is not carboxyl. The relative anti-inflammatory potency of R-805 is comparable to indomethacin. Calculation of acute therapeutic indices (LD50/ED50) for 8 acidic anti-inflammatory drugs show R-805 to possess a more favourable index than the other drugs examined.     

Gemcitabine: a new chemotherapy agent for solid cancers

Gemcitabine, a new nucleotide analogue, is a promising chemotherapeutic agent for pancreatic, lung, ovarian and breast carcinomas. Its low toxicity (mainly hematologic) makes it a good choice for palliative treatment in patients who would otherwise be unable to tolerate aggressive therapy. The combination of gemcitabine with other anticancer agents such as cisplatin and anthracyclines appears to be associated with high response rates. Finally, gemcitabine is a potent radiosensitizing agent and should definitely be tested in combination with radiotherapy mainly in locally advanced disease.     

Topotecan: a new topoisomerase I inhibiting antineoplastic agent

OBJECTIVE: To review the pharmacologic, pharmacokinetic, therapeutic, and safety aspects of irinotecan, a new antineoplastic agent, and to assess its role in the treatment of colorectal and lung cancer. DATA SOURCES: English-language articles from the MEDLINE database, January 1990-March 1998; Pharmacia & Upjohn Company; published articles and meeting abstracts. STUDY SELECTION: Studies in humans with cancer, clinical case reports, and open clinical studies were reviewed. Efficacy studies were limited to trials with at least 20 evaluable patients. DATA EXTRACTION: Relevant data were extracted from published reports and abstracts. DATA SYNTHESIS: Irinotecan is an effective agent for the treatment of advanced colorectal cancer. It demonstrates significant activity as a first-line agent and in patients with disease that is refractory to fluorouracil-containing regimens. Activity against lung cancer has also been demonstrated. Limited data indicate activity against cancers of the ovary, cervix, stomach, and in non-Hodgkin's lymphomas. Major toxicity consists of myelosuppression and diarrhea. CONCLUSIONS: Irinotecan is a useful addition to the antineoplastic drug family and offers significant efficacy for treatment of patients with fluorouracil-refractory colorectal cancer.     

AIDS: new developments. VI. HIV reservoirs during intensive antiretroviral treatment

Treatment of human immunodeficiency virus (HIV) infected persons with potent antiretroviral combination therapy results in a strong decline of the viral load in the blood. Whether this effect is reached in all tissues and different infected cell types is an important question. There are several potential virus reservoirs. Lymphoid tissue constitutes the largest virus compartment. With potent, often protease inhibitor containing combinations the HIV-RNA decline in lymphoid tissue runs parallel to that in the blood. The central nervous tissue is a potentially important reservoir, because of the limited penetration of several antiretrovirals, especially protease inhibitors. A few short studies with different combinations showed a decline of the amount of virus in the cerebrospinal fluid. The risk of local resistance developing is not known. There are only few studies of the effects of potent anti-HIV therapy on semen but prostate and testis tissue do not appear inaccessible to treatment. The reservoir of latently infected cells that cannot be reached by the immune system or by the viral replication inhibiting therapy, can possibly be reached with immune stimulating agents. This will cause HIV replication and cell death, while the anti-HIV therapy will prevent further replication of the produced virions. This approach is still experimental, however.     

Evaluation of the novel anti-inflammatory agent tetrandrine as a pulpotomy medicament in a canine model

Tetrandrine, a bisbenzylisoquinoline alkaloid with unique broad-spectrum anti-inflammatory properties, was evaluated as a pulpotomy medicament in a canine model. Histological sections were evaluated after three days (acute inflammation) and six weeks (chronic inflammation) by two criteria: 1) intensity and degree of inflammation, and 2) extent of pulp involvement. The results of the three-day dressings revealed significant neutrophil infiltration in only 30% of teeth treated with tetrandrine, compared with 81%, 84%, and 100% of teeth treated with Ledermix, (Lederle Pharmaceuticals, Wolfrathausen, Germany), formocresol (Creighton Pharmaceuticals, Sydney, Australia) and saline (controls) respectively (P < 0.01). After six weeks, there was significant lymphocyte infiltration in only 30% of teeth treated with tetrandrine, compared with 66%, 90%, and 100% on teeth treated with Ledermix, formocresol, and saline controls respectively. (P < 0.01). In both three-day and six-week specimens in tetrandrine-treated teeth the extent of inflammation was limited to less than one-third of the coronal section of the pulp, whereas teeth treated with Ledermix or formocresol showed cellular infiltration extending to greater than two-thirds of the pulp (P < 0.01). Comparative studies with berbamine, a natural analog of tetrandrine, showed that it was less potent than tetrandrine, but significantly better than Ledermix and formocresol on both acute and chronic pulp inflammation (P < 0.05 and P < 0.01 respectively). These results suggest that tetrandrine may have value as a pulpotomy medicament.     

Pathogenetic aspects of the L-arginine-NO metabolic pathway in arteriosclerosis and possible therapeutic aspects

A yearly pattern in the occurrence of uterine cervical cancer (UCC), obtained from cytological examinations reported as type V (cases concluding a malignant alteration), has been previously shown for data obtained in the Monterrey Metropolitan Area (state of Nuevo Leon, Mexico) for a span of 10 years (1978-1987), with a peak of relative incidence in the month of February being high stable for consecutive years. With the aim of extending and validating those results, we analyzed the monthly totals of positive detected cases of UCC in the states of Nuevo Leon, Chihuahua, Coahuila, and Tamaulipas (covering most of Northern Mexico) during the same period. To eliminate bias due to the seasonal variation in the number of screening smears, data were first expressed in relation to the number of cytological examinations done the same month. The least-squares fit of a 1-year cosine curve to the data of relative incidence in the four states reveals a statistically significant yearly pattern (p = .008), with a maximum of relative incidence in February almost double that during the rest of the year. Results indicate that the relative incidence of UCC is higher than the yearly average during the winter, with secondary peaks in May and October. In view of the nonsinusoidal waveform in the incidence of UCC, we undertook a multiple-component analysis, allowing several cosine functions to be simultaneously fitted to the data. Results indicate that the yearly pattern in the relative incidence of UCC can be represented by a model that includes two components with periods of 12 and 4 months (p = .004). The same model can be documented as statistically significant independently for each of the four states. These results, summarizing over 2200 positive cases of UCC detected in more than 1,100,000 screening smears, are in full agreement with those found previously for part of the state of Nuevo Leon and reveal a highly stable and predictable yearly pattern of variation in the relative incidence of UCC in Northern Mexico.