Effect of intracerebroventricularly injected insulin on urinary sodium excretion by cerebroventricular streptozotocin-treated rats

Recent evidence suggests that insulin may influence many brain functions. It is known that intracerebroventricular (icv) injection of nondiabetogenic doses of streptozotocin (STZ) can damage insulin receptor signal transduction. In the present study, we examined the functional damage to the brain insulin receptors on central mechanisms regulating glomerular filtration rate and urinary sodium excretion, over four periods of 30 min, in response to 3 æl insulin or 0.15 NaCl (vehicle) injected icv in STZ-treated freely moving Wistar-Hannover rats (250-300 g). The icv cannula site was visually confirmed by 2 percent Evans blue infusion. Centrally administered insulin (42.0 ng/æl) increased the urinary output of sodium (from 855.6 ± 85.1 to 2055 ± 310.6 delta percent/min; N = 11) and potassium (from 460.4 ± 100 to 669 ± 60.8 delta percent/min; N = 11). The urinary sodium excretion response to icv insulin microinjection was markedly attenuated by previous central STZ (100 æg/3 æl) administration (from 628 ± 45.8 to 617 ± 87.6 delta percent/min; N = 5) or by icv injection of a dopamine antagonist, haloperidol (4 æg/3 æl) (from 498 ± 39.4 to 517 ± 73.2 delta percent/min; N = 5). Additionally, insulin-induced natriuresis occurred by increased post-proximal tubule sodium rejection, despite an unchanged glomerular filtration rate. Excluding the possibility of a direct action of STZ on central insulin receptor-carrying neurons, the current data suggest that the insulin-sensitive response may be processed through dopaminergic D1 receptors containing neuronal pathways

Effect of intracerebroventricularly injected insulin on urinary sodium excretion by cerebroventricular streptozotocin-treated rats.

Recent evidence suggests that insulin may influence many brain functions. It is known that intracerebroventricular (icv) injection of nondiabetogenic doses of streptozotocin (STZ) can damage insulin receptor signal transduction. In the present study, we examined the functional damage to the brain insulin receptors on central mechanisms regulating glomerular filtration rate and urinary sodium excretion, over four periods of 30 min, in response to 3 microl insulin or 0.15 NaCl (vehicle) injected icv in STZ-treated freely moving Wistar-Hannover rats (250-300 g). The icv cannula site was visually confirmed by 2% Evans blue infusion. Centrally administered insulin (42.0 ng/ micro l) increased the urinary output of sodium (from 855.6 85.1 to 2055 310.6 delta%/min; N = 11) and potassium (from 460.4 100 to 669 60.8 delta%/min; N = 11). The urinary sodium excretion response to icv insulin microinjection was markedly attenuated by previous central STZ (100 micro g/3 micro l) administration (from 628 45.8 to 617 87.6 delta%/min; N = 5) or by icv injection of a dopamine antagonist, haloperidol (4 micro g/3 micro l) (from 498 +/- 39.4 to 517 +/- 73.2 delta%/min; N = 5). Additionally, insulin-induced natriuresis occurred by increased post-proximal tubule sodium rejection, despite an unchanged glomerular filtration rate. Excluding the possibility of a direct action of STZ on central insulin receptor-carrying neurons, the current data suggest that the insulin-sensitive response may be processed through dopaminergic D1 receptors containing neuronal pathways.

Effects of seasonal allergic rhinitis on selected cognitive abilities.

BACKGROUND: Many allergy patients complain of slowed thinking, memory problems, and difficulty sustaining attention during their allergy seasons. OBJECTIVE: This study evaluated the effect of symptomatic allergic rhinitis on speed of cognitive processing, ability to divide and sustain attention, working memory, and recent verbal memory. METHODS: Symptomatic ragweed-allergic rhinitis patients and nonatopic control subjects did cognitive testing in, out of, and in ragweed seasons. RESULTS: Test results indicate that, during ragweed seasons, allergic patients experience subtle slowed speed of cognitive processing but not deficits in attention and recent memory. Some patients also have difficulties in working memory. CONCLUSIONS: These findings suggest that having allergic reactions to ragweed pollen causes significant cognitive difficulties in a subgroup of patients.

Novel metabolites of warfarin produced by Beauveria bassiana and Streptomyces rimosus: a novel application of hplc-nmr.

1. Biotransformation of warfarin by the fungus Beauveria bassiana (ATCC 7159) yielded the first reported phase II warfarin metabolite, 3'4'-dihydroxywarfarin-3'-[4-methoxyglucoside], another previously unreported metabolite, 3',4'-dihydroxywarfarin and also 4'-hydroxywarfarin. 2. Biotransformation of warfarin by Streptomyces rimosus (NRRL 2234) yielded the previously unreported metabolites, 12-hydroxywarfarin, 4'-hydroxy-11-methoxywarfarin, and also 7-hydroxywarfarin and 4'-hydroxywarfarin, which have not been previously reported as biotransformation products from this organism. 3. Hplc-nmr has been used to identify biotransformation products of warfarin by S. rimosus directly from the microbial broth without prior isolation and purification.

Cognitive slowing and working memory difficulties in chronic fatigue syndrome.

OBJECTIVE: Patients with chronic fatigue syndrome (CFS) commonly report problems with attention, memory, learning, and speed of cognitive processing. This study attempted to evaluate these complaints using objective test criteria. METHOD: A test battery composed of six tests assessing these cognitive functions was given on two consecutive days. Twenty CFS patients were compared with 20 healthy control subjects and 14 patients with a history of major depression or dysthymia matched by age, intelligence, education level, and sex. RESULTS: Compared with control subjects, CFS patients consistently scored lower on tests in which motor and cognitive processing speeds were a critical factor, eg, reaction-time tasks. They also had more difficulty on working-memory tests in which rapid cognitive processing speed is also an important factor. The effort made on the first day of testing did not result in a decline in cognitive function on the following day. CFS patients did not qualify as having affective disorder by several different diagnostic criteria. Nonetheless, CFS patients' test performances did not differ from patients with a history of major depression or dysthymia. CONCLUSIONS: It is concluded that, although CFS and major depression and dysthymia have distinct clinical features, these disorders have slowed motor and cognitive processing speed in common.

Considerations for using ketoconazole in solid organ transplant recipients receiving cyclosporine immunosuppression.

Drug interactions involving cyclosporine following transplantation are a challenging issue for the transplant clinician. This is especially true when ketoconazole is the second agent used in conjunction with cyclosporine. Because both agents are metabolized by the cytochrome P-450 IIIA4 enzyme system, cyclosporine levels rise dramatically in the presence of ketoconazole. Many other agents interact with ketoconazole, either by competitive enzyme inhibition in the liver and gastrointestinal tract, or by reducing the absorption of ketoconazole by agents that increase the pH of the gastrointestinal tract. Despite the potential cost savings when using ketoconazole to reduce cyclosporine doses, adverse effects associated with ketoconazole put patients at risk when using this combination. Close monitoring of cyclosporine levels is imperative when adding ketoconazole to cyclosporine, and once the dosage adjustments are complete, the addition of a third drug that interacts with either cyclosporine or ketoconazole could result in an unexpected rejection episode or toxic cyclosporine side effect.

Oral administration of an easily prepared solution of injectable methotrexate diluted in water: A comparison of serum concentrations vs methotrexate tablets and clinical utility.

OBJECTIVE: To investigate whether the injectable formulation of methotrexate (MTX) given as an easily prepared oral solution of MTX diluted in water results in serum concentrations similar to those obtained with MTX tablets; to describe an easy and safe method of dispensing the drug. METHODS: Six patients (5 women, 1 man) with rheumatoid arthritis were given 10 mg of liquid MTX orally. The liquid was prepared by diluting 0.4 ml of the injectable formulation of MTX (50 mg/2 ml) in 8 ounces of water. One to 2 weeks later these patients were given 10 mg of MTX in the tablet form. MTX serum concentrations were determined using a fluorescence polarization immunoassay. The area under the concentration vs time curve (AUC), maximum concentration (Cmax) and the time to reach maximum concentration (tmax) were determined from the resulting concentration vs time curves. RESULTS: There was no statistical difference in the variables measured (AUC, Cmax, tmax), demonstrating comparable concentrations with these 2 methods of MTX administration. Patients found the medication easy to administer, potential hazards with the use of needles were avoided, and the cost of the drug was greatly decreased. CONCLUSION: The administrator of this easily prepared MTX solution is an alternative to the conventional administration of MTX tables, and may be of particular benefit in patients with financial limitations.

An assessment of cognitive function and mood in chronic fatigue syndrome.

Data were gathered regarding the associates of chronic fatigue syndrome (CFS) with: (1) speed of cognitive processing, (2) motor speed, (3) ability to sustain attention, and (4) mood. Patients were given a brief neuropsychological test battery before and after double-blind treatment with terfenadine or placebo and completed a daily mood rating scale (Positive and Negative Affect Schedule) during the study. CFS patients exhibited slower cognitive processing and motor speed and lower positive affect, as compared to data reported from previous studies of healthy subjects and other patient groups; however, CFS patients did not exhibit deficits in sustained attention in comparison to other groups. The CFS patients' ability to attend to verbal versus figural stimuli and mood ratings were different from those reported in studies of patients with depression. Because of methodological limitations, these findings are preliminary, but they encourage further assessment of cognitive dysfunction and mood in CFS.

Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs.

OBJECTIVE: Many patients with chronic disease use alternative therapies. Our objective was to investigate complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs, and to analyze these pills. METHODS: Medical records of 5 patients with complications were reviewed. Pills from symptomatic and asymptomatic individuals were analyzed for possible content of undeclared prescription drugs. RESULTS: All pills analyzed contained mefenamic acid and diazepam. Complications related to the presence of these substances included, among others, massive gastrointestinal bleeding. CONCLUSION: Chinese herbal medications may contain undeclared prescription drugs including nonsteroidal antiinflammatory drugs and benzodiazepines.

Effects of allergy season on mood and cognitive function.

The study was conducted to evaluate the effects of having allergic reactions (ie, being in allergy seasons without taking medications) on: (1) speed of cognitive processing, (2) psychomotor speed, (3) ability to sustain attention, (4) verbal learning and memory, and (5) mood. Subjects (ten atopic, eight control) were given a neuropsychologic test and mood rating battery in an A-B-A design ie, in, out of, and in allergy seasons. Only atopic subjects exhibited declines in verbal learning, slower decision-making and psychomotor speed on both simple and choice reaction time tests, and lower positive affect during their allergy seasons in comparison to out of allergy seasons. Atopic subjects did not demonstrate declines in ability to sustain attention. Biochemical mechanisms may cause these changes.

Allergy and depression: a neurochemical threshold model of the relation between the illnesses.

Empirical studies suggest a very high prevalence of atopic disorder in people with depression. Research indicates that individuals with allergy have cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic-adrenergic activity play a casual role in depression behaviors. It is hypothesized that the allergic state or allergic reactions can accentuate cholinergic-adrenergic activity imbalances in the central nervous system of a small subgroup of people at risk for endogenous depression thereby producing depression symptomatology.

Determination of dextromethorphan and its O-demethylated metabolite from urine.

A high-performance liquid chromatography (HPLC) assay for the simultaneous quantitation of dextromethorphan and its O-demethylated metabolite dextrorphan from urine is described. A cyano analytical column was used with a mobile phase consisting of MeOH 16%, acetonitrile 3%, and triethylamine 0.06% at pH 2.8 and a flow rate of 1.0 ml/min. Betaxolol was used as the internal standard. Standard curves from 50 ng/ml to 10,000 ng/ml (dextrorphan), and from 50 ng/ml to 8,000 ng/ml (dextromethorphan) were developed. The peaks eluted at 7.8 min (dextrorphan), 12.2 min (betaxolol), and 17.8 min (dextromethorphan). The coefficients of variance ranged from 1.3 to 4.5% at 250 ng/ml and 0.9 to 2.5% at 5,000 ng/ml. This assay was used to determine dextromethorphan/dextrorphan molar ratios in healthy male volunteers for the purpose of determining phenotype status for the P450IID6 isozyme.

The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

During the screening of fungi for inhibitors of squalene synthase, Phoma sp. C2932 was found to produce three structurally related novel inhibitors. These compounds, designated the squalestatins, exhibited potent activity against both mammalian (rat liver) and fungal (Candida albicans) squalene synthase. Furthermore, they also had broad spectrum in vitro antifungal activity.

Analysis of metoprolol enantiomers in human serum by liquid chromatography on a cellulose-based chiral stationary phase.

Metoprolol is a lipophilic, cardioselective beta-adrenergic blocking agent commercially available as a racemic compound. A normal phase high-performance liquid chromatographic method was developed to directly determine individual enantiomeric concentrations of metoprolol in human serum. Separation of the enantiomers was accomplished by a cellulose-tris(3,5-dimethylphenylcarbamate) chiral stationary phase. Metoprolol enantiomers were detected by means of fluorescence with excitation and emission wavelengths of 275 and 315 nm, respectively. Standard curves were linear over the concentration range 12.5-400 ng/ml for each enantiomer. Within-day coefficient of variation was less than 15% at all concentrations and the between-day coefficient of variation ranged from 4.1 to 11.2%. The limit of detection was determined to be 5 ng/ml for each enantiomer and the stereoselective resolution (alpha) of R- and S-metoprolol was 3.08. The assay was employed to determine enantiomeric serum concentrations of metoprolol in healthy male volunteers.