Biomedical subjects

K R Scott

Publications and source records attributed to K R Scott.

At least 19 recordsLinked to original sources

PubMed2006

Comparison of hypotensive response following intravenous injection of parathyroid hormone 1-84 and 1-34 in conscious rats.

Activation of parathyroid hormone 1 (PTH-1) receptors on vascular smooth muscle cells causes relaxation and decreases blood pressure in rats and humans. However, when PTH(1-84) and PTH(1-34) were injected in anesthetized rats, PTH(1-34) produced a greater decrease in blood pressure. This study quantified the dose-response relationship of the hypotensive response to intravenously injected PTH(1-84) and PTH(1-34) in conscious rats and assessed the role that the C-terminal region of PTH(1-84) played in the differences. Mean arterial pressure (MAP) decreased rapidly following injection of both peptides (0-100 nmol/kg) and reached a nadir at 1-2 minutes before increasing at a rate that was dose- and time-dependent. PTH(1-34) produced a greater hypotensive effect than PTH(1-84) at most doses tested and was significantly different from PTH(1-84) at 1-10 nmol/kg. The greatest difference in MAP decrease between PTH(1-84) and PTH(1-34) (24 and 35 mm Hg, respectively) occurred at 10 nmol/kg. Median effective dose (ED50) values for PTH(1-84) and PTH(1-34) were significantly different (5.9 and 1.3 nmol/kg, respectively). The C-terminal PTH fragments PTH(7-84), PTH(39-84), and PTH(53-84) did not affect MAP when injected alone (10 nmol/kg), nor did they influence the hypotensive response when given at a 10-fold molar excess in combination with PTH(1-84) or PTH(1-34) (1.4 nmol/kg). In conclusion, PTH(1-84) is a less potent but, because it induced the same maximum response, not a less efficacious hypotensive agent than PTH(1-34) when administered by bolus intravenous injection in conscious rats. We found no evidence to support the concept that the C-terminal region of PTH is responsible for this difference in potency.

Animals↗

PubMed2005

Enaminones 9. Further studies on the anticonvulsant activity and potential type IV phosphodiesterase inhibitory activity of substituted vinylic benzamides.

Structure-activity relationship studies were employed to synthesize a series of 3- and 3,4-substituted benzamides from 3-amino-2-cyclohexenones. An improved method for the synthesis of benzamides from 3-amino-2-cyclohexenones is presented which provided significantly higher yields (71-79%) for the reported compounds. NMR and X-ray structural analyses were undertaken to note the possible intra- and intermolecular interactions of the synthesized analogs. Molecular modeling studies were used to determine the minimized configuration and were compared to their X-ray structures for correlation. These new entities were evaluated as potential anticonvulsants and type IV phosphodiesterase inhibitors (PDE4).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

QSAR of the anticonvulsant enaminones; molecular modeling aspects and other assessments.

The enaminones represent potentially useful agents for the clinical treatment in generalized tonic-clonic seizures (Epilepsia, 1993, 34(6), 1141-1145, Biopharm. Drug Disp. 2003, 397-407). A regression analysis was performed to provide a quantitative structure-activity relationship (QSAR) correlation model for prediction of activity for the anticonvulsant enaminones. Molecular modeling was performed to determine the molecular confluence of the Unverferth model (J. Med. Chem. 1998, 41, 63-73) to the enaminones. Conclusions related to the sodium channel model were assessed.

Animals↗

PubMed2004

Multidrug resistance and anticonvulsants: new studies with some enaminones.

The multidrug resistance (MDR), often conferred by the active extrusion of drugs from the cell, is a phenomenon often seen in cancer cells that may become resistant to a wide spectrum of drugs with varying chemical structures or cellular targets. This event has recently been reported for anticonvulsants. Studies in our laboratories on this occurrence with some enaminones have shown that the enaminones display high efflux ratios and are recognized by P-glycoprotein (P-gp) and/or the multidrug resistance protein (MRP), which have been reported as the main efflux transporters responsible for the development of MDR. Recent studies have uncovered interesting structural analogues that can modulate the functional activity of P-gp, suggesting a possible increase in the bioavailabillity of P-gp substrate drugs when administered concurrently.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Synthesis and anticonvulsant activity of enaminones. Part 7. Synthesis and anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone derivatives.

Further investigation of the potential anticonvulsant activity of the enaminones was attempted to discern the possible role of metabolites as the active/co-active entities of the esters of the enaminones. A series of 5-methyl-2-cyclohexene enaminones, the hypothesised metabolites corresponding to a sequence of active and inactive esters were synthesised and evaluated for anticonvulsant activity. With two exceptions, ethyl 4-[(4-cyanophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1k), and 3-[N-(4-cyanophenyl)amino]-5-methyl-2-cyclohexenone (3g), and ethyl 4-(phenylamino)-6-methyl-2-cyclohexenone (1n), and 3-N-(phenylamino)-5-methyl-2-cyclohexenone (3j), anticonvulsant screening data were parallel, with the ester and their putative decarboxylated analogue displaying similar activity. The most active analogue evaluated in this series, ethyl 4-[(4-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1e), which displayed an ED(50) of 16.7 mg kg(-1) and a TD(50) of 110.7 mg kg(-1) (protective index, PI = TD(50)/ED(50) = 6.6) in the maximal electroshock seizure (MES) test in mice and an ED(50) of 3.0 mg kg(-1) and a TD(50) >250 mg kg(-1) (PI > 83.3) in rats in the same evaluation, making this compound the most potent enaminone emanating from our laboratories. Pharmacokinetic evaluation of compound 1e in rats using LC/MS analysis unequivocally provides evidence that this compound is converted into the decarboxylated analogue 3a in the brain and the urine.

Animals↗

PubMed2002

LC/MS determination of the enaminones E139, DM5 and DM27 in rat serum.

Enaminones, E139, DM5 and DM27, have been recently recognized as potential anticonvulsant compounds. The molecular masses of these enarminones were proven using ion trap Finnigan mass spectrometer. For conduction of biological studies in animals, a sensitive and selective high-performance liquid chromatography-mass spectrometry (LC/MS) was developed for the determination of the selected enaminones in rat serum. A simple protein precipitation procedure was followed for cleaning up the serum samples before analysis. LC/MS determinations were performed using an APCI probe at 430 degrees C. Positive ions (M+1)(+) were acquired in MS/MS-SRM mode at m/z 308.1 (parent m/z 340.2) for E139 and m/z 262.1 (parent m/z 294.1) for DM5. On the other hand, DM27 and E118 (internal standard) were measured in SIM mode at m/z 236.5 and 222.5, respectively. Quantitation was based on measurement of the peak area ratio of enaminones (E139, DM5, DM27) and E118 as an internal standard. Calibration curves were linear (r>0.9989) over the concentration range 100-1000 ngml(-1) and were free from serum interference. Precision and accuracy studies of control samples showed intra-day and inter-day %RSD <10.1 and % deviation from nominal concentrations (%DEV) from -4.3 to +10.1. Recoveries of E139, DM5 and DM27 from quality control rat serum samples using protein precipitation method were 92.3, 89.4 and 89.6%, respectively. The reported data suggest the utility of this developed method for structural elucidation and for performing pharmacokinetics studies on the selected enaminones in rats.

Aniline Compounds↗

PubMed2002

Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives.

Due to the exceptional anticonvulsant activity displayed by substituted aniline enaminones, related pyridine derivatives and phenothiazines synthesised in our laboratories, the further investigation of various aromatic heterocycles was undertaken. Condensation of cyclic 1,3-diketo esters with 3-, and 5-aminoisoxazole derivatives led to a series of potent anti-maximal electroshock (MES) analogues, three of which occurred in the 3-amino series: ethyl ester (10), orally (po) active in rats [ED(50) 68.9 mg kg(-1), TD(50) > 500 mg kg(-1), protective index (PI = TD(50)/ED(50)) > 49.6]; methyl ester (9), ED(50) 68.9 mg kg(-1) intraperitoneally (ip) in mice, TD(50) > 500 mg kg(-1), PI > 7.3, and tert-butyl ester (8), ED(50) 28.1 mg kg(-1) po in rats, TD(50) > 500 mg kg(-1), PI > 17.8. Sodium channel binding studies, as well as evaluations against pentylenetetrazol, bicuculline, and picrotoxin on isoxazole 10 were all negative, leading to an unknown mechanism of action. X-ray diffraction patterns of a representative of the 3-amino series (isoxazoles 6-11) unequivocally display the existence of intramolecular hydrogen bonding of the nitrogen to the vinylic proton in the cyclohexene ring, providing a pseudo three ring structure which was also shown previously with the vinylic benzamides. Physicochemical-permeability across the BBB suggested an efflux mechanism for the previously synthesised aniline enaminones, but not with isoxazole 10.

Amines↗

PubMed2001

Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants.

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood-brain barrier (BBB) transport might be influenced by the presence of an efflux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 microM) and probenecid (100 microM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 microM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated mice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviolet and fluorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid significantly ( p>0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically significant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (-/-) mice brains were significantly higher ( p<0.05) compared with those in mdr 1 a/b (+/+) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may influence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Enhancing the permeation of marker compounds and enaminone anticonvulsants across Caco-2 monolayers by modulating tight junctions using zonula occludens toxin.

Zonula occludens toxin (Zot), a protein elaborated from Vibrio cholerae, has been shown to be capable of reversibly opening tight junctions between intestinal cells The objective of this study was to examine the effect of Zot on the flux of various molecules across Caco-2 cell monolayers. In addition, the transport of a series of anticonvulsants, the enaminones was also evaluated in the presence of Zot. The flux of [(14)C]mannitol, [(14)C]inulin and various enaminones across Caco-2 cell monolayers (n=6) was examined after pre-incubation for 1h with Zot (0 or 4000ng/ml) or phosphate-buffered saline (PBS). At the end of the incubation period, the flux of radiolabeled compounds or enaminones (1x10(-4)M) was assessed over a 2-h period. In addition, dose-response studies with Zot (0, 1000, 2000 or 4000ng/ml) were performed using mannitol. The flux of both mannitol and inulin significantly increased (P<0.05) in the presence of Zot. The transport of the enaminones with Zot ranged from 9.42 to 26.83x10(-5)cm/s vs. 4.68 to 13.83x10(-5)cm/s without Zot. Zot significantly increased the transport of all agents tested. This suggests that the co-administration of drugs with Zot may be a useful delivery strategy to increase the intestinal permeability and hence oral absorption of poorly bioavailable agents.

Anticonvulsants↗

PubMed2001

The effects of production and presentation level on the auditory distance perception of speech.

Although both perceived vocal effort and intensity are known to influence the perceived distance of speech, little is known about the processes listeners use to integrate these two parameters into a single estimate of talker distance. In this series of experiments, listeners judged the distances of prerecorded speech samples presented over headphones in a large open field. In the first experiment, virtual synthesis techniques were used to simulate speech signals produced by a live talker at distances ranging from 0.25 to 64 m. In the second experiment, listeners judged the apparent distances of speech stimuli produced over a 60-dB range of different vocal effort levels (production levels) and presented over a 34-dB range of different intensities (presentation levels). In the third experiment, the listeners judged the distances of time-reversed speech samples. The results indicate that production level and presentation level influence distance perception differently for each of three distinct categories of speech. When the stimulus was high-level voiced speech (produced above 66 dB SPL 1 m from the talker's mouth), the distance judgments doubled with each 8-dB increase in production level and each 12-dB decrease in presentation level. When the stimulus was low-level voiced speech (produced at or below 66 dB SPL at 1 m), the distance judgments doubled with each 15-dB increase in production level but were relatively insensitive to changes in presentation level at all but the highest intensity levels tested. When the stimulus was whispered speech, the distance judgments were unaffected by changes in production level and only decreased with increasing presentation level when the intensity of the stimulus exceeded 66 dB SPL. The distance judgments obtained in these experiments were consistent across a range of different talkers, listeners, and utterances, suggesting that voice-based distance cueing could provide a robust way to control the apparent distances of speech sounds in virtual audio displays.

Adult↗

PubMed2001

Informational and energetic masking effects in the perception of multiple simultaneous talkers.

Although many researchers have examined the role that binaural cues play in the perception of spatially separated speech signals, relatively little is known about the cues that listeners use to segregate competing speech messages in a monaural or diotic stimulus. This series of experiments examined how variations in the relative levels and voice characteristics of the target and masking talkers influence a listener's ability to extract information from a target phrase in a 3-talker or 4-talker diotic stimulus. Performance in this speech perception task decreased systematically when the level of the target talker was reduced relative to the masking talkers. Performance also generally decreased when the target and masking talkers had similar voice characteristics: the target phrase was most intelligible when the target and masking phrases were spoken by different-sex talkers, and least intelligible when the target and masking phrases were spoken by the same talker. However, when the target-to-masker ratio was less than 3 dB, overall performance was usually lower with one different-sex masker than with all same-sex maskers. In most of the conditions tested, the listeners performed better when they were exposed to the characteristics of the target voice prior to the presentation of the stimulus. The results of these experiments demonstrate how monaural factors may play an important role in the segregation of speech signals in multitalker environments.

Adult↗

PubMed2000

Determination of the enaminone DM5, an anti-epileptic agent, in mouse plasma and brain tissue by high-performance liquid chromatography with ultraviolet detection.

Enaminone derivatives of the 4-carbomethoxy-5-methylcyclohexane-1,3-dione series represent a new and potentially active series of compounds for the treatment of Epilepsy. Enaminone esters have been previously evaluated as compounds with potent oral anticonvulsant activity similar to class 1 anticonvulsants phenytoin, carbamazepine, and lamotrigine. DM5, a member of this class with -Cl in the para-substituted position, has been assessed to have the most potent pharmacological activity (ED50) in both the mouse and rat. A selective and specific high-performance liquid chromatography method was developed to quantitate DM5 in plasma and brain tissue in mice. Reverse phase chromatography with ultraviolet (lambda = 307 nm) detection was utilized to quantitate eluate. A C18 analytical column was used and the mobile phase consisted of acetonitrile and 0.05 M NaH2PO4 buffer (60:40; v/v). Liquid-liquid extraction with ether was used to extract the DM5 from plasma or brain homogenates. DM5 and carbamazepine (internal standard) eluted at approximately 6.0 and 9.0 min without any interfering peaks. The calibration curves were found to be linear (r > or = 0.9999) in the range of 0.1-5.0 microg/ml or microg/g. Intra-run precision's were in all in the range of 90%. The absolute recovery of the analyte in brain and plasma samples was < or = 90%. The valid method accurately quantified DM5 in plasma and brain tissue samples collected from a pharmacokinetic study consisting of an intravenous bolus in the tail vein of wild type and genetically altered mice.

Aniline Compounds↗

PubMed2000

Enaminones-versatile therapeutic pharmacophores. Further advances.

Enaminones, enamines of ss-dicarbonyl compounds, have been know for many years. In our initial account (Current Med. Chem. 1994, 1, 159-175), we reported on the anticonvulsant activity of a series of enaminones, notably methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en- 1-oate, 9a (R=CH3, R1=4-Cl), which, in animal tests, compared favorably to phenytoin and carbamazepine. Since that time, further research in our laboratory and other laboratories have expanded the therapeutic potential of these compounds. In addition to new anticonvulsant derivatives, we have uncovered a novel brain transport mechanism for the enaminones and developed a preliminary regression model for further synthetic direction. These topics will each be presented and elaborated.

Amines↗

PubMed1999

Synthesis, characterization and anticonvulsant activity of enaminones. Part 6: Synthesis of substituted vinylic benzamides as potential anticonvulsants.

A comparison of enaminones from various unsubstituted and p-substituted benzamides to the analogous benzylamines has been undertaken with the aim of elucidating the essential structural parameters necessary for anticonvulsant activity. Initial studies on methyl 4-N-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 3a, 3-N-(benzylamino)cyclohex-2-en-1-one, 3p, and 5,5-dimethyl-3-N-(benzylamino)-cyclohex-2-en-1-one, 3r indicated that benzylamines possessed significant anti-maximal electroshock seizure (MES) activity. Evaluation of the analogous benzamides revealed significant differences in anticonvulsant activity, these differences were most probably related to the differences in their three-dimensional structures.

Animals↗

PubMed1998

Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothizin-4[10H]-one derivatives.

A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-on es is herein reported. 2-Aminothiophenols underwent cyclocondensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing dimethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-on es, 4ak. In the case of the carbo-tert-butoxy derivatives (4c and 4k) prolonged reaction times led to the isolation of the respective 3-unsubstituted-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones (41 and 4m) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4k, which was active at 30 mg/kg intraperitoneally (ip) in mice in the maximal electroshock seizure (MES) evaluation, with no toxicity noted at dosages up to 300 mg/kg. Oral (p.o.) rat evaluation of 4k in the MES evaluation provided an ED50 of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD50/ED50) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity.

Animals↗

PubMed1996

Orbital infections in patients with human immunodeficiency virus infection.

BACKGROUND: Opportunistic infections frequently involve the anterior and posterior segments of the eye but rarely occur in the orbit in patients with human immunodeficiency virus (HIV) infection. The authors managed eight patients with HIV and unilateral orbital infections who presented between July 1988 and March 1995. METHODS: Records of the patients were reviewed. A literature review of orbital infections in patients infected with HIV also was conducted. RESULTS: There were five men and three women, with a mean age of 33.8 years. The mean CD-4 cell count from five of the eight patients was 18.4 cells/mm3. Invasive aspergillosis was the most common orbital infection occurring in four patients, all of whom had contiguous sinus involvement and intracranial extension. Orbital cellulitis with subperiosteal abscesses secondary to ethmoiditis caused by Propionibacterium acnes and Pseudomonas aeruginosa developed in two patients. Orbital cellulitis and panophthalmitis secondary to Staphylococcus aureus endogenous endophthalmitis developed in one patient, and one patient had presumed syphilitic optic neuritis, orbital periostitis, and necrotizing vasculitis. Five patients had permanent visual loss, including four who had loss of light perception. Four patients died of orbital diseases within 1 year of presentation, and three deaths were attributed to intracranial spread of Aspergillus fumigatus. Other organisms reported in the literature that caused orbital infections in patients with HIV include Rhizopus arrhizus, Toxoplasma gondii, and Pneumocystis carinii. CONCLUSION: Opportunistic infections of the orbit from bacterial, fungal, and parasitic organisms should be recognized as a serious complication of systemic HIV infection and are associated with a high ocular morbidity and mortality rate.

AIDS-Related Opportunistic Infections↗

PubMed1995

Synthesis and anticonvulsant activity of enaminones. 3. Investigations on 4'-, 3'-, and 2'-substituted and polysubstituted anilino compounds, sodium channel binding studies, and toxicity evaluations.

In a continuing evaluation of the aniline-substituted enaminones, the synthesis of additional para-substituted analogs has been made in an attempt to further quantify the electronic (sigma) and lipophilic (pi) requirements for anticonvulsant activity in this series. In addition, meta- and ortho-substituted and polysubstituted compounds have been synthesized and evaluated for anticonvulsant activity. In the para-substituted series, 4-cyano analogs (32 and 33) (+ sigma, - pi), which were highly active via intraperitoneal (ip) injection in mice, were inactive on oral (po) administration in rats. The para-substituted trifluoromethoxy (+ sigma, + pi) analog (8) had significant potency by both routes. Meta substitution limited the activity due to steric factors. Bromo and iodo substituents produced active para-substituted analogs (5 and 17) but were inactive when substituted in the meta position (37 and 41, respectively). Ortho substitution provided no clear relationship due to nonparametric deviations. Neither 1, the prototype enaminone, nor 2, the putative metabolite, produced significant nephrotoxicity or hepatotoxicity. Sodium channel binding of 1 and 8 indicated that 8 displayed relatively potent sodium channel binding but 1 showed weaker effects with IC50 values of 489 and 170 microM respectively against [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTX-B).

Animals↗

PubMed1994

Cyclization reactions leading to beta-hydroxyketo esters.

The purpose of the research was to synthesize beta-diketo esters and to evaluate them for anticonvulsant activity. The reaction of methyl vinyl ketone with dimethyl malonate in the presence of potassium carbonate gave an uncyclized product that underwent a Claisen condensation to yield methyl 2-hydroxy-4-oxocyclohex-2-en-1-oate (5a). Similarly, other cyclized beta-hydroxyketo esters were prepared, and their spectrometric data confirmed that the enol tautomers were preferred to the beta-diketo tautomers. The synthetic work clarified the reaction pathway for the Michael addition of malonate esters to enones. Of the intermediates and products tested for anticonvulsant activity, dimethyl 2,2-bis-(3-oxobutyl)malonate (9a) was found to possess anticonvulsant property. However, it is emphasized that the beta-hydroxyketo esters could be useful intermediates in the synthesis of enaminone anticonvulsants.

Animals↗