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K Russell

Publications and source records attributed to K Russell.

At least 19 recordsLinked to original sources
PubMed1996

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Amides↗
PubMed1996

The effects of pharmacological modulation of KATP on the guinea-pig isolated diaphragm.

The purpose of the present study was to investigate the functional consequences of KATP modulation in the normal and the metabolically inhibited guinea-pig isolated diaphragm using the K+ channel openers cromakalim, pinacidil, RP49356 (N-methyl-2-(3-pyridil)-tetrahydrothiopyran-2-carbothiami de-1-oxide) and ZM260384 (2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine -4-yl)pyridine-N-oxide) and the K+ channel inhibitors glibenclamide, phentolamine and ciclazindol. All K+ channel openers accelerated the decline in function induced by intermittent tetanic contractions following metabolic inhibition and delayed the development of contracture. Cromakalim also improved the recovery of twitch tension following 10 min intermittent tetanic stimulation in the hypoxic guinea-pig diaphragm preparation. Of the K+ channel inhibitors tested, only ciclazindol, at the highest concentration tested (10 microM), significantly delayed the decline in tetanic tension following metabolic inhibition in the guinea-pig isolated diaphragm. None of the inhibitors significantly accelerated the development of contracture. All inhibitors however, antagonised the actions of the K+ channel opener, cromakalim. The results indicate that opening of KATP can accelerate the decline in function following metabolic inhibition in the guinea-pig isolated diaphragm. In the absence of K+ channel openers however, KATP does not appear to contribute to this decline under the conditions of the present study.

Adenosine Triphosphate↗
PubMed1996

Gross anatomic evidence of partitioning in the human fibularis longus and brevis muscles.

Evidence from a variety of studies suggests that many mammalian muscles are partitioned with respect to their architecture and innervation. Each of these specific muscle subvolumes is innervated by an individual muscle nerve branch, contains motor unit territories with a unique array of physiological attributes and has been known as a neuromuscular compartment or segment. This gross anatomic study investigated for evidence of neuromuscular segmentation in human fibularis (peroneus) longus and brevis muscles. Forty-three legs (24 left, 19 right) from embalmed adult cadavers were dissected. Any architectural segment within these muscles were identified. The specific innervation patterns of these muscles were also described. The fibularis longus muscle was consistently found to have connective tissue partitions that separated it into four parts: anterior superficial, anterior deep, posterior superficial, and posterior deep. The innervation pattern of this muscle was consistent with the segments defined by the connective tissue partitions. There were consistently four primary motor branches, each supplying a specific portion of the fibularis longus muscle. While a typical branching pattern was recognized, there was some variability as to the order of these branches as they originated. The fibularis brevis muscle was consistently found to have a central connective tissue partition that separated it into two portions: anterior and posterior. In 91% of the fibularis brevis muscles, there were two primary motor branches, one for each of the two segments of the muscle. In the other 9%, only one primary motor branch supplying the muscle could be identified.

Adult↗
PubMed1996

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study.

OBJECTIVES: To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer. METHODS: Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. RESULTS: Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. CONCLUSIONS: Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

Aged↗
PubMed1996

Activity of the adrenal fetal zone in preterm infants continues to term.

In term babies, steroids from the fetal zone of the adrenal gland decline in the blood and urine in the first few weeks after birth. In infants born prematurely, fetal zone steroids (3 beta-OH-5ene steroids) persist but it is not known for how long. The present study set out to address this by examining changes in the synthesis and metabolism of adrenal steroids with postconceptional age, using serial measurements of steroid metabolites in the urine. 21 preterm infants, median gestation 29 weeks (range 24-31 weeks) and median birth weight 933g were examined. 3 beta-OH-5ene steroids represented around 90% of the total steroids excreted until 2 weeks past term, falling to 55% by 12 weeks after term. 3 beta-OH-5ene steroids were excreted in the urine at levels of 1500-2000 micrograms kg-1 d-1, until 3-4 weeks past term, after which these urinary fetal zone steroid metabolites declined, falling to 500 micrograms kg-1 d-1 six weeks past term. We conclude that activity of the adrenal fetal zone in preterm infants continues to term, after which it diminishes. This suggests that it is gestation that determines fetal zone activity rather than birth.

Adrenal Cortex↗
PubMed1996

Genetic analysis of TAP2 in systemic lupus erythematosus patients from two ethnic groups.

The aim of this study was to determine whether the TAP2 (Transporter associated with Antigen Processing 2) locus is involved in susceptibility to systemic lupus erythematosus (SLE). We adopted the interethnic approach to overcome problems in the analysis resulting from linkage disequilibrium. The TAP2 gene polymorphisms of the codons corresponding to amino acid positions 379, 565 and 665 were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in 186 patients (151 white Europeans, 35 Afrocaribbeans) and 183 controls (79 white Europeans, 104 Afrocaribbeans). In the European SLE patients, the frequency of the TAP2 type V-A-TA was marginally lower compared with the control group (31% vs 42%), with negative linkage disequilibrium between this TAP2 type and DR3 probably accounting for the difference. For the European SLE patients, we confirmed a significant association of DR3 with disease status [odds ratio = 4.16, 95% confidence interval (CI), 2.08-8.39] and in the patients with DR3 there was a significantly high frequency of the TAP2 type V-A-T-. In the Afrocaribbean SLE patients, any associations of disease status with TAP2 phenotype were the inverse of those in the European patients. Thus, in these patients the frequency of V-A-TA was higher than in controls (46% vs 26%, OR = 2.4, 95% CI 1.01-5.74), while the frequency of V-A-T- was lower (26% vs 40%, not significant). Despite possible sampling error, the lack of a difference in TAP2 status between cases and controls within ethnic groups and, if anything, an inverse association across ethnic groups, makes it unlikely that the TAP2 polymorphism studied here is of primary relevance to SLE susceptibility.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

The relationship of thoracic lymphadenopathy to pulmonary interstitial disease in diffuse and limited systemic sclerosis: CT findings.

OBJECTIVE: Mediastinal lymphadenopathy is frequently associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). This study compared the extent of lymphadenopathy in diffuse and limited SSc with the presence and type of ILD found on CT scans. SUBJECTS AND METHODS: Seventy-three patients with diffuse and limited SSc underwent thoracic CT. The presence of lymphadenopathy was correlated with the frequency and type of ILD. RESULTS: Fifty-eight percent (18/31) of patients with diffuse cutaneous SSc and 40% (17/42) of patients with limited cutaneous SSc had lymphadenopathy. A significant relationship was found between lymphadenopathy and the presence of interstitial disease (p = .0002). Seventy-two percent (18/25) of patients with a ground-glass parenchymal pattern of interstitial disease and 74% (14/19) of patients with a honeycomb pattern had lymphadenopathy. CONCLUSION: Lymphadenopathy is prevalent in patients with SSc and ILD regardless of clinical subtype or interstitial pattern. Lymphadenopathy appears to increase as a function of the profusion rather than the morphology of ILD.

Female↗
PubMed1995

Calcium dependent K-channels in guinea pig and human urinary bladder.

This study provides evidence for the presence of large conductance Ca(2+)-dependent K-channels in guinea pig and human urinary bladder smooth muscle. A23187, a Ca(2+)-ionophore, increased charybdotoxin and iberiatoxin sensitive 42K efflux in human urinary bladder smooth muscle cells, suggesting that large conductance Ca(2+)-dependent K-channels are present in these cells. NS004, a large conductance Ca(2+)-dependent K-channel opener, relaxed guinea pig bladder strips precontracted with 15 mM KCl which is inhibited by iberiatoxin. In addition, NS004 also evoked an iberiatoxin sensitive increase in 86Rb/42K efflux in guinea pig and human urinary bladder smooth muscle cells, demonstrating that NS004 activates large conductance Ca(2+)-dependent K-channels to achieve its relaxation effect in the bladder.

Animals↗
PubMed1995

Relative importances of outer membrane permeability and group 1 beta-lactamase as determinants of meropenem and imipenem activities against Enterobacter cloacae.

The roles of outer membrane permeability and Bush group 1 beta-lactamase activity in determining Enterobacter cloacae susceptibility to either meropenem or imipenem were investigated. A beta-lactamase-deficient strain was obtained by mutagenesis from a clinical isolate of E. cloacae, and a porin-deficient strain was selected from this mutant with cefoxitin. Both strains were transformed with the plasmid pAA20R, which contained the gene coding for the carbapenem-hydrolyzing CphA beta-lactamase, and the carbapenem permeability coefficients were measured by the Zimmermann and Rosselet technique (W. Zimmermann and A. Rosselet, Antimicrob. Agents Chemother. 12:368-372, 1977). The permeability coefficient of meropenem was roughly half that of imipenem in the normally permeable strain and almost seven times lower than that of imipenem in the porin-deficient strain. In the porin-deficient strain, the virtual absence of porins caused the MICs of meropenem to increase from 8 to 16 times, while it did not affect the MICs of imipenem. Conversely, the beta-lactamase affected imipenem but not meropenem activity: meropenem showed a similar activity in the parent strain and in the beta-lactamase-deficient mutant with both a low- and high-density inoculum, whereas imipenem was 16 times less active against the parent strain when the high-density inoculum was used. It is concluded that outer membrane permeability and stability to group 1 beta-lactamase have different impacts on the activities of meropenem and imipenem against E. cloacae.

Bacterial Proteins↗
PubMed1995

K-channel opening activity of ZD6169 and its analogs: effect on 86Rb efflux and 3H-P1075 binding in bladder smooth muscle.

Zeneca ZD6169, (S)-N-(4-benzoylphenyl)-3,3,3-trifluoro- 2-hydroxy-2-methylpropionamide, is a novel compound which relaxes urinary bladder smooth muscle in vitro. The effect of ZD6169 and two of its analogs on 86Rb efflux and 3H-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. ZD6169 concentration dependently increased the rate of 86Rb efflux from guinea pig bladder strips. 86Rb efflux evoked by ZD6169 and its analogs was blocked by glibenclamide (30 muM) but not by charybdotoxin, apamin or alpha-dendrotoxin, suggesting that this compound activates KATP channels in guinea pig bladder. In addition, interaction of ZD6169 with KATP channels was also confirmed in human bladder smooth muscle cells. Specific binding of 3H-P1075, a potent opener of KATP channels, to guinea pig urinary bladder strips was observed. 3H-P1075 binding was inhibited by known KATP openers. ZD6169 inhibited binding of 3H-P1075 to urinary bladder strips like other structurally different KATP openers, e.g. cromakalim and pinacidil. Potencies for inhibition of 3H-P1075 binding by ZD6169 and other potassium channel openers correlate well with potencies for increase in 86Rb efflux and bladder muscle relaxation studies. It is concluded that Zeneca ZD6169 is a potassium channel opener which activates ATP-sensitive K-channels in guinea pig urinary bladder strips as well as in human bladder cells. Furthermore, binding studies suggest that the effects of ZD6169 and its analogs are mediated by binding to the site labeled by 3H-P1075 in guinea pig bladder strips.

Amides↗
PubMed1995

Zeneca ZD6169 and its analogs from a novel series of anilide tertiary carbinols: in vitro KATP channel opening activity in bladder detrusor.

The potassium (K+) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoinhibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K+ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 +/- 0.22 223 +/- 37 mumol/l. This result suggests that ZD6169 may act as a K+ channel opener. Similar to the prototypic ATP-sensitive K+ (KATP) channel opener cromakalim, the K+ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KCl. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 mumol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 +/- 1.2 mV and increased the whole cell KATP current in isolated guinea pig smooth muscle cells by 34.9 +/- 7.9 pA. This is comparable to the increase of 26.8 +/- 5.0 pA obtained with 10 mumol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the KATP channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K+ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K+ channel openers that activate KATP channels in vitro to relax bladder detrusors.

Adenosine Triphosphate↗
PubMed1995

ZENECA ZD6169: a novel KATP channel opener with in vivo selectivity for urinary bladder.

(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide (ZD6169) is a novel ATP-sensitive potassium channel opener. Bladder activity and selectivity after oral dosing were studied in conscious, normotensive rats and dogs by monitoring cystometric and cardiovascular (CV) parameters. The reference ATP-sensitive K+ channel opener cromakalim was also evaluated in this study. ZD6169 significantly reduced micturition frequency in rats (ED50 = 0.16 mg/kg), but its effect on CV parameters was minimal (ED20 = 30 mg/kg), yielding a selectivity dose ratio of 187. The duration of action was between 7 and 24 hr at doses of 0.3 and 3 mg/kg, but it was more than 24 hr at 10 mg/kg. The ED50 value for bladder activity in dogs was less than 1.0 mg/kg, and the ED20 value for CV activity was slightly greater than 15 mg/kg but less than 20 mg/kg; the selectivity ratio was greater than 15. A significant improvement in bladder compliance was noted in dogs with ZD6169, and the bladder activity in rats was blocked by i.v. glibenclamide (3 mg/kg). Cromakalim had a bladder profile similar to that of ZD6169 but appeared to be more selective for CV parameters. In conclusion, ZENECA ZD6169 is a unique ATP-sensitive K+ channel opener with in vivo selectivity of relaxing bladder smooth muscle. This agent has the potential for treating patients with urge incontinence.

Adenosine Triphosphate↗
PubMed1994

Impact of a multileaf collimator on treatment morbidity in localized carcinoma of the prostate.

PURPOSE: To evaluate the effectiveness of variable multileaf collimation, three-dimensional treatment planning, and computer-controlled conformal radiation therapy of prostate cancer. METHODS AND MATERIALS: Two hundred and forty-five patients with locally advanced prostate cancer have completed treatment over a 9-year time span using a multileaf collimator and conformal treatment techniques on the University of Washington cyclotron. All patients had three-dimensional treatment planning with computed tomography scans in the treatment position, and had treatment fields individually shaped to the target volume with a continuously variable multileaf collimator. Treatment was delivered under computer control with network transfer of the multileaf collimator settings from the treatment planning computer to the cyclotron control system. RESULTS: The multileaf collimator combined with three-dimensional treatment planning results in elegant dose distributions. These neuron dose distributions resulted in a reduced local/regional tumor failure rate with no increase in complications when compared to control treatment with photons in a randomized trial. Neutron treatment delivered at other institutions without conformal beam shaping resulted in the same improvement in local-regional tumor control rates, but was associated with a significantly higher normal tissue complication rate than seen with conformal neutron beam delivery techniques (grade 3 and 4 cumulative late normal tissue toxicity rates of 39% vs. 10%, p = 0.0007). CONCLUSIONS: Conformal treatment of prostate cancer using a multileaf collimated neutron beam results in increased local/regional tumor control rates with low normal tissue toxicities. This experience is directly applicable to the conformal treatment of prostate cancer with photons.

Humans↗
PubMed1994

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Academic Medical Centers↗