Nandini Cossons

Publications (11) View all

• Article: Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis.

  R J Evans, R M Moldwin, N Cossons, A Darekar, I W Mills, D Scholfield
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  ABSTRACT: In this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain. Patients with interstitial cystitis received a single intravenous dose of 200 μg/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed. A total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was -1.4 [-2.2, -0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%). Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.
  The Journal of urology 03/2011; 185(5):1716-21. · 4.02 Impact Factor
• Article: Dose-escalating study of the pharmacokinetics and tolerability of fesoterodine in children with overactive bladder.

  Bimal Malhotra, Ahmed El-Tahtawy, Ellen Q Wang, Amanda Darekar, Nandini Cossons, Tim J Crook, David Scholfield, Pramod Reddy
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  ABSTRACT: To determine the pharmacokinetics, safety and tolerability of fesoterodine, and assess the utility of 3-day bladder diaries (exploratory objective) in pediatric subjects with neurogenic detrusor overactivity or idiopathic overactive bladder (OAB). In this 8-week open-label study, subjects (8-17 years, >25 kg) received fesoterodine 4 mg for 4 weeks, then 8 mg for 4 weeks. Blood samples were obtained at weeks 4 and 8. Of 21 subjects enrolled, 11 had neurogenic detrusor overactivity and 10 had idiopathic OAB; 1 discontinued (personal reasons). Mean age and weight were 13.2 years and 54.0 kg for boys (n = 12) and 13.1 years and 49.2 kg for girls (n = 9). 5-Hydroxy-methyltolterodine plasma concentrations did not differ by diagnosis and were consistent with predictions based on adult data. Treatment-related adverse events (all mild or moderate) included 1 event each of dry mouth, constipation, dry eyes and blurred vision, and 2 events each of nausea and increased post-void residual volume. Three-day bladder diaries proved feasible. Oral administration of fesoterodine in pediatric subjects (>25 kg) with idiopathic OAB or neurogenic detrusor overactivity produced steady-state plasma 5-hydroxy-methyltolterodine exposures similar to those in adults. The doses given were well tolerated.
  Journal of pediatric urology 03/2012; 8(4):336-42. · 1.38 Impact Factor
• Article: Investigation of the clinical efficacy and safety of pregabalin alone or combined with tolterodine in female subjects with idiopathic overactive bladder.

  Josef Marencak, Nandini H Cossons, Amanda Darekar, Ian W Mills
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  ABSTRACT: To assess the efficacy and safety of pregabalin alone or in combination with tolterodine extended release (ER) in subjects with idiopathic OAB. This 26-week, multicenter, randomized, double-blind, placebo-controlled, three-period crossover study enrolled women aged ≥ 18 years that were diagnosed with OAB and reported ≥ 8 micturitions/24 hr and ≥ 4 urgency episodes/week on 5-day bladder diary at baseline. Subjects were randomized to 1 of 10 treatment sequences and received three of five treatments, each for 4 weeks with 4-week washout periods: standard-dose pregabalin/tolterodine ER (150 mg twice daily [BID]/4 mg once daily [QD], n=102), pregabalin alone (150 mg BID, n=105), tolterodine ER alone (4 mg QD, n=104), low-dose pregabalin/tolterodine ER (75 mg BID/2 mg QD, n=105), and placebo (n=103). Subjects completed 5-day diaries at the end of treatment and washout periods. The primary endpoint was change from baseline to week 4 in mean voided volume (MVV) per micturition. The primary comparison was standard-dose pregabalin/tolterodine ER versus tolterodine ER alone; secondary comparisons were pregabalin alone versus tolterodine ER alone and versus placebo. Baseline-adjusted changes in MVV were significantly greater after treatment with standard-dose pregabalin/tolterodine ER (39.5 ml) versus tolterodine ER alone (15.5 ml; P<0.0001), and with pregabalin alone (27.4 ml) versus tolterodine ER alone (P=0.005) and placebo (11.9 ml; P=0.0006). Treatments were generally well tolerated; discontinuation rates due to adverse events were 4%, 2%, 5%, 0%, and 1% with standard- and low-dose pregabalin/tolterodine ER, pregabalin, tolterodine ER, and placebo, respectively. Pregabalin, alone or with tolterodine ER may offer an alternative treatment option for idiopathic OAB in women.
  Neurourology and Urodynamics 09/2010; 30(1):75-82. · 2.96 Impact Factor
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  Available from: Nandini Cossons

  Article: Circular YAC vectors containing short mammalian origin sequences are maintained under selection as HeLa episomes.

  T O Nielsen, N H Cossons, M Zannis-Hadjopoulos, G B Price
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  ABSTRACT: pYACneo, a 15.8-kb plasmid, contains a bacterial origin, G418-resistance gene, and yeast ARS, CEN, and TEL elements. Three mammalian origins have been cloned into this circular vector: 343, a 448-bp chromosomal origin from a transcribed region of human chromosome 6q; X24, a 4.3-kb element containing the hamster DHFR origin of bidirectional replication (oribeta), and S3, a 1.1-kb human anti-cruciform purified autonomously replicating sequence. The resulting constructs have been transfected into HeLa cells, and G418-resistant subcultures were isolated. The frequency of G418-resistant transformation was 1.7-8.7 times higher with origin-containing YACneo than with vector alone. After >45 generations under G418 selection, the presence of episomal versus integrated constructs was assessed by fluctuation assay and by PCR of supercoiled, circular, and linear genomic cellular DNAs separated on ethidium bromide-cesium chloride gradients. In stable G418-resistant subcultures transfected with vector alone or with linearized constructs, as well as in some subcultures transfected with circular origin-containing constructs, resistance was conferred by integration into the host genome. However, several examples were found of G418-resistant transfectants maintaining the Y.343 and the YAC.S3 circular constructs in a strictly episomal state after long-term culture in selective medium, with 80-90% stability per cell division. The episomes were found to replicate semiconservatively in a bromodeoxyuridine pulse-labeling assay for </=130 cell generations after transfection. Furthermore, after </=172 cell generations rescued episomal DNA could be isolated intact and unrearranged, and could be used to retransform bacteria. These versatile constructs, containing mammalian origins, have the capacity for further modification with human telomere or large putative centromere elements, in an effort to move towards construction of a human artificial chromosome.
  Journal of Cellular Biochemistry 02/2000; 76(4):674-85. · 2.87 Impact Factor
• Article: Human cruciform binding protein belongs to the 14-3-3 family.

  A Todd, N Cossons, A Aitken, G B Price, M Zannis-Hadjopoulos
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  ABSTRACT: Cruciform DNA has been implicated in the initiation of DNA replication. Recently, we identified and purified from human (HeLa) cells a protein, CBP, with binding specificity for cruciform DNA. We have reported previously that the CBP activity sediments at approximately 66 kDa in a glycerol gradient. Here, photochemical cross-linking studies and Southwestern analyses confirm that a 70 kDa polypeptide interacts specifically with cruciform DNA. Microsequence analysis of tryptic peptides of the 70 kDa CBP reveals that it is 100% homologous to the 14-3-3 family of proteins and shows that CBP contains the epsilon, beta, gamma, and zeta isoforms of the 14-3-3 family. In addition to polypeptides with the characteristic molecular mass of 14-3-3 proteins (30 and 33 kDa), CBP also contains a polypeptide of 35 kDa which is recognized by an antibody specific for the epsilon isoform of 14-3-3. Cruciform-specific binding activity is also detected in 14-3-3 proteins purified from sheep brain. Immunofluorescene studies confirm the presence of the epsilon, beta, and zeta isoforms of 14-3-3 proteins in the nuclei of HeLa cells. The 14-3-3 family of proteins has been implicated in cell cycle control, and members of this family have been shown to interact with various signaling proteins. Cruciform binding is a new activity associated with the 14-3-3 family.
  Biochemistry 11/1998; 37(40):14317-25. · 3.42 Impact Factor