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Funder: Barts and the London Charity project (no. MGU0360) Senior Investigator award no. NF-SI-0512-10052, Funder: NIHR Cambridge BRC (no. IS-BRC-1215-20014), Funder: NIHR Biomedical Research Centre at Barts and The London School of Medicine and Dentistry, Funder: National Medical Research Council and BRC of Singapore, Funder: NIHR Birmingham Biomedical Research Centre (grant reference number BRC-1215-20009) European Union’s Horizon 2020 Research Innovation Program under grant agreement no. 633983 (ENSAT-HT), Funder: Barts and The London Charity, Funder: Barts and the London Charity project (no. MGU0360), Funder: Barts and the London Charity project, Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Background Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival but remains a formidable undertaking associated with significant post-operative morbidity and mortality. We aim to share our experience of managing these complex patients within a high-volume UK centre. Methods A retrospective review of a prospectively maintained database was performed on all patients who underwent resection for pCCA at our unit between 2009–2021. Kaplan–Meier analysis was used to estimate overall and disease-free survival (OS/DFS). Post-op complications were graded using the Clavien-dindo classification and reported as minor (Grade1/2) or major complications (Grade3/4). Results 102 patients underwent surgery for pCCA at our unit between 2009–2021. The majority of patients required pre-operative biliary drainage via ERCP and metal stent insertion. Following MDT and CPEX assessment eligible patients underwent an initial staging laparoscopy followed by curative resection. 30% of patients required a PVE to increase the proposed functional liver remnant volume prior to surgery. The majority of patients (76%) had Bismuth-Corlette IIIA/B or IV disease necessitating a major liver resection along with radical bile-duct resection. Post-op morbidity rates were high with 42% experiencing a major (grade3/4) complication. Of these patients 14 individuals subsequently died culminating in a 90-day mortality rate of 13.7%. Median LOS was 11 days (IQR 5–59). Median OS for the entire cohort was 36.3 months (CI:26.7–45.8) with a nominal 5-year survival rate of 34.6%. 40% of patients received adjuvant chemotherapy post-op. During follow up 59% of patients suffered disease recurrence with a median DFS of 20.1 months (CI: 11.5–33.5). The administration of palliative chemotherapy upon recurrence was associated with an improvement in survival of 11 vs 5.3 months (HR 3.5 p 0.01). Conclusions Surgery for pCCA remains a significant undertaking for both patient and clinician with high rates of morbidity and mortality. Long term survival is achievable but recurrence rates remain a challenge. Overall our mortality, morbidity and survival rates are comparable to that reported in other Western centres.

Aims Several putative prognostic models have been developed to stratify patients with peri-hilar cholangiocarcinoma (PHC) by Overall Survival (OS). The objective of this study was to evaluate the utility of these models in determining prognosis for all patients presenting to a tertiary referral centre with PHC. Methods Three hundred and two patients diagnosed with PHC referred to a regional tertiary referral centre between 2008 and 2019 had their demographic and survival data retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. Univariate and multivariate modelling was utilised to determine significant prognostic variables. Concordance indices were constructed for the prognostic models to determine internal validity within the cohort. Results Multivariate analysis demonstrated that: pre-interventional ECOG status (p 0.02); bilirubin levels (p 0.001); resectional status (p 0.001) and Mayo Clinic (MC) model (p 0.003) were significant predictors of OS. MC staging system demonstrated utility in stratifying patients by OS in pre-interventional patients with peri-hilar cholangiocarcinoma in all comers (p 0.001) and patients who did not progress to resection (p=0.021). There was strongly significant concordance between pre-intervention MC staging and OS in all comers in this cohort (C-index 0.59). Conclusions This study has validated the use of the MC model in a pre-interventional clinic setting. Bilirubin, a standardised easily obtainable serological biomarker, should be considered for incorporation into the MC model to refine patient stratification by OS.

Aims Human equilibriative nucleoside transporter protein 1 (hENT1) facilitates nucleoside transport into the cell. Immunohistochemically-detected hENT1 is increased in cholangiocarcinoma tumour cells and in highly metabolising cells. The Mackey 10D7G2 hybridoma has demonstrated prognostic utility in Pancreatic Ductal Adenocarcinoma. The Proteintech Polyclonal hENT1 antibody's prognostic utility has not been assessed. Cellular Ki67 expression is linked to tumour proliferation. This study aims to assess the antibodies’ prognostic utility for resectable hilar cholangiocarcinoma. Methods Between 2009–2016, 54 patients underwent resection for peri-hilar cholangiocarcinoma. Formalin-Fixed Paraffin Embedded blocks from 44 specimens were retrieved. A Tissue-Matched Array was constructed and stained for each antibody. H-scores were utilised to determine expression intensity. Correlation of expression was determined by Pearson correlation co-efficient and Chi-squared. Silencing RNA for transfected HepG2 cell-lines was used to determine accurate hENT1 staining by the Proteintech antibody. Demographic and survival characteristics were acquired from a prospectively held database, and were calculated with global log-rank calculations. Results There was significant correlation between the Mackey and Proteintech antibodies (p Conclusion While the Proteintech antibody demonstrates concordance with the 10D7G2 antibody in determining hENT1 expression, they didn't demonstrate significant prognostic ability. Standard histopathological co-variates retain prognostic utility within the cohort.

In the absence of pollination, female reproductive organs senesce leading to an irrevocable loss in the reproductive potential of the flower and directly affecting seed set. In self-pollinating crops like wheat (Triticum aestivum), the post-anthesis viability of the unpollinated carpel has been overlooked, despite its importance for hybrid seed production systems. To advance our knowledge of carpel development in the absence of pollination, we created a relatively high-throughput phenotyping approach to quantify stigma and ovary morphology. We demonstrate the suitability of the approach, which is based on light microscopy imaging and machine learning, for the detailed study of floral organ traits in field grown plants using both fresh and fixed samples. We show that the unpollinated carpel undergoes a well-defined initial growth phase, followed by a peak phase (in which stigma area reaches its maximum and the radial expansion of the ovary slows), and a final deterioration phase. These developmental dynamics were largely consistent across years and could be used to classify male sterile cultivars, however the absolute duration of each phase varied across years. This phenotyping approach provides a new tool for examining carpel morphology and development which we hope will help advance research into this field and increase our mechanistic understanding of female fertility in wheat.

Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery.A retrospective review of a prospective database of patients undergoing surgery for pCCA at a Western centre between January 2009-2020.Eighty-five patients underwent surgical resection for pCCA with a median overall survival of 36.3 months. Post-op (90day) morbidity rates were high with 46% of patients developing a major complication (Clavien-Dindo grade 3-4). Post-op mortality rate was 13%. In total 38% (28/74) of patients experienced at least 1 episode of delayed morbidity (90-days of surgery) resulting in 53 separate admissions with a median LOS of 7 days (IQR 2-15). These episodes were predominately secondary to biliary obstruction with the majority requiring radiological intervention (Clavien-Dindo grade 3). The development of long-term morbidity was associated with increased recurrence rates and correlated with poorer OS (27.6 months vs. 65.7 months HR 2.2 CI 1.63-2.77).Routinely cited 90-day morbidity and mortality does not accurately capture the patient morbidity experienced following surgery for pCCA. Surgery clearly offers a survival benefit and should be pursued in selected patients, but they must be fully counselled on the potential for long-term morbidity before embarking on this strategy.

High-dose chemotherapy with autologous stem cell transplant (ASCT) has been a mainstay of high-risk neuroblastoma treatment for several decades, demonstrating improvements in event-free survival but with risks of serious or even life-threatening acute toxicities, severe long-term adverse health effects for survivors, and ongoing contention regarding overall survival benefit. The merits of ASCT in the modern era of immunotherapy are a source of debate among parents, advocates, and some physicians. Here we examine evidence for and against ASCT, explore parent attitudes and their turmoil over decision-making, and strongly encourage international research consortia to develop a coordinated strategy to accelerate progress toward a future that avoids the routine use of ASCT in high-risk neuroblastoma.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma (APA) is a common, curable cause of hypertension, but invasive methods of diagnosis and treatment contribute to -17%, the pre-specified margin of non-inferiority. The best univariate predictors of complete clinical cure were home systolic blood pressure (SBP)

Background Several potential prognostic models have been developed to stratify patients with peri-hilar cholangiocarcinoma (PHC) by Overall Survival (OS). The American Joint Committee on Cancer (AJCC) staging system is a post-resectional model utilising tumour-specific pathological parameters to stratify and predict OS. The Mayo Clinical (MC) scoring system has been developed utilising primarily clinical, serological, and radiological variables to predict survival in all patients with a diagnosis of peri-hilar cholangiocarcinoma. The objective of this study was to evaluate the utility of these models in determining prognosis for all patients presenting to a tertiary treatment centre with PHC. Methods Three hundred and two patients diagnosed with PHC referred to a regional tertiary referral centre between 2008 and 2019 had their demographic and survival data retrospectively analysed from a prospectively held database linked to Hospital Episode Statistics and Somerset Cancer Registry data. One hundred and twenty seven patients were surgically explored. Eight-four patients underwent resection. One-hundred and seventy-four (57.6%) patients underwent palliative endoscopic therapy. Univariate and multivariate modelling was utilised to determine significant prognostic variables. Concordance Indices (C-Indices) were constructed for the prognostic models to determine internal validity within the cohort. Results Multivariate analysis demonstrated that: pre-interventional ECOG status (p Conclusions The predictive performance of the stated prognostic models for OS have poor utility. Simple pre-interventional serological, functional and radiological variables appear to provide better prognostic indication of OS. Variables not incorporated in the AJCC registry have a significant effect upon post-resectional OS and require full incorporation in to model prognostication.

Background Human equilibriative nucleoside transporter protein 1 (hENT1) is a trans-membranous protein which facilitates nucleoside transport in to the cell. Immunohistochemically-detected hENT1 abundance is increased in cholangiocarcinoma tumour cells compared to matched non-tumour cells and increased in highly metabolising cells. The privately-held Mackey 10D7G2 hybridoma has demonstrated prognostic utility in Pancreatic Ductal Adenocarcinoma patients. The commercially available Proteintech Polyclonal hENT1 antibody’s prognostic utility has not been previously assessed. Cellular Ki67 expression has been linked to mitotic indices of tumour proliferation. This proof-of-concept study aims to assess the antibodies prognostic utility for hilar cholangiocarcinoma patients undergoing surgical resection. Methods Between February 2009 and February 2016 54 patients underwent resection for peri-hilar cholangiocarcinoma. Formalin-Fixed Paraffin Embedded (FFPE) blocks from a sub-set of 44 resected specimens were retrieved. Appropriate areas of tumour were sampled from the blocks and a Tissue-Matched Array (TMA) was constructed. The TMA underwent staining for each antibody. H-scores were utilised to determine intensity of expression. Correlation of expression between antibodies was determined by Pearson correlation co-efficient and Chi-squared where appropriate. Silencing RNA transfected HepG2 cell-lines was used to determine hENT1 staining by the Proteintech antibody. Demographic and survival characteristics for the patients were acquired from a prospectively held database linked to Hospital Episode Statistics. Survival characteristics were calculated with global log-rank calculations. Results There was significant correlation between the Mackey 10D7G2 and the Proteintech antibodies (p Conclusions While the Proteintech antibody demonstrates concordance with the 10D7G2 antibody in determining hENT1 expression the antibodies did not demonstrate significant prognostic ability in this proof-of-concept study. Standard histopathological co-variates retain prognostic utility within the cohort.

Highlight Phs-A1 confers resistance to sprouting in wheat by delaying the rate of seed dormancy loss and is distinct from the previously proposed PM19 candidate genes., The precocious germination of cereal grains before harvest, also known as pre-harvest sprouting, is an important source of yield and quality loss in cereal production. Pre-harvest sprouting is a complex grain defect and is becoming an increasing challenge due to changing climate patterns. Resistance to sprouting is multi-genic, although a significant proportion of the sprouting variation in modern wheat cultivars is controlled by a few major quantitative trait loci, including Phs-A1 in chromosome arm 4AL. Despite its importance, little is known about the physiological basis and the gene(s) underlying this important locus. In this study, we characterized Phs-A1 and show that it confers resistance to sprouting damage by affecting the rate of dormancy loss during dry seed after-ripening. We show Phs-A1 to be effective even when seeds develop at low temperature (13 °C). Comparative analysis of syntenic Phs-A1 intervals in wheat and Brachypodium uncovered ten orthologous genes, including the Plasma Membrane 19 genes (PM19-A1 and PM19-A2) previously proposed as the main candidates for this locus. However, high-resolution fine-mapping in two bi-parental UK mapping populations delimited Phs-A1 to an interval 0.3 cM distal to the PM19 genes. This study suggests the possibility that more than one causal gene underlies this major pre-harvest sprouting locus. The information and resources reported in this study will help test this hypothesis across a wider set of germplasm and will be of importance for breeding more sprouting resilient wheat varieties.

Summary The identification of genetic markers linked to genes of agronomic importance is a major aim of crop research and breeding programmes. Here, we identify markers for Yr15, a major disease resistance gene for wheat yellow rust, using a segregating F2 population. After phenotyping, we implemented RNA sequencing (RNA-Seq) of bulked pools to identify single-nucleotide polymorphisms (SNP) associated with Yr15. Over 27 000 genes with SNPs were identified between the parents, and then classified based on the results from the sequenced bulks. We calculated the bulk frequency ratio (BFR) of SNPs between resistant and susceptible bulks, selecting those showing sixfold enrichment/depletion in the corresponding bulks (BFR > 6). Using additional filtering criteria, we reduced the number of genes with a putative SNP to 175. The 35 SNPs with the highest BFR values were converted into genome-specific KASP assays using an automated bioinformatics pipeline (PolyMarker) which circumvents the limitations associated with the polyploid wheat genome. Twenty-eight assays were polymorphic of which 22 (63%) mapped in the same linkage group as Yr15. Using these markers, we mapped Yr15 to a 0.77-cM interval. The three most closely linked SNPs were tested across varieties and breeding lines representing UK elite germplasm. Two flanking markers were diagnostic in over 99% of lines tested, thus providing a reliable haplotype for marker-assisted selection in these breeding programmes. Our results demonstrate that the proposed methodology can be applied in polyploid F2 populations to generate high-resolution genetic maps across target intervals.

Next Generation Sequencing (NGS) is providing new methodologies to improve and complement traditional genetic approaches. These strategies, collectively termed NGS-enabled genetics, consist of identifying variation in bulks of plants that have been assembled based on a specific phenotype of interest. We examined NGS-enabled genetics in hexaploid wheat by using near isogenic lines (NIL) differing across a specific disease resistance locus. RNA-Seq of NILs allowed the identification of SNPs across this locus and helped distinguish allelic SNPs from homoeologous variants. F2 bulks were assembled based on opposing disease resistance phenotypes and the frequency of the informative allelic SNPs was examined across bulks using RNA-Seq. Variants enriched in the corresponding bulks are expected to be most closely linked to the phenotype of interest and were prioritized for validation. Recent advances in cereal genomics in the form of wheat gene models, sequenced diploid progenitors, and the advances in the Chromosome-based Survey Sequencing Project enabled us to develop a pipeline to automatically design SNP-based markers. These high-throughput assays were used to genotype the original individuals used to assemble the bulks and to generate a genetic map across the target locus. Linked markers are now being incorporated into marker assisted selection programs by breeders.

Targeted Induced Local Lesions in Genomes (TILLING) is a reverse genetics approach to identify novel sequence variation in genomes, with the aims of investigating gene function and/or developing useful alleles for breeding. Despite recent advances in wheat genomics, most current TILLING methods are low to medium in throughput, being based on PCR amplification of the target genes. We performed a pilot-scale evaluation of TILLING in wheat by next-generation sequencing through exon capture. An oligonucleotide-based enrichment array covering ~2 Mbp of wheat coding sequence was used to carry out exon capture and sequencing on three mutagenised lines of wheat containing previously-identified mutations in the TaGA20ox1 homoeologous genes. After testing different mapping algorithms and settings, candidate SNPs were identified by mapping to the IWGSC wheat Chromosome Survey Sequences. Where sequence data for all three homoeologues were found in the reference, mutant calls were unambiguous; however, where the reference lacked one or two of the homoeologues, captured reads from these genes were mis-mapped to other homoeologues, resulting either in dilution of the variant allele frequency or assignment of mutations to the wrong homoeologue. Competitive PCR assays were used to validate the putative SNPs and estimate cut-off levels for SNP filtering. At least 464 high-confidence SNPs were detected across the three mutagenized lines, including the three known alleles in TaGA20ox1, indicating a mutation rate of ~35 SNPs per Mb, similar to that estimated by PCR-based TILLING. This demonstrates the feasibility of using exon capture for genome re-sequencing as a method of mutation detection in polyploid wheat, but accurate mutation calling will require an improved genomic reference with more comprehensive coverage of homoeologues.

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of activity. This double-blind, randomized, parallel-group study was designed to demonstrate the lack of effect of steady-state concentrations of gemifloxacin on the pharmacodynamic effects of warfarin. Healthy male subjects received loading doses of warfarin on days 1 and 2. The warfarin dose was freely titrated until day 10, with the aim of achieving a stable international normalized ratio (INR) for prothrombin time within the range 1.3–1.8 by day 14. On days 14–24 the dose of warfarin was fixed. On days 18–24, subjects also received 320 mg of gemifloxacin or matched placebo, once daily. Thirty-five subjects entered into and completed the co-administration phase of the study. The mean (standard deviation) baseline INR (mean of days 16–18) and INR for day 24 for gemifloxacin plus warfarin were 1.52 (0.12) and 1.46 (0.15), respectively. Corresponding values for placebo plus warfarin were 1.46 (0.11) and 1.42 (0.17). The point estimate (90% confidence interval) for the difference in day 24 INR, adjusted for baseline, between gemifloxacin and placebo was 0.02 (–0.08, 0.12), which translates to an INR (relative to placebo least squares mean of 1.43) of 1.02 (0.95, 1.09). The 90% confidence interval for the difference in INR between the gemifloxacin and placebo groups was completely contained within the 25% equivalence range. There were no changes of clinical significance in vital signs, 12-lead electrocardiogram readings or laboratory parameters for any subject during the co-administration phase of the study, and no adverse experiences relating to coagulation were reported during this period. It is concluded that the pharmacodynamic effects of warfarin are not affected by gemifloxacin, and therefore both drugs can be co-administered without dosage adjustment.

We present a case of true spontaneous cholesterol embolisation causing acute renal failure. There was no history of vascular procedural interventions or thrombolytic therapy prior to her presentation, but the patient did have a history of difficult hypercholesterolemia and atherosclerosis. This case highlights the importance of remembering cholesterol embolisation as a potential cause of acute renal failure despite no apparent precipitant, especially with the presence of unexplained eosinophilia.

Scuba diving injuries vary greatly in severity and prognosis. While decompression sickness (DCS) and arterial gas embolism can be tracked easily, other forms of diving injury remain unaccounted for.The purpose of this paper is to assess rates of overall self-reported scuba-diving-related injuries, self-reported DCS-like symptoms, and treated DCS and their association with diver certification level, diving experience and demographic factors.We analyzed self-reported data from a Divers Alert Network membership health survey conducted during the summer of 2011. Poisson regression models with scaled deviance were used to model the relative rates of reported injuries. Models were adjusted for sex, age, body mass index (BMI) and average annual dives, based on the bias-variance tradeoff.The overall rate of diving-related injury was 3.02 per 100 dives, self-reported DCS symptoms was 1.55 per 1,000 dives and treated DCS was 5.72 per 100,000 dives. Diving-related injury and self-reported DCS symptom rates decreased for higher diver certification levels, increasing age, increasing number of average annual dives and for men; they increased for increasing BMI.Diving injury rates may be higher than previously thought, indicating a greater burden on the diving community. Self-reported DCS-like symptoms are a small fraction of all dive-related injuries and those receiving treatment for DCS are an even smaller fraction. The small number of divers seeking treatment may suggest the mild nature and a tendency towards natural resolution for most injuries.

Background: A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing. Objective: This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects. Methods: A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg; 16:1 ratio) was administered to subjects at the start of a meal. After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures. The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 μg/mL, the time above the MIC (T > MIC) would be approximately ≥40% over a 12-hour dosing interval. Results: The study enrolled 24 and 31 healthy male and female subjects, respectively. Their mean age was 35 years (range, 18–58 years) and mean body weight was 69 kg (range, 51–86 kg). After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase. The mean T > MIC for an amoxicillin MIC of 4 μg/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate. By 12 hours, plasma amoxicillin concentrations were very low (∼0.05 μg/mL), suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen. The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate. No deaths or serious adverse events were reported. Conclusions: The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria—including beta-lactamase—producing organisms—and strains with amoxicillin MICs ≤4 μg/mL.

This double-blind, randomized, parallel-group comparative study investigated the phototoxic potential of gemifloxacin mesylate, a potent, novel fluoroquinolone antimicrobial. Forty healthy male and female volunteers received repeat dosing for 7 days with 160 mg or 320 mg of gemifloxacin (o.d., p.m.), 500 mg of ciprofloxacin (b.d.) or placebo (b.d.). On day 5 (large step) and day 6 (small step), graded series of wavebands were irradiated onto the back of each volunteer (phototesting). Skin reactions were assessed 0–30 min (immediate erythema) and 24 and 48 h (delayed erythema) after irradiation. Both gemifloxacin, 320 mg o.d., and ciprofloxacin, 500 mg b.d., were associated with mild phototoxicity following 7 days of administration. The range of mean phototoxic indices (the ratio of minimal erythemal dose at baseline compared with that on day 7 at the end of dosing) was 1.00–2.19 for gemifloxacin and 0.97–2.23 for ciprofloxacin. The abnormal responses occurred within the ultraviolet A region (335–365 ± 30 nm) and were maximal at 24 h. Susceptibility to phototoxicity had cleared 48 h after stopping the drug. The phototoxicity observed with gemifloxacin, 160 mg o.d., was lower than that at the higher dose and similar to that of placebo, suggesting that gemifloxacin phototoxicity is dose dependent. There were no clinically important changes in the safety profiles of gemifloxacin and ciprofloxacin compared with placebo in healthy volunteers after 7 days of repeat dosing. This study demonstrated that gemifloxacin, 320 mg o.d. given for 7 days, has a low potential to cause mild photosensitivity which is similar to that of ciprofloxacin, 500 mg b.d., given for the same period.

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4–8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8–15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300–400 mg twice daily, for 22 days. On days 5–11 and 16–22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (Cmax) for theophylline ranged from 8.12 to 17.71 mg/l and from 8.79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC(0–12)) were 84.6–177.5 mg·h/l and 94.8–165.1 mg·h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC(0–12) and Cmax (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose.