Professor Garth Rapeport - Pulmocide and NHLI, Imperial College - CEO

Professor Garth Rapeport

Pulmocide and NHLI, Imperial College

CEO

London | United Kingdom

Main Specialties: Infectious Disease, Pharmacology, Pulmonary Disease, Pulmonary Disease & Critical Care Medicine

ORCID logohttps://orcid.org/0000-0002-5795-6500

Professor Garth Rapeport - Pulmocide and NHLI, Imperial College - CEO

Professor Garth Rapeport

Introduction

I work on the discovery of novel antiviral and antifungal drugs for the treatment of life threatening lung infection. My primary interest is in lung infection with a focus on asthma, cystic fibrosis and the immunocompromised especially lung transplant patients.

Primary Affiliation: Pulmocide and NHLI, Imperial College - London , United Kingdom

Specialties:

Research Interests:

Experience

Sep 2013
CEO and founder Pulmocide
Jul 2011
Visiting Professor, NHLI , Imperial College
Jun 2007
CEO and founder Respivert

Publications

34Publications

1035Reads

16Profile Views

970PubMed Central Citations

In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris.

J Antimicrob Chemother 2019 Oct;74(10):2943-2949

Medical Microbiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

OBJECTIVES:

Management of Candida auris infection is difficult as this yeast exhibits resistance to different classes of antifungals, necessitating the development of new antifungals. The aim of this study was to investigate the susceptibility of C. auris to a novel antifungal triazole, PC945, optimized for topical delivery.

METHODS:

A collection of 50 clinical isolates was obtained from a tertiary care hospital in North India. Nine isolates from the UK, 10 from a CDC panel (USA) and 3 from the CBS-KNAW culture collection (Japanese and South Korean isolates) were also obtained. MICs (azole endpoint) of PC945 and other triazoles were determined in accordance with CLSI M27 (third edition). Quality control strains were included [Candida parapsilosis (ATCC 22019) and Candida krusei (ATCC 6258)].

RESULTS:

Seventy-four percent of isolates tested showed reduced susceptibility to fluconazole (?64?mg/L). PC945 (geometric mean MIC?=?0.058?mg/L) was 7.4-fold and 1.5-fold more potent than voriconazole and posaconazole, respectively (both P?<?0.01). PC945 MIC values correlated with those of voriconazole or posaconazole, and only three isolates were found to be cross-resistant between PC945 and other azoles. ERG11 sequence analysis revealed several mutations, but no correlation could be established with the MIC of PC945. Tentative epidemiological cut-off values (ECOFFs) evaluated by CLSI's ECOFF Finder (at 99%) with 24?h reading of MICs were 1, 4 and 1?mg/L for PC945, voriconazole and posaconazole, respectively. MIC values for quality control strains of all triazoles were in the normal ranges.

CONCLUSIONS:

PC945 was found to be a more potent inhibitor than posaconazole, voriconazole and fluconazole of C. auris isolates collected globally, warranting further laboratory and clinical evaluations.


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https://academic.oup.com/jac/article/74/10/2943/5536332
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http://dx.doi.org/10.1093/jac/dkz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753477PMC
October 2019
61 Reads
5.313 Impact Factor

Current approaches to the discovery of novel inhaled medicines.

Drug Discov Today 2018 10 20;23(10):1705-1717. Epub 2018 May 20.

Pulmocide Ltd, 52 Princes Gate, Exhibition Road, London SW7 2 PG, UK. Electronic address:

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https://linkinghub.elsevier.com/retrieve/pii/S13596446173058
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http://dx.doi.org/10.1016/j.drudis.2018.05.017DOI Listing
October 2018
114 Reads
6.691 Impact Factor

Effects of intranasally dosed posaconazole on fungal load and biomarkers in Aspergillus fumigatus infected immunocompromised mice.

Mycoses 2017 Nov 11;60(11):728-735. Epub 2017 Jul 11.

Laboratory of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Japan.

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http://doi.wiley.com/10.1111/myc.12653
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http://dx.doi.org/10.1111/myc.12653DOI Listing
November 2017
74 Reads
1.805 Impact Factor

Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice.

Antimicrob Agents Chemother 2017 09 24;61(9). Epub 2017 Aug 24.

Laboratory of Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Japan.

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http://dx.doi.org/10.1128/AAC.00124-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571324PMC
September 2017
122 Reads
4.476 Impact Factor

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection.

Antimicrob Agents Chemother 2017 Apr 24;61(5)

Antimicrob Agents Chemother.

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

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July 2017
2 Reads

Discovery of novel benzothienoazepine derivatives as potent inhibitors of respiratory syncytial virus.

Bioorg Med Chem Lett 2017 05 23;27(10):2201-2206. Epub 2017 Mar 23.

Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.

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http://dx.doi.org/10.1016/j.bmcl.2017.03.053DOI Listing
May 2017
29 Reads
2.420 Impact Factor

The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit.

Br J Clin Pharmacol 2004 Feb;57(2):199-208

Pfizer Global Research & Development, Pfizer Ltd., Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

Aim: To investigate the effect of diet upon liver function tests and serum lipids within the restricted environment of a Phase I unit.

Methods: An open randomized three-way crossover study was designed with subjects consuming three types of diet. The diets comprised, a balanced normal calorie diet, a high-carbohydrate high-calorie diet and a high-fat high-calorie diet. Each diet was consumed in a randomized sequence over 8 days with a recovery period of 14 days between periods. The blood concentrations of various laboratory parameters were measured at intervals throughout each dietary period and during the recovery periods.

Results: Blood transaminase activity and triglyceride concentrations increased significantly whilst subjects consumed a high-carbohydrate high-calorie diet but not when fed either a high-fat high-calorie diet or a balanced normal calorie diet.

Conclusions: The rises in transaminases and triglycerides were caused by the carbohydrate content of the diet rather than its calorific value. Sucrose rather than starch was the carbohydrate which caused the rise in transaminases and triglycerides. The importance of controlling diet in Phase I studies is stressed.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884438PMC
http://dx.doi.org/10.1046/j.1365-2125.2003.01969.xDOI Listing
February 2004
2 Reads
70 Citations
3.878 Impact Factor

Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.

Neuroimage 2002 Aug;16(4):999-1014

Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.

We present a method for investigating the dynamic pharmacological modulation of pain-related brain activity, measured by BOLD-contrast fMRI. Noxious thermal stimulation was combined with a single infusion and washout of remifentanil, a short-acting opioid analgesic agent. The temporal profile of the effect site concentration of remifentanil, estimated from a pharmacokinetic model, was incorporated into a linear model of the fMRI data. The methodology was tested in nine healthy male subjects. During each imaging session the subjects received noxious thermal stimulation to the back of the left hand, prior to infusion, during infusion to a remifentanil effect site concentration of 1.0 ng/ml, and during washout of the remifentanil. Infusions were repeated with saline. Remifentanil-induced analgesia was confirmed from subjective pain intensity scores. Pain-related brain activity was identified in a matrix of regions using a linear model of the transient BOLD responses to noxious stimulation. Of those regions, there was a significant fractional reduction in the amplitude of the pain-related BOLD response in the insular cortex contralateral to the stimulus, the ipsilateral insular cortex, and the anterior cingulate cortex. Statistical parametric mapping of the component of pain-related BOLD responses that was linearly scaled by remifentanil concentration confirmed the contralateral insular cortex as the pain-processing region most significantly modulated by remifentanil compared to saline. The mapping of specific modulation of pain-related brain activity is directly relevant for understanding pharmacological analgesia. The method of examining time-dependent pharmacological modulation of specific brain activity may be generalized to other drugs that modulate brain activity other than that associated with pain.

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http://dx.doi.org/10.1006/nimg.2002.1146DOI Listing
August 2002
9 Reads
180 Citations
6.357 Impact Factor

Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo.

Chem Res Toxicol 2001 Aug;14(8):965-74

Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3GE, U.K.

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http://dx.doi.org/10.1021/tx0001981DOI Listing
August 2001
1 Read
3.529 Impact Factor

Absence of effect of sertraline on time-based sensitization of cognitive impairment with haloperidol.

J Clin Psychiatry 1996 ;57 Suppl 1:7-11

Pfizer Central Research, Sandwich, Kent, United Kingdom.

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June 1996
1 Read
5.498 Impact Factor

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response.

Cancer Chemother Pharmacol 1989 ;24(1):45-9

University Department of Clinical Oncology, Newcastle General Hospital, Newcastle-upon-Tyne, U.K.

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

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http://dx.doi.org/10.1007/bf00254104DOI Listing
June 1989
1 Read
150 Citations
2.769 Impact Factor

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist.

Br J Cancer 1988 Nov;58(5):651-3

CRC Department of Medical Oncology, Glasgow.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246838PMC
http://dx.doi.org/10.1038/bjc.1988.278DOI Listing
November 1988
2 Reads
4.836 Impact Factor

Neuropharmacology of emesis induced by anti-cancer therapy.

Trends Pharmacol Sci 1988 Sep;9(9):334-41

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http://dx.doi.org/10.1016/0165-6147(88)90106-xDOI Listing
September 1988
1 Read
432 Citations
11.539 Impact Factor

The serotonin type 3 receptor antagonist BRL 43694 and nausea and vomiting induced by cisplatin.

BMJ 1988 Jul;297(6641):110-1

University Department of Clinical Oncology, Newcastle General Hospital, Newcastle upon Tyne.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1833825PMC
http://dx.doi.org/10.1136/bmj.297.6641.110DOI Listing
July 1988
2 Reads

Clinical pharmacokinetics of allopurinol.

Clin Pharmacokinet 1986 Sep-Oct;11(5):343-53

Allopurinol is a widely used drug in the management of hyperuricaemia. It is rapidly and extensively absorbed following oral administration. The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. Up to 80% of allopurinol is recovered in the urine within 24 hours, mainly in the form of oxypurinol. Allopurinol is negligibly absorbed after rectal administration. In animals, allopurinol is found in highest concentrations in vascular tissue, blood, liver, intestine and heart. It is negligibly bound to plasma proteins. Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. Allopurinol inhibits the metabolism of 6-mercaptopurine and azathioprine, which require dosage modifications. The interaction of allopurinol with oral anticoagulants and phenytoin has not been clearly established in clinical practice.

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http://dx.doi.org/10.2165/00003088-198611050-00001DOI Listing
January 1987
2 Reads
138 Citations
5.053 Impact Factor

Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine.

Eur J Clin Pharmacol 1984 ;26(4):453-6

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http://dx.doi.org/10.1007/bf00542140DOI Listing
August 1984
2 Reads
2.966 Impact Factor

Variability of phenytoin protein binding in epilepsy.

Authors:
W G Rapeport

Arch Neurol 1984 Apr;41(4):363

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http://dx.doi.org/10.1001/archneur.1984.04050160025007DOI Listing
April 1984
7.419 Impact Factor

Effect of carbamazepine on haem biosynthesis in man.

Eur J Clin Invest 1984 Apr;14(2):107-10

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http://dx.doi.org/10.1111/j.1365-2362.1984.tb02097.xDOI Listing
April 1984
3 Reads
2.734 Impact Factor

Neuropharmacology of emesis induced by anti-cancer therapy

VOLUME 9, ISSUE 9, P334-341, SEPTEMBER 01, 1988

Trends in Pharmacological Sciences

https://doi.org/10.1016/0165-6147(88)90106-X

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November -0001
2 Reads

Top co-authors

Kazuhiro Ito
Kazuhiro Ito

National Heart and Lung Institute

14
Pete Strong
Pete Strong

Pulmocide Ltd.

9
Thomas Colley
Thomas Colley

Imperial College London

7
Yasuo Kizawa
Yasuo Kizawa

Nihon University

7
Genki Kimura
Genki Kimura

Nihon University School of Pharmacy

6
Takahiro Nakaoki
Takahiro Nakaoki

Laboratory of Physiology and Anatomy

5
Lindsey Cass
Lindsey Cass

Pulmocide Ltd

4
Yuki Nishimoto
Yuki Nishimoto

Division of Diabetes and EndocrinologyKobe University Hospital

4
Matthew Coates
Matthew Coates

University of Sydney

4
John Murray
John Murray

University of New South Wales

4