The timing of liver resection in patients with colorectal cancer and synchronous liver metastases: a population-based study of current practice and survival.

AIM: There is uncertainty regarding the optimal sequence of surgery for patients with colorectal cancer (CRC) and synchronous liver metastases. This study was designed to describe temporal trends and inter-hospital variation in surgical strategy, and to compare long-term survival in a propensity score-matched analysis. METHOD: The National Bowel Cancer Audit dataset was used to identify patients diagnosed with primary CRC between 1 January 2010 and 31 December 2015 who underwent CRC resection in the English National Health Service. Hospital Episode Statistics data were used to identify those with synchronous liver-limited metastases who underwent liver resection. Survival outcomes of propensity score-matched groups were compared. RESULTS: Of 1830 patients, 270 (14.8%) underwent a liver-first approach, 259 (14.2%) a simultaneous approach and 1301 (71.1%) a bowel-first approach. The proportion of patients undergoing either a liver-first or simultaneous approach increased over the study period from 26.8% in 2010 to 35.6% in 2015 (P < 0.001). There was wide variation in surgical approach according to hospital trust of diagnosis. There was no evidence of a difference in 4-year survival between the propensity score-matched cohorts according to surgical strategy: bowel first vs simultaneous [hazard ratio (HR) 0.92 (95% CI: 0.80-1.06)] or bowel first vs liver first [HR 0.99 (95% CI: 0.82-1.19)]. CONCLUSION: There is evidence of wide variation in surgical strategy in dealing with CRC and synchronous liver metastases. In selected patients, the simultaneous and liver-first strategies have comparable long-term survival to the bowel-first approach.

Early definitive treatment rate as a quality indicator of care in acute gallstone pancreatitis.

BACKGROUND: Early definitive treatment (cholecystectomy or endoscopic sphincterotomy in the same admission or within 2 weeks after discharge) of gallstone disease after a biliary attack of acute pancreatitis is standard of care. This study investigated whether compliance with early definitive treatment for acute gallstone pancreatitis can be used as a care quality indicator for the condition. METHODS: A retrospective cohort study was conducted using the Hospital Episode Statistics database. All emergency admissions to National Health Service hospitals in England with a first time diagnosis of acute gallstone pancreatitis in the financial years 2008, 2009 and 2010 were examined. Trends in early definitive treatment between hospital trusts were examined and patient morbidity outcomes were determined. RESULTS: During the study interval there were 19 510 patients with an overall rate of early definitive treatment at 34·7 (range 9·4-84·7) per cent. In the 1-year follow-up period, 4661 patients (23·9 per cent) had one or more emergency readmissions for complications related to gallstone pancreatitis. Of these, 2692 (57·8 per cent) were readmissions for acute pancreatitis; 911 (33·8 per cent) were within the first 2 weeks of discharge, with the remaining 1781 (66·2 per cent) occurring after the point at which definitive treatment should have been received. Early definitive treatment resulted in a 39 per cent reduction in readmission risk (adjusted risk ratio (RR) 0·61, 95 per cent c.i. 0·58 to 0·65). The risk was further reduced for acute pancreatitis readmissions to 54 per cent in the early definitive treatment group (adjusted RR 0·46, 0·42 to 0·51). CONCLUSION: In acute gallstone pancreatitis, compliance with recommended early definitive treatment varied considerably, with associated variation in outcomes. Compliance should be used as a quality indicator to improve care.

The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

Association between cardiac high-energy phosphate metabolism and whole body metabolism in healthy female adults.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56+/-14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio - an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

A feasibility study to investigate the utility of a home-based exercise intervention during and after neo-adjuvant chemotherapy for oesophago-gastric cancer-the ChemoFit study protocol.

BACKGROUND: Treatment of locally advanced oesophago-gastric adenocarcinoma usually entails neo-adjuvant chemotherapy (NAC) and surgery. Surgery is associated with high morbidity and mortality. Cardiopulmonary reserve of patients having major surgery is related to postoperative outcomes. Complications are associated with poorer quality of life and may affect prognosis. Preventing complications may be beneficial to both of these and have cost implications. Prehabilitation may improve recovery from surgery by increasing a patients' fitness before surgery. Designing a potentially cost and resource effective regimen which improves cardiopulmonary reserve may have a beneficial impact on patient outcomes after surgery. METHODS: The ChemoFit study is a non-randomised, single-arm and single-centre pilot study designed to investigate the feasibility of a home-based prehabilitation exercise intervention for patients receiving neoadjuvant treatment prior to oesophago-gastric surgery. Forty patients will be recruited at a single high-volume centre. The simple, home-based exercise intervention involves patients increasing their daily step-count during and after NAC and in the weeks leading up to surgical resection of the cancer. Additionally, quality of life assessments (QLQ-C30 and QLQ-OG25), oncological treatment delivery and participant perceptions of the study assessed by focus groups and questionnaires will be performed. The primary outcomes are to assess feasibility of the exercise intervention. The secondary outcomes will evaluate changes in cardiopulmonary reserve, sarcopenia and fat composition. DISCUSSION: It is anticipated that during an important teachable moment, the diagnosis and treatment of cancer, our patients will be open to the possibility of improving their fitness during chemotherapy and before major cancer surgery. It is possible that the negative impact of NAC on cardiopulmonary fitness could be prevented by implementing a home-based prehabilitation programme during and after NAC, prior to surgery for oesophago-gastric adenocarcinoma. TRIAL REGISTRATION: This study has been approved by the Health Research Authority (REC 18/WA/0427). Newcastle upon Tyne Hospitals NHS Foundation Trust (NUTH) will act as the study sponsor and the work is funded by a grant awarded by The Jon Moulton Charitable Foundation, supported by a research post funded by the Sir Bobby Robson Foundation. Trial registration: Clinicaltrials.gov, NCT04194463. Registered 11th December 2019-retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04194463.

Can age-based estimates of weight be safely used when resuscitating children?

BACKGROUND: Prescribing medication appropriate to a child's bodily dimensions is fundamental to paediatric emergency medicine. Mathematical formulae are frequently used in clinical practice to estimate children's weights. In 1995 the UK's paediatric reference data, describing age-related changes in bodily proportions (both weight and height), were updated and published. This study assesses the validity of using mathematical estimates, age-based estimates or length-based estimates of weight (the latter both compiled from this reference data) by comparison with actual physical measurements recorded in a paediatric clinic setting. METHODS: A prospective study was carried out in a paediatric outpatient setting recording age, weight and height for statistical comparison with these three possible methods. RESULTS: 544 children aged 0-11 years were recruited, with mean (SD) age, weight and height of 5.3 (2.9) years, 21.4 (10) kg and 108 (22) cm, respectively. CONCLUSIONS: Both length-based and age-based estimates of weight outperformed the currently accepted "gold standard" mathematical estimate when applied to children up to 11 years of age (approximately 35 kg). Length-based estimates were statistically superior, but the physical limitations and technical constraints posed when attempting to accurately measure a child's length in emergency environments may favour the simplicity of using the child's age against tables of growth chart reference data to provide an estimate of their weight.

The effect of temperature on bougies: a photographic and manikin study.

We investigated the effect of temperature on single use and reuseable bougies. In a photographic study, three bougies (Portex Venn reuseable (R), Portex single use (S) and Breathesafe single use (B)) were exposed to increasing temperatures and sequential photographs were taken of the bougies uncoiling from a preformed curve. Bougie type was associated with rate of uncoiling, type R maintaining its curve the longest but changing temperature did not affect this. In a randomised cross-over manikin study, 16 anaesthetists attempted to pass two bougies (Portex reuseable (R) and Portex single use (S)) at three temperatures (10, 20 and 30 degrees C) into the trachea of a manikin. Type R was significantly associated with higher success rate of tracheal placement compared to type S. Change of temperature was significant with success rate increasing with lower temperature. The odds of success at 10 degrees C was six times that at 30 degrees C (OR (95%) 6.7 (1.7, 25.7)). We concluded that both bougies performed best at 10 degrees C.

Novel Toxoplasma gondii inhibitor chemotypes.

We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC50 values ranging from 0.3 to 2µM, comparable to that of 0.25 to 1.5µM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

Influence of atrial fibrillation on outcome following mitral valve repair.

BACKGROUND: To investigate the outcome of patients in atrial fibrillation (AF) following mitral valve repair, clinical and echocardiographic follow-up was undertaken in 400 consecutive patients who underwent mitral valvuloplasty from 1987 to 1999. METHODS AND RESULTS: The main indications for surgery were degenerative (81.4%), endocarditis (7.1%), rheumatic (6.6%), ischemic (4.6%), and traumatic (0.3%) mitral valve disease. After excluding 6 paced patients and 1 patient in nodal rhythm, we compared the outcomes of 152 patients in AF against 241 patients in sinus rhythm. For patients in AF versus those in sinus rhythm, more AF patients were older (mean age 67.2+/-8.8 versus 61.9+/-11.8 years, respectively; P<0.001), more were assigned to a poorer New York Heart Association (NYHA) class (77.6% versus 66.0% in NYHA III/IV, respectively; P=0.01), and more demonstrated impaired ventricular function (78.9% versus 46.2% with moderate or severe impairment, respectively; P<0.001). For patients in AF versus those in sinus rhythm, there was no difference in 30-day mortality (2.0% versus 2.1%, respectively; P=0.95), repair failure (5.4% versus 3.6%, respectively; P=0.41), stroke (5.4% versus 2.2%, respectively; P=0.11), or endocarditis (2.3% versus 0.9%, respectively; P=0.27) on follow-up at a median of 2.8 years (interquartile range 1.1 to 6.0). On echocardiography, the proportion of patients with mild regurgitation or worse was 13.3% (AF patients) versus 10.8% (patients in sinus rhythm) (P=0.70). Patients in AF versus those in sinus rhythm had lower survival at 3 years (83% versus 93%, respectively) and 5 years (73% versus 88%, respectively). Univariate analysis identified factors affecting survival as AF (P=0.002), age >70 years (P=0.041), and poor ventricular function (P<0.001). However, by use of a multivariate model, only poor ventricular function remained significant (P=0.01). CONCLUSIONS: AF does not affect early outcome or durability of mitral repair. The onset of AF may be indicative of disease progression because of its association with poor left ventricular function.

Extended ganciclovir prophylaxis in lung transplantation.

BACKGROUND: Positive cytomegaloviral status of the donor or of the recipient adversely affects survival and enhances the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The role of ganciclovir prophylaxis in cytomegalovirus infection in respect to obliterative bronchiolitis or to BOS development is not known. METHODS: From the Papworth transplant database, we identified 146 patients who received organs from cytomegalovirus-positive donors. We classified patients into 3 groups as follows: Group 1 consisted of 42 patients who underwent transplantation between 1990 and 1992 when no prophylaxis was given; Group 2 consisted of 49 patients who underwent transplantation between 1992 and 1995 when 4 weeks of IV ganciclovir was given as prophylaxis; and Group 3 consisted of 55 patients who underwent transplantation between 1995 and 1998 when cytomegalovirus prophylaxis consisted of IV (1 week) followed by oral ganciclovir for a total of 3 months. Donor management, recipient management during and after surgery, and pharmacotherapy were uniform during the study period. We used survival and regression methods to compare these groups, adjusting for the transplantation type (single lung, double lung, or heart-lung) and for HLA typing. RESULTS: We found a significant difference among all 3 groups in numbers of cytomegaloviral disease episodes in the 1st year after transplantation. The number of rejection episodes in the 3 groups during the 1st post-transplant year gradually decreased from Group 1 to Group 3. We identified no statistically significant benefit in the time to BOS occurrence or in actuarial survival. CONCLUSION: Extended prophylaxis with IV and oral ganciclovir practically abolishes cytomegaloviral disease and is related to a decreased incidence of rejection episodes. However, ganciclovir prophylaxis is not related to a decreased incidence or progression of BOS or survival.

Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma.

AIMS: Malignant mesothelioma is increasing in incidence and no current therapy significantly prolongs survival. Previous surgical strategies involved high-risk open procedures without achieving histologically clear resection margins. We present the results of VATS debulking pleurectomy-decortication in advanced disease. METHODS: A consecutive series of patients with suspected malignant mesothelioma underwent thoracoscopic assessment to determine the feasibility of decortication, where this was not possible a biopsy alone was taken. Post-operative radiotherapy was administered to port sites, but no other adjuvant therapy was given. The two groups (biopsy only and pleurectomy-decortication) were composed of patients with histologically confirmed mesothelioma [28 and 51 patients, respectively]. The primary endpoint was comparison of actuarial patient survival. Secondary endpoints included post-operative air leak and duration of hospital stay. RESULTS: The overall actuarial survival was 288 days and 67% of patients had died at the time of data analysis. The groups were matched for patient and tumour-related characteristics including age (66, 64 years, p=0.39) and tumour stage (median IMIG stage 3 [IQR 2-3] both groups, p=0.54). The biopsy only group had fewer air leaks (57, 84%, p=0.01) and a shorter hospital stay (4, 8 days, p=0.03). However, the pleurectomy-decortication group had favourable actuarial survival relative to the biopsy only group (416, 127 days, p<0.001). Multivariate analysis showed early stage (p<0.001), absence of pre-operative fever (p=0.03) and pleurectomy-decortication (p<0.001) as independent predictors of survival. CONCLUSION: VATS pleurectomy-decortication is feasible in the majority of cases and independently improves survival for patients with advanced malignant mesothelioma.

The FORECAST study - Focal recurrent assessment and salvage treatment for radiorecurrent prostate cancer.

BACKGROUND: One-third of men may experience biochemical failure by 8years following radical radiotherapy for localised prostate cancer. Over 90% of men are started on androgen deprivation therapy (ADT) which is non-curative and confers systemic side-effects. Focal salvage therapy (FST) limits collateral tissue damage and may improve therapeutic ratios. In order to deliver FST, distant disease must be ruled-out and intra-prostatic disease must be accurately detected, localised and characterised. AIM: FORECAST - Focal Recurrent Assessment and Salvage Treatment - is a study designed to evaluate a novel imaging-based diagnostic and therapeutic complex intervention pathway for men who fail radiotherapy. METHODS: Men with biochemical failure following radical prostate radiotherapy, prior to salvage therapy will be recruited. They will undergo whole-body multi-parametric MRI (WB-MRI), choline PET/CT, bone-scan and pelvic-mpMRI and then MRI transperineal-targeted biopsies (MRI-TB) and Transperineal Template Prostate Mapping Biopsy (TPM). Those suitable for FST will undergo either high intensity focused ultrasound (HIFU) or cryotherapy. RESULTS: Primary outcome measures: a) the accuracy of WB-MRI to detect distant metastatic disease; b) accuracy of prostate mpMRI in local detection of radiorecurrent prostate cancer; c) detection accuracy of MRI-TB; and d) rate of urinary incontinence following FST. CONCLUSION: Focal salvage therapy may confer lower rates of morbidity whilst retaining disease control. In order to deliver FST, intra- and extra-prostatic disease must be detected early and localised accurately. Novel diagnostic techniques including WB-MRI and MRI-TB may improve the detection of distant and local disease whilst reducing healthcare burdens compared with current imaging and biopsy strategies.

Lymphatic transport of proteins after s.c. injection: implications of animal model selection.

Subcutaneous (s.c.) administration continues to be the main route for the delivery of protein drugs due to their poor bioavailability by most non-parenteral routes. While small drug molecules are rapidly and extensively absorbed after s.c. injection, the systemic bioavailability of protein drugs is often incomplete and variable. Given the widespread use of the s.c. route for protein drugs, surprisingly little is known about the factors that govern the rate and extent of protein absorption from the interstitial space and the role of the lymphatic system in the transport of these molecules to the systemic circulation. The few studies that have directly addressed the role of lymphatic transport in protein bioavailability are complicated by the use of methods and models that vary widely. In this review we will evaluate the available literature describing the lymphatic transport of proteins after s.c. injection and more specifically, address the impact of experimental variation (e.g. site of cannulation, animal model, anesthesia) on the interpretation of the data obtained. We will also describe in some detail the sheep model currently in use in our laboratory, which allows both estimation of the extent of uptake of protein drugs into the lymphatics draining the injection site, and quantification of the contribution of lymphatic transport to the absolute bioavailability.

Variation in the diffusion and release of ribonuclease through and from esterified hyaluronic acid membranes: effect of changes in matrix characteristics.

50 h) were detected for the transport and release of a model protein (ribonuclease A) compared with that for the translucent region which showed no lag time. The results highlight the importance of carefully controlling matrix formation to ensure reproducible transport and release characteristics from polymer matrices.

Mechanisms controlling diffusion and release of model proteins through and from partially esterified hyaluronic acid membranes.

The effects of polymer percent esterification and protein molecular weight on the diffusion of two model proteins, deoxyribonuclease (DNase) and ribonuclease A (RNase A), through and from partially esterified hyaluronic acid membranes were compared. The permeability of the polymer membranes was inversely related to the degree of polymer esterification and the molecular weight of the protein. Transport rates of proteins through the membranes decreased dramatically over narrow ranges of polymer esterification. As expected, the apparent diffusivity of the larger protein in the polymer matrix was more sensitive to changes in membrane hydration than that of the smaller protein. These observations demonstrated the dependence of the mobility of large molecular weight proteins on polymer hydration and chain relaxation. The relationship between protein diffusion through and release from the modified hyaluronate matrices was also investigated using RNase A as a model. The release profiles from fully esterified membranes showed lag behavior and varied with protein load and hyaluronate hydrolysis rates, while release from less esterified membranes was rapid and independent of polymer esterification or hydrolysis. Potential applications of modified hyaluronate matrices in the controlled delivery of proteins are discussed.

Lymphatic transport of proteins after subcutaneous administration.

This mini-review summarizes the relevant literature regarding the lymphatic transport of proteins after subcutaneous administration. A review of the physiology of the lymphatics and inherent anatomical differences between blood and lymph capillaries is presented followed by a brief overview of the general characteristics of protein absorption and bioavailability following S.C. injection. A description of factors known to directly affect the lymphatic uptake of macromolecules follows and is supported by representative data from this laboratory. A brief perspective on the importance of lymphatic uptake and transport in understanding the biopharmaceutical properties of protein drugs and potentially targeting the lymphatics is presented.

Lymphatic transport of halofantrine in the triple-cannulated anesthetized rat model: effect of lipid vehicle dispersion.

Halofantrine hydrochloride is an important, highly lipophilic anti-malarial agent. A triple-cannulated anesthetized rat model was used to investigate the potential lymphatic transport of halofantrine (Hf). The effect of formulating Hf in vehicles representative of different physical (digestion) states of triglyceride lipid was also evaluated. The lipid vehicles were either a lipid solution, emulsion, or micellar system comprised of 50 microL of a 2:1 molar ratio of oleic acid:glycerol monooleate containing 2 mg of Hf free base. Lymph was collected from the mesenteric lymph duct, and blood was sampled from the jugular vein following intraduodenal infusion of the different formulations. Lymphatic transport was a major contributor to bioavailability as demonstrated by the recovery of up to approximately 20% of the administered dose in the intestinal lymph. The rank order effect of the vehicles for the promotion of lymphatic transport was micellar > emulsion > lipid solution. Lymphatic drug transport was predominantly associated with chylomicron-based transport. The extent of Hf absorption via the portal blood, estimated from the systemic plasma profiles in the lymph-cannulated rats, was largely independent of the administered formulations. These data indicate that lymphatic transport of the free base of Hf is a major contributor to oral bioavailability when formulated in appropriate lipid vehicles. The data suggest that formulation as increasingly disperse systems facilitates transport in this animal model.

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N-phosphonooxymethyl prodrugs in rats and dogs.

N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.

Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion.

The intestinal lymphatic transport of halofantrine, an important, highly lipophilic antimalarial drug, has been studied in a conscious rat model after oral administration. In these studies, the lymphatic transport of Hf free base when coadministered with lipid was approximately 20% of the administered dose compared with 5% transport after administration of the HCl salt with or without lipid. These differences in transport can be attributed to the increased lipophilicity of the free base (relative to the HCl salt) thereby facilitating greater association of Hf base with the products of luminal lipid digestion and the subsequent interaction with the intestinally derived chylomicrons responsible for lymphatic drug transport. In contrast to previous results in an anesthetized rat model where lymphatic transport was dependent on the characteristics of the intraduodenally administered lipid formulations, the lymphatic transport of Hf base in the conscious rat was independent of both the class of administered lipid (triglyceride or fatty acid) and the extent of formulation dispersion (micellar lipid or lipid solution). Considering the different lymphatic transport profiles of Hf base in the anesthetized and conscious rat models, it is proposed that the lipid vehicle effects observed in the intraduodenally dosed anesthetized model most likely reflects the lack of gastric processing by preduodenal lipase and the shear action of the stomach otherwise present in the conscious rat model.