Health behaviour practices and expectations for a local cancer survivorship programme: a cross-sectional study of survivors of childhood cancer in Hong Kong.

INTRODUCTION: Lifestyle choices may influence health outcomes in cancer survivors. This study of childhood cancer survivors in Hong Kong investigated factors associated with health-protective and health-damaging behaviours; it also examined expectations of a survivorship programme. METHODS: This cross-sectional study recruited survivors of childhood cancer ≥2 years after treatment. Survivors completed a structured questionnaire to report their health practices and the perceived values of survivorship programme components. Multivariable logistic regression analysis was conducted to identify factors associated with health behaviours. RESULTS: Two hundred survivors were recruited (mean age=23.4 ± 8.8 years; mean duration since treatment, 13.4 ± 7.6 years). Comparatively few survivors exercised ≥4 days/week (16.0%), used sun protection (18.0%), and had a balanced diet (38.5%). Furthermore, comparatively few survivors reported that they had not undergone any immunisation (24.5%) or were unsure (18.5%) about their immunisation history. Most adult survivors were never-drinkers (71.0%) and never-smokers (93.0%). Brain tumour survivors were more likely to have unhealthy eating habits, compared with haematological malignancy survivors (odds ratio [OR]=2.45; 95% confidence interval [CI]=1.29-4.68). Lower socioeconomic status was associated with inadequate sun protection (OR=0.20; 95% CI=0.05-0.83), smoking (OR=5.13; 95% CI=1.48-17.75), and exposure to second-hand smoke (OR=3.52; 95% CI=1.42-8.69). Late-effects screening (78.5%) and psychosocial services to address psychological distress (77%) were considered essential components of a survivorship programme. CONCLUSIONS: Despite the low prevalences of health-damaging behaviours, local survivors of childhood cancer are not engaging in health-protective behaviours. A multidisciplinary programme addressing late effects and psychosocial aspects may address the multifaceted needs of this special population.

Update on the association between dry eye disease and meibomian gland dysfunction.

Dry eye disease is one of the most common ophthalmic complaints; it results from the activity of various pathways and is considered a multifactorial disease. An important factor that contributes to the onset of dry eye disease is meibomian gland dysfunction. Meibomian gland dysfunction causes a disruption in the tear film lipid layer which affects the rate of tear evaporation. This evaporation leads to tear hyperosmolarity, eventually triggering the onset of dry eye disease. Dry eye disease and meibomian gland dysfunction are strongly associated with each other, such that many of their risk factors, signs, and symptoms overlap. This review aimed to provide an update on the association between dry eye disease and meibomian gland dysfunction. A stepwise approach for diagnosis and management is summarised.

Survey on common reference intervals for general chemistry analytes in Hong Kong.

INTRODUCTION: Reference intervals (RIs) are essential tool for proper interpretation of results. There is a global trend towards implementing common RIs to avoid confusion and enhance patient management across different laboratories. However, local practices with respect to RIs lack harmonisation. METHODS: We have conducted the first local survey regarding RIs for 14 general chemistry analytes in 10 chemical pathology laboratories that employ four different analytical platforms (Abbott Architect, Beckman Coulter AU, Roche Cobas, and Siemens Dimension EXL). Analytical bias was assessed by an inter-laboratory results comparison of external quality assurance programmes. RESULTS: Sufficient inter-laboratory and inter-platform agreement regarding the 10 analytes (albumin, alanine aminotransferase, aspartate aminotransferase, chloride, gamma-glutamyl transferase, phosphate, potassium, sodium, total protein, and urea) were demonstrated. However, the RIs were heterogeneous across all laboratories, with percentage differences of the upper RI value of up to 47% for aspartate aminotransferase (absolute difference of 16 U/L), 29% for urea (1.8 mmol/L), and 18% for potassium (0.8 mmol/L). The percentage difference between lower RI values was up to 24% for urea (0.6 mmol/L), 22% for phosphate (0.16 mmol/L), and 8% for total protein (5 g/L). The coefficients of variation of the upper RI values of potassium and sodium were 1.2 times and 1.0 times of their corresponding between-subject biological variation, respectively, representing unnecessary variations that are overlooked and unchecked in current practice. CONCLUSIONS: We recommend the use of common RIs for general chemistry analytes in Hong Kong to prevent interpreter confusion, improve electronic data transfer, and unite laboratory practice. This is the first local study on this topic, and our data can lay the groundwork for increasing harmonisation of RIs across more laboratory tests.

Changing social contact patterns under tropical weather conditions relevant for the spread of infectious diseases.

Weather conditions and social contact patterns provide some clues to understanding year-round influenza epidemics in the tropics. Recent studies suggest that contact patterns may direct influenza transmission in the tropics as critically as the aerosol channel in temperate regions. To examine this argument, we analysed a representative nationwide survey dataset of contact diaries with comprehensive weather data in Taiwan. Methods we used included model-free estimated relative changes in reproduction number, R 0; relative changes in the number of contacts; and model-based estimated relative changes in mean contacts using zero-inflated negative binomial regression models. Overall, social contact patterns clearly differ by demographics (such as age groups), personal idiosyncrasies (such as personality and happiness), and social institutions (such as the division of weekdays and weekend days). Further, weather conditions also turn out to be closely linked to contact patterns under various circumstances. Fleeting contacts, for example, tend to diminish when it rains hard on weekdays, while physical contacts also decrease during weekend days with heavy rain. Frequent social contacts on weekdays and under good weather conditions, including high temperature and low absolute humidity, all might facilitate the transmission of infectious diseases in tropical regions.

Effectiveness of a discharge planning and community support programme in preventing readmission of high-risk older patients.

OBJECTIVE: To examine the effectiveness of Integrated Care and Discharge Support for elderly patients in reducing accident and emergency department attendance, acute hospital admissions, and hospital bed days after discharge. Factors that compromise its effectiveness were investigated and cost analysis was performed. DESIGN: Cohort prospective study. SETTING: Integrated Care and Discharge Support for elderly patients in Hong Kong West Cluster. PARTICIPANTS: Home-dwelling patients recruited between April 2012 and March 2013 into Integrated Care and Discharge Support for elderly patients in Hong Kong West Cluster. RESULTS: A total of 1090 older patients were studied. The Integrated Care and Discharge Support for elderly patients programme reduced accident and emergency department attendance by 40% (P<0.001), acute hospital admissions by 47% (P<0.001), and hospital bed days by 31% (P<0.001) at 6 months after implementation. Improvements in Barthel Index 20 (P<0.001) and Modified Functional Ambulation Category scale (P<0.001) were observed. Of the patients, 85 (7.8%) died within 6 months of initiation of the programme. Only 26 (2.4%) older patients required institutionalisation in residential care homes within 6 months after the programme. Increasing age (P=0.025) and high Charlson Comorbidity Index score (P=0.001) were positive predictors for accident and emergency department attendance. A high albumin level (P=0.001) and living alone (P=0.033) were negative predictors for accident and emergency department attendance. Of the patients, 310 (28.4%) had no reduction in bed days after the programme. Increasing age (P=0.025) and number of medications (P=0.003) were positive predictors for no reduction in bed days; while higher haemoglobin level (P=0.034) was a negative predictor. There was a potential annual cost-saving of HK$22.5 million (approximately US$2.9 million). CONCLUSION: The Integrated Care and Discharge Support for elderly patients programme reduced accident and emergency department attendance, acute hospital admissions and hospital bed days, and was potentially cost-saving. Age, Charlson Comorbidity Index, albumin level, and living alone were factors associated with accident and emergency department attendance. Age, number of medications, and haemoglobin level were associated with no reduction in bed days. Further study of the cost-effectiveness of such programme is warranted.

Diffusion of aromatic compounds in nonaqueous solvents: a study of solute, solvent, and temperature dependences.

Tracer diffusivities (limiting mutual diffusion coefficients) of nonassociated aromatic compounds in n-hexane and cyclohexane have been measured at 298.2 K by Taylor's dispersion method. These new data, together with other diffusivities of nonassociated pseudoplanar solutes reported in the literature, are used to determine the separate effects of solute and solvent on tracer diffusion. The data show that for a given pseudoplanar solute diffusing in different solvents at 298.2 K, the tracer diffusivity is dependent not only on the fractional viscosity of the solvent but also on a function of the solvent's molar density, molecular mass, and free volume fraction. For different pseudoplanar aromatic solutes diffusing in a particular solvent at a constant temperature, there is a linear relationship between the reciprocal of the tracer diffusivity and the molecular volume of the solutes. The results are discussed in respect to relevant theories and experimental studies in the literature. An idealized relation, developed on the basis of the Einstein equation by incorporating the newly found solute and solvent dependences, is capable of describing a total of 176 diffusivities of nonassociated pseudoplanar solutes in various solvents at different temperatures to within an average error of ±2.8%.

Mortality and health services utilisation among older people with advanced cognitive impairment living in residential care homes.

OBJECTIVES: To study the demography, clinical characteristics, service utilisation, mortality, and predictors of mortality in older residential care home residents with advanced cognitive impairment. DESIGN: Cohort longitudinal study. SETTING: Residential care homes for the elderly in Hong Kong West. PARTICIPANTS: Residents of such homes aged 65 years or more with advanced cognitive impairment. RESULTS: In all, 312 such residential care home residents (71 men and 241 women) were studied. Their mean age was 88 (standard deviation, 8) years and their mean Barthel Index 20 score was 1.5 (standard deviation, 2.0). In all, 164 (53%) were receiving enteral feeding. Nearly all of them had urinary and bowel incontinence. Apart from Community Geriatric Assessment Team clinics, 119 (38%) of the residents attended other clinics outside their residential care homes. In all, 107 (34%) died within 1 year; those who died within 1 year used significantly more emergency and hospital services (P<0.001), and utilised more services from community care nurses for wound care (P=0.001), enteral feeding tube care (P=0.018), and urinary catheter care (P<0.001). Independent risk factors for 1-year mortality were active pressure sores (P=0.0037), enteral feeding (P=0.008), having a urinary catheter (P=0.0036), and suffering from chronic obstructive pulmonary disease (P=0.011). A history of pneumococcal vaccination was protective with respect to 1-year mortality (P=0.004). CONCLUSION: Residents of residential care homes for the elderly with advanced cognitive impairment were frail, exhibited multiple co-morbidities and high mortality. They were frequent users of out-patient, emergency, and in-patient services. The development of end-of-life care services in residential care homes for the elderly is an important need for this group of elderly.

The association between risk factors and hypertension in perak, malaysia.

INTRODUCTION: Hypertension is a major public health problem in Malaysia. A survey was initiated to examine the association of modifiable and non-modifiable risk factors for hypertension in Perak, Malaysia. METHODS: A total of 2025 respondents aged 30 years and above were recruited using a multi-stage sampling method. Hypertension was defined as self-reported hypertension and/or average of two blood pressure readings at single occasion with SBP ≥ 140mmHg or DBP ≥ 90 mmHg. Body mass index (BMI) was defined using the Asian criteria and International Physical Activity Questionnaire (IPAQ) was used to evaluate physical activity. Body weight, height and blood pressure were obtained using standard procedures. Univariate analyses were conducted to examine the associations between risk factors and hypertension. Multiple logistic regression was used to examine each significant risk factor on hypertension after adjusted for confounders. RESULTS: In total, 1076 (54.9%) respondents were found to be hypertensive. Significant associations (p <0.001) with hypertension were noted for increasing age, low physical activity, obese BMI, no education background and positive family history of hypertension. After adjusting for age, sex, ethnicity, education background, family history, BMI, physical activity, smoking and diet, respondents who were obese and had positive family history had higher odds for hypertension (OR:2.34; 95% CI:1.84-3.17 and 1.96 (1.59-2.42) respectively. A significant increase (p <0.001) in risk for hypertension was noted for age. Those with moderate physical activities were 1.40 (1.04-1.78) times more of having hypertension than those active. Poor diet score and smoking were not significantly associated with increased risk for hypertension. CONCLUSION: In conclusion, modifiable risk factors such as BMI and physical activity are important risk factors to target in reducing the risk for hypertension.

Hospital Careful Hand Feeding Program Reduced Feeding Tube Use in Patients with Advanced Dementia.

OBJECTIVES: Tube feeding is prevalent among patients with advanced dementia despite empirical data that suggest its lack of benefit. To provide an alternative to tube feeding for end-of-life patients, a careful hand feeding program was launched in a Hong Kong geriatric convalescent hospital in February 2017. We aim to compare the rates of feeding tube insertion before and after program implementation and determine risk factors for feeding tube insertion. For patients on careful hand feeding, we evaluated their sustainability on oral feeding and the rates of hospital readmissions compared with tube feeding patients over the next 12 months. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Advanced dementia patients ≥60 years with indication for tube feeding due to feeding problems admitted from January 2015-June 2019. METHODS: Data was collected on demographic and clinical variables, initial feeding mode (careful hand feeding vs. tube feeding), subsequent feeding mode changes, and hospital admissions over the next 12 months. Rates of feeding tube insertion, sustainability on oral feeding, and hospital readmissions were compared using Chi-square test. Risk factors for feeding tube insertion were assessed using logistic regression models. RESULTS: Among 616 advanced dementia patients admitted with feeding problems, feeding tube insertion rate declined significantly after careful hand feeding program implementation (72% vs 51% p<.001). Independent risk factors for feeding tube insertion were admission prior to program implementation, presence of dysphagia alone, dysphagia combined with poor intake, and lack of advance care planning. Among patients on careful hand feeding, 91% were sustained on oral feeding over the next twelve months and did not differ significantly before or after careful hand feeding program implementation (p=.67). There was no significant difference in hospital readmission rates between careful hand feeding patients and tube feeding patients before (83% vs 86%, p=.55) and after careful hand feeding program implementation (87% vs 85%, p=.63). CONCLUSIONS AND IMPLICATIONS: A hospital careful hand feeding program significantly reduced the feeding tube insertion rate among advanced dementia patients with feeding problems. The vast majority of patients on careful hand feeding were sustained on oral feeding over the next 12 months but their rate of hospital readmissions remained similarly high after program implementation.

Pain Relief After Total Knee Arthroplasty with Intravenous and Periarticular Corticosteroid: A Randomized Controlled Trial.

BACKGROUND: Total knee arthroplasty (TKA) is a cost-effective procedure, but it is also associated with substantial postoperative pain. The present study aimed to compare pain relief and functional recovery after TKA among groups that received intravenous corticosteroids, periarticular corticosteroids, or a combination of both. METHODS: This randomized, double-blinded clinical trial in a local institution in Hong Kong recruited 178 patients who underwent primary unilateral TKA. Six of these patients were excluded because of changes in surgical technique; 4, because of their hepatitis B status; 2, because of a history of peptic ulcer; and 2, because they declined to participate in the study. Patients were randomized 1:1:1:1 to receive placebo (P), intravenous corticosteroids (IVS), periarticular corticosteroids (PAS), or a combination of intravenous and periarticular corticosteroids (IVSPAS). RESULTS: The pain scores at rest were significantly lower in the IVSPAS group than in the P group over the first 48 hours (p = 0.034) and 72 hours (p = 0.043) postoperatively. The pain scores during movement were also significantly lower in the IVS and IVSPAS groups than in the P group over the first 24, 48, and 72 hours (p ≤ 0.023 for all). The flexion range of the operatively treated knee was significantly better in the IVSPAS group than in the P group on postoperative day 3 (p = 0.027). Quadriceps power was also greater in the IVSPAS group than in the P group on postoperative days 2 (p = 0.005) and 3 (p = 0.007). Patients in the IVSPAS group were able to walk significantly further than patients in the P group in the first 3 postoperative days (p ≤ 0.003). Patients in the IVSPAS group also had a higher score on the Elderly Mobility Scale than those in the P group (p = 0.036). CONCLUSIONS: IVS and IVSPAS yielded similar pain relief, but IVSPAS yielded a larger number of rehabilitation parameters that were significantly better than those in the P group. This study provides new insights into pain management and postoperative rehabilitation following TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Haemophagocytic lymphohistiocytosis: an uncommon clinical presentation of tuberculosis.

Secondary haemophagocytic lymphohistiocytosis is a rare but fatal complication of tuberculosis. We describe two cases, and review the local and international experience on the management of this clinical entity. Prompt treatment with anti-tuberculous drugs forms the cornerstone of therapeutic success.

Effectiveness of Partially Hydrolyzed Guar Gum in Reducing Constipation in Long Term Care Facility Residents: A Randomized Single-Blinded Placebo-Controlled Trial.

OBJECTIVES: To assess the effectiveness of partially hydrolyzed guar gum (PHGG) in improving constipation and reducing the use of laxatives among long term care facility (LTCF) residents. DESIGN: A single-center, prospective, randomized, placebo-controlled, single-blinded parallel-group trial from September 2021 to November 2021. SETTING: Four LTCF in Hong Kong. PARTICIPANTS: Fifty-two LTCF residents with chronic constipation (mean age: 83.9±7.6 years, male 38%). INTERVENTION: 5g PHGG mixed with 200ml water per day for 4 weeks was given to intervention group participants. Control group received 200ml water for 4 weeks. Participants continued their usual as-needed laxative (lactulose, senna or dulcolax) on their own initiative. MEASUREMENTS: Baseline measurements included age, gender, Charlson comorbidity index, Roackwood's Clinical Frailty Scale, body mass index and daily dietary fiber intake. Outcome measures were fecal characteristics assessed by Bristol Stool Form Scale, bowel opening frequency and laxative use frequency at baseline, first, second, third and fourth week of trial. Adverse events were measured. The study was registered on ClinicalTrial.gov; identifier: NCT05037565. RESULTS: There was no significant difference in bowel frequency and stool characteristics between the treatment group and control group. However, there was a significantly lower frequency of lactulose, senna, and total laxative use in the treatment group compared with controls in the third and fourth week. There was no significant difference in adverse effects between the two groups. CONCLUSION: This study showed that daily dietary fibre supplementation by using PHGG for 4 weeks in LTCF residents results in significantly less laxative use than placebo. It may be an effective way to reduce laxative dependence among older people living in LTCFs.

Financial abuse in a mentally incapacitated old man.

A mentally incapacitated 82-year-old man with no relatives was managed by a geriatrician-led multidisciplinary team when medical staff realised he was at risk of being exploited. They initiated a series of protective measures including an emergency guardianship application. The Guardianship Board appointed the Director of Social Welfare as his public guardian. This case illustrates that hospital staff should be alert to potential elder abuse to ensure timely protection of potential victims.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of ARQ 501 (beta-lapachone) in plasma and tumors from nu/nu mouse xenografts.

A sensitive and specific LC-MS/MS method employing positive electrospray ionization for the determination of ARQ 501 (beta-lapachone) in (nu/nu) mouse plasma and tumor tissue is described. Samples were processed using protein precipitation with acetonitrile. A d6 analog of ARQ 501 was used as the internal standard (IS). The analytes were separated using a Zorbax SB8 column (30 mm x 2.1 mm i.d. 5 microm particle size) and analyzed in the multiple reaction monitoring (MRM) mode using mass transitions of 243>159 and 249>159 m/z for ARQ 501 and d6-ARQ 501, respectively. The lower limit of quantitation (LLOQ) for ARQ 501 was 3.0 ng/mL. The calibration curve was linear in the range of 3.0-2000 ng/mL with a correlation coefficient better than 0.99. Intra- and inter-batch precisions were within 8.4% for plasma and 11.8% for tumor samples. Accuracy expressed as percentage relative error (%R.E.) ranged from -9.0 to 7.7 for both plasma and tumor samples. Recovery was between 106 and 113% for both ARQ 501 and its d6 analog. Plasma pharmacokinetic data of ARQ 501 in mouse from intraperitoneal (IP) dosing at 60 mg/kg obtained using this validated method is presented along with tumor concentration data. The C(max), AUC(0-infinity), t(1/2), Cl/F, and V(d)/F were determined to be 4016 ng/mL, 4392 h ng/mL, 3.9 h, 13.7 L/h/kg, and 76.5 L/kg, respectively. Tumor tissue concentrations were in the range 1-2 microM for approximately 2 h post-dose.

Effects of Hydrogen Bonding on Diffusion of Aromatic Compounds in Acetone: An Experimental Investigation from 268.2 to 328.2 K.

Diffusion coefficients of pseudoplanar aromatic compounds at infinite dilution in acetone have been measured at different temperatures by the Taylor dispersion technique. The data of the polar solutes that can form hydrogen bonds with acetone are compared with those of the nonpolar ones incapable of hydrogen bonding to quantify the effects of hydrogen-bonded association on diffusion. The effects are further found to correlate strongly with the overall hydrogen-bonded acidity of the polar solutes containing proton-donating groups. For the nonpolar solutes in this study, the diffusivities at different temperatures can be expressed very well by the recently developed molecular-modified fractional Stokes-Einstein relation with only two constants. An innovative model for solute diffusion in liquid solutions, which is constructed by combining the molecular-hydrodynamic relation for nonpolar solutes with the overall hydrogen-bonded acidity scale for polar solutes, is introduced for representing the diffusivities of different types of disc-shaped molecules at various temperatures. An equation developed from this model is demonstrated to be capable of calculating a total of 191 diffusion data of both the hydrogen-bonded and the nonassociated aromatic solutes in acetone from 268.2 to 328.2 K to a standard deviation of 2.7%.

Diffusion of Aromatic Isomers in Acetone: An Investigation on the Effects of Intramolecular and Intermolecular Hydrogen Bonding.

Limiting mutual diffusivities of o- and m-isomers of methylaniline, nitroaniline, nitrophenol, and aminophenol were measured in acetone at 298.2 K by the Taylor dispersion method. The data reveal that all of the o-substituted solutes capable of intramolecular hydrogen bonding diffuse faster than their m-counterparts without such bonding. By taking into account of the small corrections for the differences in molecular shape and steric hindrance between the o- and m-isomers that can form solute-solvent complexes, the net effects of intramolecular hydrogen bonding were uncovered to render the o-isomers greater in diffusivity by 3-15% as compared to their m-isomers in this study. For aromatic amines and phenols diffusing in acetone, the overall effects of intermolecular hydrogen bonding on diffusivity were ascertained by comparing the available diffusivity data of the associated aromatic solutes with those of the nonassociated ones. The intermolecular effects that cause solutes to diffuse slower were found to vary from approximately 12-39% in the present work. The results indicate that both of the opposite intra- and intermolecular effects are significant. In addition, the quantified effects were analyzed to show that they are closely related to the nature and position of the functional groups contained in the aromatic solutes, including those that are unable to form hydrogen bonds with acetone. A relation that can correlate the diffusivities of the hydrogen-bonded aromatic amines and phenols in acetone with the overall acidities of the compounds is also presented.

Augmentation of 1-beta-D-arabinofuranosylcytosine cytotoxicity in human tumor cells by inhibiting drug efflux.

Dipyridamole is a potent inhibitor of membrane nucleoside transport into mammalian cells. Since the membrane transporter mediates both the influx and the efflux of nucleosides, dipyridamole should be able to block nucleoside efflux from cells as well. In human ovarian carcinoma cells (2008) and promyelocytic leukemia cells (HL60), we observed that sequential treatment with 20 microM dipyridamole 2 h after their initial exposure to varying concentrations of 1-beta-D-arabinofuranosylcytosine (ara-C) increased the cytotoxicity of this nucleoside analogue by 100 to 300% at all drug concentrations tested. In washout experiments in which cells were exposed to radiolabeled ara-C for 2 h and reincubated in fresh medium, the presence of 20 microM dipyridamole in the reincubation medium resulted in significantly elevated levels of intracellular radioactivity at the end of a 24-h period. High performance liquid chromatography analyses of cellular nucleotide pools during this 24-h period revealed that cells treated with the sequential ara-C/dipyridamole regimen have 2-to 3-fold higher levels of ara-CTP at all time points studied. Using alkaline elution assays, we measured a 30% increase in DNA strand breaks in cells treated with ara-C followed by dipyridamole when compared to cells treated with ara-C alone, while dipyridamole alone did not produce DNA lesions. ara-C resistance in tumor cells is associated with either the natural substrates competing with ara-C for phosphorylation and incorporation into macromolecules or increased catabolism of the parent drug. Sequential exposure regimens may overcome such tumor resistance by increasing the cellular pools of ara-C and its metabolites. A second advantage to the sequential regimen is that the prolonged retention of ara-C in non-S-phase cells may improve its efficacy. The applicability of such regimens in treating human cancer awaits the results from preclinical efficacy and toxicity trials.

Mechanism of synergy between N-phosphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line.

Previous results from our laboratory have shown that the nucleoside transport inhibitor dipyridamole (DP) markedly augmented both the in vitro and in vivo activities of the pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA). In a human ovarian carcinoma cell line (2008), DP increased the activity of PALA by 1 to 2 logs in growth rate and clonogenic assays while exhibiting no cytotoxicity of its own. The concentration of DP used (1 microM) in these assays resulted in over 80% reduction in uridine uptake in the 2008 cells at the end of 1 h. The activity of PALA and PALA plus DP was completely antagonized by the addition of exogenous uridine in a dose-dependent manner. Addition of other nucleosides to concentrations as high as 1000 microM failed to rescue the ovarian cells from the drug combination, and combining two nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular nucleotide pool analysis by anion-exchange high-performance liquid chromatography revealed that dipyridamole further reduced the already depressed uridine triphosphate and cytidine triphosphate pools of cells exposed to PALA, while the guanosine triphosphate pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the uridine triphosphate and cytidine triphosphate pools, but the absolute levels remained below control values. The acute drug-induced changes in nucleotide pools in 2008 xenografts growing in athymic mice paralleled those observed in vitro. Evidence presented here supports the ability of DP to potentiate PALA activity against a human ovarian carcinoma cell line. The mechanism of synergy relates to the inhibition of pyrimidine salvage in the tumor cells via the blockade of uridine uptake.

Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate.

Dipyridamole (DP) and N-phosphonacetyl-L-aspartate (PALA) act synergistically in vitro against many cell lines and in vivo against human ovarian carcinoma xenografts. We have conducted a phase I clinical trial of DP p.o. (50 mg/m2, every 6 h) in combination with PALA (starting at 500 mg/m2 i.v. with 300-mg dose escalations). Sixty-five patients were entered into this study, and we have established the maximum tolerated dose of PALA to be 4.5 g/m2 when combined with DP, which is approximately 80% of the previously reported maximum tolerated dose for PALA alone. The observed toxicities of DP plus PALA were mild and were similar to those reported for PALA alone. Bone marrow toxicities were not evident at any PALA dose. Ten patients with a mean pretreatment plasma uridine concentration of 3.49 +/- 1.28 (SD) microM had their plasma uridine reduced to 2.29 +/- 0.70 microM 9 h after DP p.o. A peak plasma DP concentration of 1.86 +/- 0.99 microM was achieved approximately 2 h after p.o. dosing. Nine patients who had a reduced plasma uridine concentration of 2.46 +/- 0.61 microM after 1 week of DP had their plasma uridine further reduced by PALA to 0.87 +/- 0.23 microM 7 h post-PALA. Daily plasma uridine measurements in two patients during their DP treatment confirmed the previously described pattern for Day 1, but the data suggest a slight recovery (15%) in plasma uridine by Day 2. Daily sampling in two other patients after a single PALA dose of 4.2 g/m2 showed that their plasma uridine declined 5 h after the PALA dose and remained depressed for 6 days in one patient and 11 days in the other. These results suggest that DP worked in synergy with PALA to lower circulating uridine in cancer patients. The mechanism for the ability of DP to reduce plasma uridine is not known, but there is evidence that DP can inhibit cellular efflux of uridine as well as its uptake. DP may reduce plasma nucleoside pools in addition to blocking nucleoside salvage and therefore have general applicability in other chemotherapy regimens.