Quality Assurance in Radiotherapy (RT)-Specific Trials: Indian Scenario.

AIMS: There is evidence that proper radiotherapy trial quality assurance (RTTQA) translates into improved outcomes for patients. However, the practice of RTTQA is heterogeneous and implemented in a diverse manner across trials. In this paper, we review the RTTQA report for randomised trials (RCT) conducted in India and present our experience with RTTQA for various clinical trials and highlight the key achievements and challenges. MATERIALS AND METHODS: Search was performed using the keywords and the variations thereof for "radiotherapy" and author affiliations from India, its states and major metropolitan cities. Pubmed search filters were used to restrict results to RCT published in the past 5 years (2019-2024). Reporting of RTTQA procedures from publications and protocols was documented along with the protocol-specified dosimetric goals. We also evaluated a few clinical trials performed in the Department of Radiation Oncology at Tata Medical Center. The different RTTQA procedures and results for four representative clinical trials have been described. RESULTS: A formal RTTQA process was reported by only one out of 24 randomised controlled trials and formal dosimetric goals were pre-specified by 9 of 13 trials where IMRT was used as treatment. RTTQA requirements were tailored for each clinical trial at Tata Medical Center. For the HYPORT trial, the RTTQA process focused on ensuring the matchline doses were homogenous. HYPORT B trial commissioned the use of a simultaneous integrated boost technique which emphasised conformal avoidance of dose spillage to contralateral breast and lung. HYPORT Adjuvant and PROPARA trials are multicentre clinical trials. While HYPORT Adjuvant focussed on ensuring that the dose delivery met the predefined constraints, segmentation of the target volume was important for the PROPARA trial. CONCLUSION: We demonstrate different RTTQA procedures required for representative clinical trials and highlight key challenges encountered.

Salvage Using Polatuzumab Vedotin Based Therapy in Relapsed Refractory Large B-Cell Lymphomas: Early Experience from a Real-World Middle-Income Setting Using Named-Patient Compassionate Access Program.

Polatuzumab vedotin is a novel immunotherapy antibody-drug conjugate targeting CD79b. It has been used in relapsed/refractory (R/R) large B-cell lymphomas since its FDA approval in 2019. Presently, this drug is unaffordable or unavailable for patients in Lower-Middle Income Countries (LMIC) like India. This is a retrospective study of adult (> 18 years) patients with R/R large B-cell lymphoma failing two prior lines of therapy, who received Polatuzumab based salvage therapy on a compassionate or named-patient access program. Between May 2019 and April 2022, 10 patients received Polatuzumab vedotin, and 9 were evaluable. The most common regimen used was Polatuzumab-Bendamustine-Rituximab. Out of 43 infusions administered, the adverse event profile was manageable [One grade-2 infusion reaction, 4 patients developed grade 3-4 hematological toxicity and none had grade 3-4 non-hematological toxicities]. Ten infusions were administered in the day care service. After a median of 4.5 cycles (range 1-8), 4 patients achieved CR, 2 had partial response (PR), and 3 had progressive disease (PD). With a median follow up of 491 days (range 8-1048 days), four patients are alive (three in CR and one in PR), three patients have died and three patients were lost to follow up. Early real-world experience from a LMIC setting demonstrates feasibility and a favourable safety profile of Polatuzumab vedotin based approach, along with encouraging response rates in a subset of patients.

A Phase I/II Study of Stereotactic Hypofractionated Once-weekly Radiation Therapy (SHORT) for Prostate Cancer.

AIMS: Stereotactic radiation therapy has been investigated predominantly in patients with low-intermediate-risk disease. We conducted a clinical trial of stereotactic hypofractionated radiation therapy delivered in once-weekly fractions on patients with all-risk non-metastatic disease to test feasibility, acute toxicities and patient-reported outcomes. MATERIALS AND METHODS: In this phase I/II study, 30 patients with prostatic adenocarcinoma, any Gleason score, T1-4N0 and prostate-specific antigen ≤60 ng/ml were treated with volumetric intensity modulated arc radiation therapy to a dose of 35 Gy in five fractions delivered once weekly. Patients with high-risk disease also received elective nodal irradiation to a dose of 25 Gy in five fractions simultaneously. Androgen deprivation was offered to intermediate- and high-risk patients. The primary outcome was acute toxicity. Secondary outcome measures included biochemical control and late toxicity. Patient-reported outcomes were measured using the International Prostate Symptom Score and European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ). RESULTS: All 30 patients completed treatment per-protocol. Most patients had T3 (60%) and Gleason 7 (50%) tumours. The median prostate-specific antigen was 17 ng/ml. High-risk disease was present in 20 patients (66.7%). There was a low incidence of acute toxicities (grade 2 + urinary 3.3%, grade 2 rectal 0%). Within the EORTC QLQ framework, only the urinary symptom score showed a clinically meaningful worsening from a mean of 20/100 at baseline to 34/100 at the end of treatment (P < 0.001), but reduced to 24/100 at 6 months (P = 0.08). With a median follow-up of 41.5 months, two patients each reported grade 2 late urinary and rectal toxicity. The 3- and 4-year biochemical control rates were 96.7 and 87.9%, respectively. CONCLUSION: In a cohort of mainly high-risk cancers, stereotactic once-weekly radiation therapy was easy to implement and well tolerated, with a low incidence of acute and late toxicity and excellent biochemical control.

Helical Radiotherapy in Early Laryngeal Cancers Could Lead to Excess Local Recurrence: Lessons From a Phase II Prospective Study.

AIMS: A prospective study was conducted to investigate the feasibility and efficacy of carotid-sparing intensity-modulated radiotherapy (CSIMRT) in early glottic cancers (EGC). MATERIALS AND METHODS: Eighteen patients underwent CSIMRT using helical tomotherapy to a dose of 55 Gy/20 fractions/4 weeks. Carotid intimal thickness (CIT) at prespecified carotid levels was measured using B-mode ultrasound at 6, 18 and 36 months. Serial changes in CIT were also measured in a control prospective cohort of 18 patients with head and neck cancers receiving bilateral neck nodal radiation over the same time period (54-60 Gy/30 fraction/6 weeks). The outcomes of 18 patients undergoing CSIMRT were compared against a retrospective consecutive cohort of 41 patients with EGC to confirm comparable local control. RESULTS: No significant CIT differences were identified between patients undergoing CSIMRT versus the control group. However, four patients in the CSIMRT group had a local recurrence between 8 and 39 months. In all patients the epicentre of the recurrence was noted at the anterior part of the larynx. The 5-year local recurrence-free survival was 75.1% (95% confidence interval 56.6-99.7%). By contrast, in the group of EGC patients treated without carotid sparing, local recurrence was noted only in a single patient (patient treated with helical tomotherapy) and the 5-year local recurrence-free survival was 97.1% (95% confidence interval 91.8-100%) (Log-rank P = 0.01). CONCLUSION: We failed to show the safety of CSIMRT using helical tomotherapy in this population of EGC patients. Use of CSIMRT also did not translate into a substantial reduction in CIT until 36 months. Use of CSIMRT using rotational arc techniques such as helical tomotherapy may be associated with a greater risk of local recurrence due to intrafractional motion interplay effects.

Comparison of Epidemiology and Outcomes in Neuro-Oncology Between the East and the West: Challenges and Opportunities.

Although neoplasms of the brain and central nervous system (CNS) are relatively uncommon, comprising only 1-2% of the overall cancer burden, they represent a substantial source of morbidity and mortality worldwide. The age-adjusted annual incidence of CNS tumours is reportedly low; however, there is substantial global variability in its incidence, with nearly a five-fold difference between regions with the highest rates in developed countries in the West and those with the lowest rates in developing countries in South-East Asia, including India, possibly attributable to key differences in environmental factors, genetic susceptibilities and cultural practices, as well as resource constraints in low-middle income countries precluding precise ascertainment and accurate diagnosis. The burden of CNS tumours is further compounded by the fact that they require highly specialised and skilled multidisciplinary care, including access to modern neuroimaging, neurosurgery, neuropathology and molecular biology, radiotherapy, chemotherapy and rehabilitation services, which may not be widely available in an integrated manner in large parts of the world with a large variation in clinical pathways, non-uniformity of care and resultant heterogeneity in clinical outcomes. CNS tumours encompass a heterogeneous spectrum of histopathological entities with differences in presentation, distinct molecular/genetic alterations, diverse biological behaviour and varying clinical outcomes. Survival is highly dependent on histology, grade and molecular biology, but varies widely across continents, even for the same tumour type and grade. In general, survival is higher in children with primary brain tumours than in adults, largely due to the differences in histological distribution across age groups. However, there is widespread variability, with 5-year survival for paediatric brain tumours being <40% in some low-middle income countries compared with 70-80% in the developed world. This review compares the descriptive epidemiology and clinical outcomes of primary brain tumours between the East and the West that pose unique challenges but also provide new opportunities in contemporary neuro-oncological practice.

Continuous hyperfractionated accelerated radiotherapy using modern radiotherapy techniques for nonsmall cell lung cancer patients unsuitable for chemoradiation.

INTRODUCTION: The continuous hyperfractionated and accelerated radiotherapy (CHART) regimen of radiotherapy (RT) for nonsmall cell lung cancer is underused outside the UK. We present the first Indian experience of using CHART for patients, who were not suitable for chemotherapy or concurrent chemo-RT. METHODS: We retrospectively reviewed the data of patients treated using CHART at our institution between January 2014 and December 2015. RESULTS: Thirty-seven patients were treated using CHART. Planning methods and dosimetry parameters are described. Three-dimensional conformal RT was used for treatment planning and delivery in 23 patients and volumetric modulated arc RT was necessary for 14 patients. Patients in our series had a median age of 70 years (interquartile range 65.50-74.00) and 86.5% had Stage III disease. Median follow-up was short at 13.0 months. Actuarial rates of 1-year progression-free survival, 1-year overall survival (OS), and 2-year OS were 31.9%, 59.5%, and 28.5%, respectively. This treatment was well tolerated with manageable and some reversible acute esophageal toxicity (91.9% CONCLUSION: Our results indicate that CHART is feasible, safe, and well tolerated in Indian patients who are clinically found to be not suitable for either sequential or concurrent chemo- RT.

Actual gains in dosimetry and treatment delivery efficiency from volumetric modulated arc radiotherapy for inoperable, locally advanced lung cancer over five-field forward-planned intensity-modulated radiotherapy.

AIMS: Volumetric modulated arc radiotherapy (VMAT) is used for inoperable, locally advanced nonsmall cell lung cancer, where three-dimensional conformal radiotherapy (3D-CRT) cannot yield an acceptable plan. METHODS: The planning and treatment data were prospectively collected on the first 18 patients treated using VMAT plans. We analyzed the actual dosimetric gain and impact on treatment, compared with complex multisegment 3D-CRT (five-field forward-planned intensity-modulated radiotherapy [IMRT]) that were generated for treatment. Proportion of planning target volume (PTV) receiving 95% dose (PTV-V95%) conformity index (CI), conformity number (CN), dose homogeneity index (DHI), monitor units (MUs), and treatment time were also analyzed. RESULTS: The PTV coverage (PTV-V95%) was improved from a median of 91.41% for 5-F forward-IMRT to 98.25% for VMAT (P < 0.001). The CI improved with a mean of 1.12 for VMAT and 1.31 for 5-F forward-IMRT (P < 0.001). The mean DHI improved from 1.15 for forward-IMRT to 1.08 for VMAT (P < 0.001). The mean CN improved from 0.62 for forward-IMRT to 0.87 for VMAT (P < 0.001). No significant increase in the low-dose bath (V5, V10 and mean lung dose) to the lung was seen. Significantly higher number of MUs (P < 0.001) and shorter treatment delivery times (P = 0.03) were seen with VMAT. CONCLUSION: VMAT resulted in improvement in target volume coverage, demonstrated by PTV-V95%, CI, CN, and DHI, without any increase in the low-dose bath to the lung. For conventional fractionation, VMAT requires more MUs (P < 0.001) but has a shorter treatment delivery time (P = 0.03) per fraction.

High-dose Neural Stem Cell Radiation May Not Improve Survival in Glioblastoma.

AIMS: To evaluate the effect of radiotherapy dose-volume parameters of neural stem cell (NSC) compartment on progression-free survival (PFS) and overall survival after post-resection chemoradiation in newly diagnosed glioblastoma. MATERIALS AND METHODS: Sixty-one patients with unifocal glioblastoma were included. Ipsilateral (NSC_Ipsi), contralateral (NSC_Contra) and combined NSC (NSC_Combined) were contoured on radiotherapy planning computerised tomography datasets. NSC dose-volume parameters were correlated with PFS and overall survival. Serial magnetic resonance imaging scans were assessed to understand the frequency of pre- and post-treatment involvement of the NSC by contrast enhancing lesions (CELs). RESULTS: Baseline involvement of NSC with CELs was seen in 67.2% and 95.9% had CELs and FLAIR abnormalities at progression. With a median follow-up of 14.1 months (interquartile range 9.4-20.6 months), median PFS and overall survival were 14.5 (95% confidence interval 11.6-17.5) and 16.2 (95% confidence interval 13.3-19.2) months, respectively. Poor Eastern Cooperative Oncology Group performance score, advanced recursive partitioning analysis class, unmethylated O6-methylguanine methyltransferase (MGMT) status, higher than median of mean NSC_Ipsi dose were associated with significantly inferior PFS and overall survival on univariate analysis. On multivariate analysis, unmethylated MGMT status, higher than median of mean doses to NSC_Ipsi and poor compliance to adjuvant temozolomide were independent predictors of inferior survival. CONCLUSIONS: In this cohort, 67.2% of newly diagnosed glioblastoma patients had NSC involved with CELs at presentation and 95.9% at progression. This might be an imaging surrogate of the current notion of gliomagenesis and progression from NSC rests. A high radiation dose to NSC_Ipsi was significantly associated with inferior survival. This could be a function of larger tumours and planning target volumes in those with pre-treatment NSC involvement. Methylated MGMT and good compliance to adjuvant temozolomide were independent predictors of better survival. Until further evidence brings hope for glioblastoma, elective, partial NSC irradiation remains experimental.

Outcomes Following a Moderately Hypofractionated Adjuvant Radiation (START B Type) Schedule for Breast Cancer in an Unscreened Non-Caucasian Population.

AIMS: Breast cancer is the most common cancer in women. Western data have confirmed hypofractionated radiation therapy to be safe and effective in the adjuvant radiation therapy of breast cancers. We report the disease-related outcomes in a non-Caucasian, unscreened population treated with hypofractionated radiation. MATERIALS AND METHODS: Unselected case notes of patients presenting to a tertiary cancer centre between June 2011 and December 2013 were reviewed from the electronic hospital case records. Patients with a diagnosis of non-metastatic invasive non-sarcomatous breast cancer were identified. Demographic information, oestrogen receptor (ER), progesterone receptor (PR), HER2 status, pathological tumour, nodal stage at diagnosis and outcomes of treatment, including systemic therapies, surgery and hypofractionated radiation, were documented. Local recurrence rates, disease-free survival (DFS) and overall survival were calculated. RESULTS: Overall 925 patents were identified, median age 53.0 years (interquartile range 45-61), 330 of whom had neoadjuvant chemotherapy. The median follow-up time was 22.6 months and 23.5 months for overall and neoadjuvant chemotherapy groups, respectively. ER, PR and HER2 status was available in 788 patients, 77.2% of whom were ER/PR positive, 14.7% had triple negative disease, while 9.5% were HER2 rich. Overall, 34.2% (113 patients) underwent breast conservation surgery; 744 (80.4%) patients were treated with systemic chemotherapy and 878 (94.9%) patients received adjuvant radiation therapy, of whom 407 (44.0%) received supraclavicular-fossa radiotherapy. Overall survival, DFS and locoregional recurrence-free survival (LRRFS) for the overall group were 93%, 86.9% and 97.1%, respectively. LRRFS in the breast conservation surgery versus mastectomy groups were 99% versus 95.5% (P=0.003), with more node-positive patients in the mastectomy group. Stage N0/1 had better LRRFS compared with N2/2 (99.1% versus 95.7%); 94.3% versus 82.3%; P=0.005, 0.000. Grade 3 (53.8%) tumours had worse overall survival compared with grade 1 or grade 2 disease (89.6% versus 100% and 96.4%; P<0.001) although the LRRFS was not significantly different between the groups (98.9% versus 97.8%; P=0.37). There was no difference in LRRFS based on molecular subtypes. CONCLUSION: Local recurrence rates following hypofractionated radiation in our population were comparable with those reported by the START trialists and were found to be safe in the medium term for patients irrespective of breast conservation surgery/mastectomy or radiotherapy to the supraclavicular field. Molecular group frequencies were comparable with Western populations but did not affect LRRFS.

Evaluating the Need for Daily Image Guidance in Head and Neck Cancers Treated with Helical Tomotherapy: A Retrospective Analysis of a Large Number of Daily Imaging-based Corrections.

AIMS: Clinical implementation of image-guided intensity-modulated radiotherapy is rapidly evolving. Helical tomotherapy treatment delivery involves daily imaging before intensity-modulated radiotherapy delivery. This can be a time consuming resource-intensive process, which may not be essential in head and neck radiotherapy, where effective immobilisation is possible. This study aimed to evaluate whether an offline protocol implementing the shifts derived from the first few fractions can be an acceptable alternative to daily imaging for helical tomotherapy. MATERIALS AND METHODS: We retrospectively analysed the set-up data of 2858 fractions of 100 head and neck cancer patients who were treated with daily online image guidance. Using summary data from all treatment fractions, we calculated the systematic error (∑) and random error (σ) in each of the three axes, i.e. mediolateral (x), craniocaudal (y), anteroposterior (z). We also calculated the translational vector of each fraction of individual patients. We then simulated two no-action-level offline protocols where set-up errors of the first three (protocol F3) or five fractions (protocol F5) were averaged and implemented for the remaining fractions. The residual errors in each axis for these fractions were determined together with the residual ∑ and σ. Planning target volume (PTV) margins using the van Herk formula were generated based on the uncorrected errors as well as for the F3 and F5 protocols. For each scenario, we tabulated the number of fractions where the residual errors were more than 5 mm (our default PTV margin). We also tried to evaluate whether errors tended to differ based on intent (radical or adjuvant), anatomical subsite or weight loss during treatment. RESULTS: Analysis from this large dataset revealed that in the tomotherapy platform, the highest set-up errors were in the anteroposterior (z) axis. The global mean was 5.4 mm posterior shift, which can be partly attributed to couch sag on this system. Uncorrected set-up errors resulted in systematic and random errors of ∑x,y,z of 1.8, 1.7 and 2 mm and σx,y,z of 1.7, 1.5 and 1.9 mm, with a required PTV margin in x, y, z axes of 5.7, 5.3 and 6.2 mm. Implementing average shifts from the first three or five fractions resulted in a substantial reduction in the residual systematic errors, whereas random errors remained constant. The PTV margins required for the residual errors after three and five fraction corrections were 3.8, 3.4 and 5.1 mm for F3 and 3.3, 2.9, 4.8 mm for F5. The proportions of fractions where there was >5 mm residual error were 1.6%, 1.1%, 2.9% in x, y and z axes in the F3 protocol and 1.5%, 0.8% and 2.6% with the F5 protocol. Although there was no difference in residual shifts > 5 mm, there was a statistically higher chance of residual errors > 3 mm larynx/hypopharynx subsites versus other sites. In patients who had more than 5% weight loss, there was no significant increase in residual errors with the F5 protocol and the required PTV margin was within our default PTV margins expansion. CONCLUSIONS: Correction of systematic errors by implementing average shifts from the first five fractions enables us to safely avoid daily imaging in this retrospective analysis. If this is validated in a prospective group it could lead to implementation of a resource sparing image-guided radiotherapy protocol both in terms of time and imaging dose. Patients with larynx/hypopharynx subsites may require more careful evaluation and daily online matching.

Predictors of weight loss during conformal radiotherapy for head and neck cancers - how important are planning target volumes?

AIMS: Nutritional compromise is common during high dose radiotherapy (RT) or chemoradiotherapy (CRT) for head and neck cancers. We aimed to identify the factors that determine nutritional outcome for head and neck cancer patients during radiotherapy. METHODS: Data from 103 patients with head and neck cancer treated with highly conformal radiotherapy to doses of 60 Gy or more in 30-33 fractions in the adjuvant or definitive setting was analyzed. All patients received complex 3D conformal radiotherapy (3DCRT) or intensity modulated radiotherapy (IMRT). Patients received regular nutritional counseling and need-based interventions. Their weight was recorded at the beginning and end of radiotherapy. Using univariate and multivariate models we tested possible predictors of weight loss of >5% and NG tube requirement. RESULTS: The mean weight loss was 3.8%. The incidence of weight loss >5% was 37.9% and NG tube placement was 24.3%. The factors significantly associated with >5% weight loss in the univariate analysis were tumor site (oro-hypopharyngeal vs. others), definitive vs. adjuvant RT; prescription dose of >60 Gy vs. 60 Gy; CRT vs. RT alone; prescription dose planning target volume (PTV) volume >235 cc and total PTV volume >615 cc. Age, sex, T stage, N stage and modality (3DCRT/IMRT) were not significant. In multivariate analysis, the total PTV volume, prescription dose PTV volume and use of chemotherapy were significant after controlling for other factors. Patients could be risk stratified based on the use of CRT and large PTV volumes. Patients with none, one or both factors had a likelihood of >5% weight loss of 0%, 30.3%, and 56.9% (p < 0.001) and likelihood of NG tube placement of 5.3%, 15.2% and 37.3% (p = 0.007). CONCLUSIONS: It is possible to predict weight loss and NG tube requirements from disease and treatment related factors. PTV volumes are important predictors of nutritional compromise. Risk stratification may enable more focused counseling and identification of patients who require preventive interventions.

The relationship between terazosin dose and blood pressure response in hypertensive patients.

A double-blind, randomized, placebo-controlled, multicenter study was conducted to describe the dose-response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4-week single-blind placebo lead-in period and a 14-week double-blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24-hour ambulatory blood pressure measurements were performed at the end of the placebo lead-in period and at the end of each 4-week fixed-dose period. The nonlinear, mixed-effect model computer program was used to analyze the dose-response relationship. There was a strong dose-response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.

Effect on bioavailability of admixing the contents of lansoprazole capsules with selected soft foods.

OBJECTIVE: This study was designed to compare the bioavailability of lansoprazole when administered as an intact capsule and when the contents are admixed with various soft foods. BACKGROUND: Patients sometimes cannot swallow or have difficulty swallowing intact capsules such as lansoprazole. To enable them to ingest the drug, the contents of the capsule can be admixed with small amounts of soft foods. METHODS: Twenty-four healthy adult volunteers participated in this single-dose, 4-period crossover study by ingesting the contents of a 30-mg lansoprazole capsule that had been emptied into either a tablespoon of yogurt (regimen A), Ensure pudding (regimen B), or cottage cheese (regimen C), or given as an intact capsule (regimen D) during the first study period. The regimen assignments were rotated at weekly intervals so that each subject received each regimen. Blood samples were obtained over the 12-hour period after administration of each regimen, and pharmacokinetic parameters were determined. RESULTS: Of the 23 subjects who completed all 4 periods of the study, 18 were male and 5 were female. Their mean (+/- SD) age was 33.3+/-11.6 years, and their ages ranged from 19 to 52 years. No statistically significant differences between regimens were detected in mean maximum concentration, area under the curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity (AUC0-infinity) using analysis of variance. A statistically significant difference was detected in the time to maximum concentration between regimens C and D at 2.1 and 1.5 hours, respectively (P < or = 0.05). Bioavailability was assessed by the two 1-sided tests procedure using a 90% CI for the AUC0-infinity ratio of test-to-reference regimens. The 90% CIs were all within an acceptable equivalence range of 0.80 to 1.25. CONCLUSION: These results indicate similar bioavailabilities between the regimen in which the lansoprazole capsule was emptied and administration of the intact capsule. However, they may have limitations in predicting the results in ill, elderly, or very young patients.

Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects.

BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single-dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three-period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3 alpha-hydroxy-isopravastatin (3 alpha-iso-PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0-infinity and Cmax of 3 alpha-iso-PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.

Effects of oral and intravenous terazosin and head-up tilt on blood pressure responses in patients with hypertension.

Terazosin is a selective alpha1-adrenoceptor antagonist. A double-blind, randomized, placebo-controlled, two-period study evaluated the effects of posture and of oral and intravenous administration of terazosin on blood pressure and heart rate in patients with hypertension. At least one week after withdrawal of all antihypertensive medications, 31 patients with sitting diastolic blood pressure of 95 to 114 mmHg were enrolled in the study. After a 24-hour, single-blind, placebo lead-in phase, the patients were randomized to receive either oral terazosin (1 mg on day 1, 2 mg on day 2, and 5 mg on days 3 and 4), a 12-hour intravenous infusion of terazosin (2.5 mg, 5 mg, or 7.5 mg), or placebo for 4 consecutive days. Head-up tilt (60 degrees for 20 minutes) evaluations were performed before and 0.5, 1.5, 2.5, 6, 12, and 16 hours after start of administration during the placebo lead-in phase and on each of the 4 days of the double-blind treatment phase. Blood pressure and heart rate were monitored every 2 minutes during the 20-minute tilt. Statistically significantly larger mean changes in blood pressure and heart rate were observed with the 7.5-mg intravenous dose of terazosin compared with those after oral terazosin or placebo. With respect to intravenous terazosin, the orthostatic changes were maximal on the first day of the 4-day treatment and increased with increasing doses of terazosin. Maximum orthostatic changes in blood pressure after oral administration of terazosin were not significantly different from those observed with placebo. The most common treatment-emergent adverse events during tilt were dizziness and nausea. Dizziness occurred more frequently with intravenous terazosin than with oral terazosin. The results of this study indicate that oral dose titration of terazosin rather than a slower rate of terazosin infusion minimized the postural effects on blood pressure and associated symptoms during head-up tilt.

Lansoprazole: administration of the contents of a capsule dosage formulation through a nasogastric tube.

A single-dose, open-label, randomized, crossover bioavailability study was conducted in 24 healthy adult male volunteers to assess an alternative method of administration of lansoprazole capsules. The results of 22 subjects were analyzed. Subjects received regimen A (granules from a 30-mg capsule mixed with apple juice and administered through a nasogastric tube) or regimen B (an intact 30-mg capsule) during the first study period. The regimens were reversed during the second period 1 week later. Blood samples were obtained over 12 hours and pharmacokinetic variables were determined. No statistically significant differences in mean time elapsed to peak concentration, mean peak concentration, area under the curve (AUC)0-t, and AUC0-infinity were detected between regimens by using analysis of variance. Bioavailability was assessed by the 90% confidence interval of the two one-sided tests on the natural logarithm of AUC. The 90% confidence interval for the AUCzero-infinity ratio was 0.955 to 1.140 for regimens A to B. These results indicate similar bioavailabilities between the two regimens and demonstrate that lansoprazole capsules may be administered by mixing the capsule contents with apple juice for administration through a nasogastric tube.