Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

Mass transport in dissolution kinetics. I: Convective diffusion to assess the role of fluid viscosity under forced flow conditions.

The quantitative influence of viscosity on dissolution kinetics is assessed under laminar flow conditions by utilizing a convective diffusion model for drug dissolution. Functional dependency of three types of viscosity inducing agents is established with respect to the parameters of fluid flow rate, diffusivity, and solubility. Studies of aqueous solutions of sucrose and of glycerol demonstrate that the decrease in dissolution rate of ethyl p-aminobenzoate is related to the decrease in solute diffusivity in these solutions, whereas the solubility change in the glycerol solutions has an additional independent simultaneous effect. Dissolution in hydroxypropyl cellulose solutions remains constant under fixed fluid flow conditions because of the negligible effect of the polymer upon the drug diffusivity. A change in fluid flow rate, however, alters the dissolution rate and correlates quantitatively with the rate of shear in the convective diffusion model. The interpretation of the effect of viscosity on dissolution kinetics with the convective diffusion model explains these phenomena quantitatively in terms of the fundamental mass transport processes.

Mass transport in dissolution kinetics. II: Convective diffusion to assess role of viscosity under conditions of gravitational flow.

Dissolution kinetics was studied in a laminar flow cell, through which aqueous solutions of increasing viscosity flowed under the force of gravity, in order to help elucidate the mechanism of drug dissolution. The viscosity was varied by addition of either hydroxypropyl cellulose, sucrose, or glycerin. The dissolution data were evaluated quantitatively in terms of a convective diffusion model for dissolution. It was demonstrated that the decrease in dissolution rate of a test compound due to viscosity in the polymer solution occurs primarily because of a decrease in the rate of shear over the dissolving surface. In solutions of sucrose or glycerin, the decrease in dissolution rate due to viscosity results because of a decrease in the diffusivity of the solute in addition to the decreased rate of shear. Also, the model accounts for the increase in solubility in the glycerin solution. Thus, the influence of viscosity on dissolution depends on whether the viscosity-inducing agent primarily affects only the flow properties of the liquid, or whether it affects diffusivity (i.e., a "micro" viscosity effect, in addition to the flow properties).

Evaluation of a convective diffusion drug dissolution rate model.

A recently introduced drug dissolution rate model based on convective diffusion was evaluated by experimentally determining dissolution rates. Alkyl p-aminobenzoates were used as the test compounds in a dissolution cell which promoted laminar flow of the liquid past the dissolving surface. The parameters evaluated were diffusivity, solubility, rate of shear, dissolving surface shape, and orientation of the surface relative to flow. The agreement between theory and experiment was quite satisfactory with respect to the functional dependence of the rate on these parameters as well as the actual magnitude of the rates.

Membrane transport of alkyl homologs: role of fluid flow in aqueous diffusion region.

Passive drug transport across a membrane involves the resistances in series offered by the membrane and the liquid layer immediately adjacent to it. The liquid layers generally are referred to as unstirred aqueous diffusion layers, suggesting that solute transport across these layers occurs solely by molecular diffusion. In accord with convective diffusion theory, recent studies showed that the transport from either a dissolving surface or a membrane surface depends not only on molecular diffusion but also on fluid convection inthe liquid adjacent to the membrane. Membrane permeation rates were determined for a series of alkyl p-aminobenzoates, and the results correlated with a model comprised of membrane diffusion and convective diffusion in the adjacent liquid region.

Convective diffusion model for a transport-controlled dissolution rate process.

A mathematical model based on convective diffusion was developed to describe the rate of dissolution form the surface of a compressed compact. Experimental studies were carried out to test the model. The basic experimental apparatus consisted of a modified rotating-filter-stationary basket dissolution test apparatus. Dissolution rates from rectangular and circular surfaces of an homologous series of p-aminobenzoate esters permitted testing the theory with respect to solubility, geometry, and agitation conditions. The correlation between experimental results and theory was reasonalby good considering that the test conditions were somewhat less than ideal.

Application of a convective diffusion model to membrane transport.

Studies were carried out on the permeation rate of butambed through a dimethicone membrane. Under conditions of "aqueous diffusion layer control", the permeation rate was accurately described by a mathematical model based on convective diffusion theory. In accordance with model, the rate of permeation from a saturated donor phase was shown to be equal to the rate of dissolution from a pure solid.

Mechanism of surface lubrication: influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets.

A mathematical expression for tablet hardness was related to lubricant mixing by considering increases in the surface coverage with prolonged mixing time. The duration of lubricant mixing significantly changed the apparent bulk volume of the mix, ejection force during tableting, hardness, and disintegration and dissolution properties of tablets. These findings may provide some rationale for the changes in processing characteristics and properties of finished drug products often encountered in the scale-up of solid dosage formulations. Several lubrication mechanisms are discussed in connection with the duration of mixing effects and scanning microscopy studies.

Bioavailability of acetazolamide tablets.

Plasma acetazolamide levels were measured by an enzymatic assay following single 250-mg oral tablet doses to 20 healthy volunteers; five different lots of acetazolamide tablets from a single manufacturer were used in a balanced incomplete block design. From the measured plasma levels, estimates of the bioavailability parameters (area under the plasma concentration versus time curve, time to peak plasma concentration, and peak plasm concentration) were obtained by least-squares digital computer fitting. No significant differences among the tablets were observed (alpha = 0.05) for the analysis of variance of the area under the curve or time to peak parameters. Two tablets, however, provided statistically higher peak plasma concentrations than the other three. Thus, lot-to-lot bioinequivalence of acetazolamide tablets was observed. Some in vitro tests employed showed general trends for correlation with the in vivo data. However, considerable refinement of these technique appears necessary for in vitro prediction of the observed lot-to-lot bioinequivalence.

Long-term results after chemoradiotherapy for locally confined squamous-cell head and neck cancer.

The long-term results after simultaneous chemoradiotherapy in 54 patients with previously untreated or minimally treated, locally confined (M0) squamous-cell carcinoma of the head and neck are presented. Multiple concurrent courses of radiation therapy and chemotherapy with cisplatin and a four-day 5-fluorouracil infusion were given. Twenty-eight patients underwent definitive surgery and 26 were treated without surgical resection. Treatment-associated toxicity was significant, including mucositis, myelosuppression, and a mean 12% loss of initial body weight. Of the 54 patients, 51 were ultimately rendered disease free by this combined modality protocol. With a follow-up ranging from 42-68 months, the projected Kaplan-Meier relapse-free survival for the entire patient cohort is 70%, with all relapses occurring within 17 months of patient entry. The projected Kaplan-Meier relapse-free survival for patients with Stage IV disease is 62%. The durability of these remissions suggests that there is a significant likelihood of cure in all patients with locally confined disease, and justifies comparative trials with standard treatment.

Determination of diclofenac sodium, famotidine and ketorolac tromethamine by flow injection analysis using dichloronitrophenol.

Diclofenac sodium, famotidine and ketorolac tromethamine were determined by flow injection analysis (FIA) with spectrophotometric detection. The sample solutions (5-50 micrograms ml-1 of diclofenac sodium, 10-80 micrograms ml-1 of famotidine and 10-120 micrograms ml-1 of ketorolac tromethamine) in methanol were injected into a flow system containing 0.01% (w/v) of 2,4,dichloro-6-nitrophenol (DCNP) in methanol. The colour produced due to the formation of a charge transfer complex was measured with a spectrophotometric detector set at 450 nm. A sampling rate of 40 per hour was achieved with high reproducibility of measurements (RSD below 1.6%). The FIA method was applied to the determination of diclofenac sodium, famotidine and ketorolac tromethamine in pharmaceutical formulations.

Evaluation of reversible polymorphic phase transitions by thermal analysis.

Crystalline states of 1,2-dihydro-6-neopentyl-2-oxonicotinic acid, an investigational antidiabetic drug, were evaluated by thermal analyses. Two polymorphs were detected for the drug, Form I (m.p. 193 degrees C) and Form II (m.p. 196 degrees C). Interconversion of the polymorphs upon cyclic solid-melt transitions provided confirmation of the crystal forms. Solidification of the melt was observed to occur either at 162 or 182 degrees C with the formation of Form I or Form II crystals, respectively. Form I underwent partial conversion to Form II upon heating at 10 degrees C min-1 when nucleating crystals of Form II were present in the sample. Differential scanning calorimetry (DSC) thermograms were recorded for different lots of the drug, solvent-recrystallized samples, and a series of known mixtures of Form I and II polymorphs. The study illustrates the usefulness of cyclic heat-cool studies to characterize polymorphic crystal forms of drugs.

Enhanced rectal absorption of itazigrel formulated with polysorbate 80 micelle vehicle in rat: role of co-administered esterase.

We investigated the effect of esterase on rectal absorption in the rat of itazigrel using polysorbate 80 (PS-80) micelle as a vehicle to overcome the poor aqueous solubility of itazigrel. The itazigrel formulation prepared with PS-80 increased the absorption compared with a 0.25% carmellose sodium suspension, probably by supplying the itazigrel solute to keep a high concentration at the epithelial surface. When esterase was co-administered with the formulations containing PS-80, the absorption of itazigrel from rat rectum was accelerated further, by rapid release of itazigrel from the micelle vehicle after enzymatic degradation of the PS-80 micelle.

Some Results for the Normal Manova Linear Functional Relationships Model.

Given the normal multivariate linear regression model Y = BX + E, with B subjected to the linear restrictions H BJ = W A, J known, W and H unknown, A known, the maximum likelihood estimates of H, B, W, are obtained. A likelihood ratio test criterion for testing H = H0 , W = W0 is provided. The results are extended to the GMANOVA model. All results are obtained in terms of the original variates directly, unlike Healy (1980) who obtains the results for the MANOVA model in terms of the canonical transformations of the original variates.

Bronchoalveolar lavage (BAL) in newly diagnosed patients with collagen vascular diseases.

Collagen vascular diseases (CVD) are commonly associated with interstitial lung diseases. Bronchoalveolar lavage (BAL) fluid analysis has important diagnostic value when considered in conjunction with other information. The present study was undertaken in newly diagnosed patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) at presentation to characterise BAL cellular constituents and elucidate the cellular picture in patients with and without pulmonary symptoms and in those with and without radiological (high resolution computed tomography) features of interstitial lung disease. All the patients were non-smokers and had not received any form of treatment for their diseases. The means of percentages of lymphocytes, neutrophils, and macrophages were 23.3%, 6.2%, 70.5% respectively. There was a significant BAL lymphocyte predominance in patients with pulmonary symptoms, and a lymphocyte and neutrophil predominance in those having radiological evidence of interstitial lung disease.

Intensive respiratory care service--our eight-year experience.

Intensive respiratory care service has come a long way from the beginning in Scandinavia in early 1952. Intensive care service (IRCU) was started at our institute in 1983 as tetanus and respiratory care ward which has developed into Department of respiratory diseases over years. We are reporting our experience of 886 cases of acute respiratory failure (ARF) treated from Jan, 1983 upto April 1990.

Clinical and pathological profile of 73 patients with lung carcinoma: is the picture changing?

OBJECTIVE: A prospective study was undertaken to study the clinical features and pathological cell type of primary lung carcinoma in our institute. METHODS: Seventy three patients were included in the study over a period of three years. These were investigated according to a study protocol which included a detailed history regarding the onset and progress of the disease, smoking habits, x-ray chest, computed tomography of the chest and upper abdomen, and flexible bronchoscopy with brushings and biopsy. RESULTS AND CONCLUSIONS: 32.85% of patients were non-smokers. The male-female ratio was 4.2:1. Male sex, age > 50 years and history of smoking are still a risk factor for lung carcinoma. Tobacco smoking of 20 pack-years or more is significantly associated with the incidence of squamous cell carcinoma compared to other cell types. Adenocarcinoma (28.8%) was the most common cell type observed. It was also the most common cell type in central location (32.8%). Adenocarcinoma was the most common cell type diagnosis amongst females (50%) and non-smokers (43.5%). Computed tomography done in 47 patients diagnosed additional eleven patients with rib or vertebral metastases in addition to the three diagnosed by chest roentgenology. Computed tomography diagnosed significant mediastinal lymphadenopathy in 16 patients in whom mediastinal lymphadenopathy was not suspected on chest roentgenology. Computed tomography confirmed liver metastases in four patients diagnosed by ultrasonography and additionally in three more patients. Bronchial brushing cytology yielded positive results in 51.72% of central tumours and 40% in peripheral tumors. Yield of endobronchial biopsy was 59% and transbronchial biopsy was sixty percent. At presentation 74.1% patients with non-small cell carcinoma were inoperable and in case of small cell carcinoma 75% had extensive disease. Fiberoptic bronchoscopy with brushings and biopsy, and computed tomography of the chest and upper abdomen are useful investigations in the diagnosis of lung carcinoma.

Bronchoscopic closure of bronchopleural fistula using gelfoam.

Management of a persistent bronchopleural fistula (BPF) can be a therapeutic challenge. The etiological factors responsible for BPF include pulmonary tuberculosis, post-thoracic resection surgeries, trauma, malignancy, necrotising infections and rupture of lung abscess. The immediate management of BPF is drainage of the pleural cavity with insertion of an intercostal drainage tube. Patients with BPF may also require surgical intervention in the form of a wedge resection or lobectomy or muscle flap surgery. We report a case of a peripheral BPF secondary to a bacterial infection, which was successfully managed by the instillation of gelfoam via flexible bronchoscopy.

Intensive respiratory care service. Organisation, orientation, system and future. Our experience of management of 288 cases.

Between Jan. 1983 and Dec. 1986, 288 patients with acute respiratory failure of varied aetiologies were admitted to tetanus and respiratory care ward. One hundred and twenty patients (41.66%) had primary respiratory diseases, 107 (37.15%) of poisoning, 24 (8.3%) had neuromuscular diseases and 37 (12.48%) had miscellaneous disorders. Ventilatory support was given for more than 6 hours to 118 patients. The overall survival was 61.81% and on ventilator 38.13%. The mortality was high with ARDS (100%), miscellaneous (100%) pneumonia with septicaemia (75%) and COAD (54.28%). Patient with COAD had high mortality with acidosis (pH less than 7.1, P less than 0.01), hypotension (systolic BP less than 90 mm of Hg, p less than 0.05) and oliguria (urine out put less than 400 ml/24 hours, p less than 0.05). Organophosphorus compound was the commonest poison (89.75%) and patients who had moderate to severe hypoxia (pO2 less than 60 mm of Hg), hypotension and an interval of more than 4 hours between the consumption of poison and admission (all P less than 0.05) expired; 68.18% expired within the first 72 hours. All the patients with primary neuromuscular paralysis and bronchial asthma survived. Hospital acquired infections (160 patients), retained secretions (108 patients) and hypotension (64 patients) were the commonest complications seen in the 288 patients. Staphylococcus aureus (32.14%) was the commonest organism isolated. Financial constraints, drug shortages and frequent failure of machines were other major problems in the intensive respiratory care unit.