Salivary parameters and their correlation with neutrophil counts in children with acute lymphoblastic leukemia.

BACKGROUND: Chemotherapy for Acute Lymphoblastic Leukemia (ALL) is known to render children immuno-deficient. A concomitant suppression of local defence mechanisms, such as saliva may further aggravate the adverse consequences of chemotherapy. The present study was conducted to evaluate alterations in salivary flow rate, pH and buffering capacity and to correlate these parameters with Absolute Neutrophil Counts (ANC). METHODS: A cohort of 43 patients, aged 3-12 years were evaluated for the aforementioned parameters at baseline, post-induction and post-consolidation phases. Salivary collection was done and ANC was measured from routine haematological reports. RESULTS: A decrease in the salivary parameters was observed at the end of Induction phase as compared to baseline, with a statistically significant decrease in unstimulated salivary flow rates (p < 0.01). Statistically significant positive correlations were found between ANC and salivary flow rate (p = 0.005), pH (p < 0.00) and buffering capacity (p < 0.00). On testing the significance of these correlations, all the values for these parameters were found to be statistically significant. CONCLUSION: Salivary parameters showed derangements over the phases of chemotherapy, with maximum decrease at the end of induction phase. The positive correlations of salivary parameters with ANC of the subjects may be considered indicative of a concomitant immunological compromise in these children.

Survival outcome in childhood ALL: experience from a tertiary care centre in North India.

BACKGROUND: Survival of children with ALL, in developing nations has not kept pace with cure rates in developed countries. Our study was designed to assess survival data and identify risk factors. PROCEDURE: Data of 762 patients with ALL were analyzed. Information regarding the clinical-demographic profile, therapy and course of illness were recorded. Status and duration at last follow-up were utilized to generate Kaplan-Meier survival curves. RESULTS: The mean age was 5.7 +/- 0.23 years (M/F, 3.2:1). Parents of 230 (30.2%) patients opted for no therapy. There were 68 and 60 deaths in induction and remission phases respectively. Besides these, 111 children either defaulted therapy or were lost to follow up. Relapsed disease was documented in 125 cases. The 5-year OS and EFS was 46% and 43% respectively. Survival analysis, using the Cox multivariate regression, for gender (P = 0.659, CI: 0.852-1.161), age (P = 0.943, CI: 0.725-1.225), symptom-diagnosis interval (P = 0.002, CI: 1.116-1.668), WCC (P < 0.001, CI: 1.353-1.814) and platelet count (P = 0.001, CI: 0.546-0.849) was performed. Bulk disease (P = 0.049, CI: 0.428-0.986), mediastinal adenopathy (P = 0.045, CI: 1.040-3.697), WCC (P = 0.016, CI: 1.395-2.691), platelet count (P = 0.031, CI: 0.431-0.967) and administration of 2 intensification blocks (P = 0.012, CI: 0.624-0.940) were found to be significant predictors of outcome by multivariate analysis. CONCLUSIONS: The management of ALL requires financial resources and access to quality supportive care. One third of our patients opted for no therapy. The other problem areas were a high proportion of therapy defaulters, lost to follow up and infection related deaths during induction and remission phases. The introduction of remedial measures for resolving the difficulties identified would hopefully improve cure rates in ALL in developing nations.

Pattern of relapsed disease in childhood all: experience from a single tertiary care center in North India.

The study was designed to determine the pattern of relapsed disease and identify problem areas in management. Relapse occurred in 111 (23.9%) of the boys and 16 (13.0%) of the girls. The majority relapsed while on chemotherapy. Isolated relapse in the marrow and in the CNS was seen in 51 (40.8%) and 24 (18.9%) patients, respectively. Isolated testicular relapse was seen in 17 (15.3%) of the 111 boys who suffered a relapse. Age and TLC at initial presentation and gender in relapsers and nonrelapsers were compared. Multivariate regression analysis showed that gender (p = .03) and TLC (p = .001) were significant predictors of relapse. Relapse of disease while on chemotherapy and high incidence of CNS and testicular relapse indicate the need for reappraisal of treatment protocols.

Stress studies on acyclovir.

Acyclovir is an antiviral drug of choice in the treatment of many types of herpes virus infections, including genital herpes simplex infections, herpetic conjunctivitis, herpes simplex encephalitis, etc. The present study describes the degradation behavior of acyclovir under different International Conference on Harmonization recommended stress conditions (hydrolysis, oxidation, photolysis, and thermal decomposition) in order to establish a validated stability-indicating high-performance liquid chromatography method. Acyclovir is found to degrade extensively in acidic conditions and oxidative stress. Mild degradation of the drug occurs in alkaline and neutral conditions. The drug is stable to dry heat. The drug is found to be sufficiently stable after light exposure in a solid state; however, photolytic degradation is observed when the drug is exposed as a solution in water. The major degradation product in acidic hydrolysis and photolysis is identified as guanine through comparison with the standard. Separation of drug and the degradation products under various conditions is successfully achieved on a C-18 column utilizing water-methanol in the ratio of 90:10. The flow rate is 1 mL/min, and the detection wavelength is 252 nm. The method is validated with respect to linearity, precision, accuracy, selectivity, specificity, and robustness. The mean values of slope and correlation coefficient are 39.307 and 0.9998 with relative standard deviation values less than 2%. The recovery of the drug is found to be in the range of 97.34% to 102.35%. From the previous study it is concluded that the stability-indicating method developed for acyclovir can be used for analysis of the drug in various stability samples.

Biodegradable microspheres for parenteral delivery.

Nowadays, emphasis is being laid to development of controlled release dosage forms. Interest in this technology has increased steadily over the past few years. Although oral administration of drugs is a widely accepted route of drug delivery, bioavailability of drug often varies as a result of gastrointestinal absorption, degradation by first-pass effect, and hostile environment of gastrointestinal tract. Transdermal administration for percutaneous absorption of drug is limited by the impermeable nature of the stratum corneum. Ocular and nasal delivery is also unfavorable because of degradation by enzymes present in eye tissues and nasal mucosa. Hence, the parenteral route is the most viable approach in such cases. Of the various ways of achieving long-term parenteral drug delivery, biodegradable microspheres are one of the better means of controlling the release of drug over a long time. Because of the lipidic nature of liposomes, problems such as limited physical stability and difficulty of freeze-drying are encountered. Similarly, for emulsions, stability on long-term basis and in suspensions, rheological changes during filling, injecting, and storage poses limitation. Also, in all these systems, the release rate cannot be tailored to the needs of the patient. Parenteral controlled-release formulations based on biodegradable microspheres can overcome these problems and can control the release of drug over a predetermined time span, usually in the order of days to weeks to months. Various FDA-approved controlled-release parenteral formulations based on these biodegradable microspheres are available on the market, including Lupron Depot Nutropin Depot and Zoladex. This review covers various molecules encapsulated in biodegradable microspheres for parenteral delivery.

The impact of weight for age on survival in acute lymphoblastic leukemia: Report from a tertiary care center in North India.

BACKGROUND: Undernutrition is considered to have a negative impact on survival in children with malignancies. The objective of this retrospective analysis was to evaluate the morbidity pattern and outcome of therapy in undernourished (UN) children with acute lymphoblastic leukemia. METHODS: A retrospective analysis of impact of weight for age was performed in children treated for ALL. The IAP & CDC criteria for undernutrition were used in the two different time periods of analysis. RESULTS: There were two cohorts in the study: Between 1995 and 2005, 360 children were evaluated where the weight for age was classified using the Indian Academy of Pediatrics criteria for undernourishment (Group A). Group B of the study included 373 children treated from 2007 to 2011, who were graded as per the Centers for Disease Control criteria for weight for age. In Group A, 35% of the children were malnourished at presentation. The morbidity and supportive care needed in the well-nourished and UN group were similar. The event-free survival and mortality were similar in both groups. Analysis of Group B showed an overall survival of 62.6% with a greater survival in children with a weight of ≥10th centile for age compared to children at the <10th centile, (P = 0.026) with a higher mortality (P = 0.011) in the UN group. CONCLUSION: Our data have yielded conflicting results. The older cohort did not show a significant difference in survival using malnutrition as a risk factor. However, in the subsequent cohort, a difference in survival was noted. This could be due to the reason that different criteria for classification of undernutrition were applied in the two groups. This analysis lays the foundation for a future prospective analysis to evaluate nutrition as an independent risk factor nutrition as an independent risk factor in the outcome of childhood malignancies.

Do traumatic lumbar punctures lead to greater relapses in acute lymphoblastic leukemia? Experience at a university hospital in India.

OBJECTIVE: The aim of the study was to evaluate the impact of traumatic lumbar puncture (TLP) at diagnosis of relapse in childhood acute lymphoblastic leukemia (ALL). Risk factors associated with TLP were assessed. MATERIALS AND METHODS: A retrospective analysis was performed from the records of children with ALL who were treated from January 2010 to December 2012. RESULTS: A total of 311 patients with median age of 5 years (range: 1-13) were treated for ALL. The cerebrospinal fluid analysis obtained from first LP revealed 275: Central nervous system 1 (CNS 1) (no blasts); 8: CNS 3 (blasts positive); and 28: TLP. Twenty-eight (9%) patients relapsed. Twelve (3.9%) had a CNS relapse. A TLP at diagnosis was not associated with an increased risk of systemic or CNS relapse (P = 0.298, 0.295). Three years event-free survival of patients with TLP and without atraumatic LP (ATLP) at diagnosis was 56 ± 5.2% and 51.8 ± 12.4%, (P = 0.520). Three years overall survival with TLP and ATLP was 73.3 ± 3.5% and 70.4 ± 12.5%, respectively, (P = 0.963). Median platelet count in patients with TLP was significantly lower than those without TLP (10,000/µL and 28,000/µL, P < 0.001). A receiver operating characteristic curve was constructed for predicting the risk of TLP based on platelet count. Area under the curve was 0.74 ± 0.05 (95% confidence interval 0.64-0.84). Platelet count < 23.5 × 109/L at the time of LP had 75% sensitivity and 64.4% specificity in predicting a TLP. CONCLUSIONS: Low platelet counts are significantly associated with risk of TLP. Traumatic LP at diagnosis was not associated with an increased risk of relapse.

Impact of iron deficiency on hemoglobin A2% in obligate ß-thalassemia heterozygotes.

INTRODUCTION: The potential impact of concomitant iron deficiency on hemoglobin A2 (HbA2)-based identification of ß-thalassemia trait (ßTT) is a worrisome issue for screening laboratories. This is especially true for resource-constrained settings where iron deficiency is widespread and molecular confirmatory tests for borderline low HbA2 values may be unavailable. METHODS: Obligate ßTT carrier individuals (n = 752) were identified during screening studies on the parents of thalassemia major patients. HbA2%, complete blood counts and serum iron, ferritin and transferrin saturation were studied. Iron-deficient individuals (n = 135) with normal range HbA2% were taken as controls. RESULTS: Concomitant iron deficiency (defined as ferritin ≤15 ng/mL and/or transferrin saturation ≤15%) was present in 20.7% (156/752) ßTT cases, that is, 33.3% females (122/366) and 8.8% males with ßTT (34/386). Mean HbA2 in iron-replete ßTT was 5.4 ± 0.8 (range 3.1-7.9) and in iron-deficient ßTT was 5.4 ± 0.9 (range 3.3-7.6). HbA2 < 4.0% was found in 23/752 (3.1%) ßTT: 13/595 iron-replete (2.2%) and 10/157 (6.4%) iron-deficient ßTT individuals. However, five of the 10 iron-deficient ßTT cases carried the silent CAP+1 (A>C) ß-thalassemia allele accounting for the borderline HbA2%. On a separate analysis, all five severely anemic ßTT (Hb < 80 g/L) and 16/17 ßTT with severe hypoferritinemia (<5 ng/mL) had HbA2 > 4.5%. The single case with serum ferritin 4.8 ng/mL and HbA2 3.3% showed a CAP+1 (A>C) mutation. CONCLUSIONS: Iron deficiency was prevalent among north Indian ßTT individuals, especially women. After adjusting for other causes of low HbA2 in ßTT, iron deficiency, even when very severe, was very unlikely to interfere significantly with HbA2-based identification of ßTT.

Quinolone antibacterial agents. Synthesis and structure-activity relationships of 8-substituted quinoline-3-carboxylic acids and 1,8-naphthyridine-3-carboxylic acids.

A series of 7,8-disubstituted 1-cyclopropyl-6-fluoroquinoline-3-carboxylic acids, 7-substituted 1-cyclopropyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids, and 10-substituted 9-fluoropyridobenzoxazine-6-carboxylic acids has been prepared and evaluated for antibacterial activity. The side chains examined at the 7-position (benzoxazine 10-position) included piperazinyl (g), 3-aminopyrrolidinyl (a), 3-(aminomethyl)pyrrolidinyl (b), and alkylated 3-(aminomethyl)pyrrolidinyl (c-f). Variations at C-8 of the quinolone ring system included hydrogen, nitro, amino, fluorine, and chlorine. The relative enhancement of in vitro activities by the side chains on the 8-hydrogen quinolone and 1,8-naphthyridine against Gram-negative organisms was a greater than b greater than g greater than c-f. The activity imparted to the substituted quinolone nucleus by the 8-substituent was in the order F greater than Cl greater than naphthyridine greater than H greater than benzoxazine greater than NH2 greater than NO2. These trends were retained in vivo.

Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity.

A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).

Nonprostanoid prostacyclin mimetics. 2. 4,5-Diphenyloxazole derivatives.

4,5-Diphenyl-2-oxazolenonanoic acid (18b) was synthesized and found to inhibit ADP-induced aggregation of human platelets with an IC50 of 2.5 microM. Acid 18b displaced [3H]iloprost from human platelet membranes in a concentration-dependent fashion, consistent with 18b inhibiting platelet function by acting as a prostacyclin mimetic. By inserting a phenoxy ring into the side-chain moiety of 18b and systematically varying the pattern of substitution and length of the tethers, more potent inhibitors of platelet aggregation were identified. A phenoxy ring inserted centrally in the side chain proved to be the optimal arrangement but significant activity was observed when the aromatic ring was bound directly to the 2 position of the heterocycle. The meta-substituted cis-(ethenylphenoxy)acetic acid 37 is the most potent platelet aggregation inhibitor synthesized as part of this study with an IC50 of 0.18 microM. Acid 37 displaces [3H]iloprost from human platelet membranes with an IC50 of 6 nM. The trans-olefinic isomer of 37 (25p) is 72-fold weaker as an inhibitor of ADP-induced platelet aggregation, but the saturated derivative 25w (BMY 42393) is intermediate in potency. Structure-activity studies using 25w as a template focused on modification of the tethers intervening between the side-chain phenyl ring and the oxazole and carboxylate termini and substitution of the phenyl ring. These studies revealed that biological activity was sensitive to both the identity of the concatenating atoms and the pattern of ring substitution. The structure-activity relationships provide insight into the topographical relationship between the diphenylated oxazole ring and the carboxylic acid terminus that comprise the nonprostanoid prostacyclin mimetic pharmacophore.

Nonprostanoid prostacyclin mimetics. 3. Structural variations of the diphenyl heterocycle moiety.

4,5-Diphenyl-2-oxazolenonanoic acid (2) and 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (3) were previously identified as nonprostanoid prostacyclin (PGI2) mimetics that inhibit ADP-induced aggregation of human platelets in vitro. The effects on biological activity of substitution and structural modification of the 4- and 5-phenyl rings of 3 was examined. Potency showed a marked sensitivity to the introduction of substituents to these aromatic rings and only the bis-4-methyl derivative 9j, IC50 = 0.34 microM, demonstrated enhanced potency compared to the parent structure 3, IC50 = 1.2 microM. Substitution at the ortho or meta positions of the phenyl rings, replacement by thiopheneyl or cyclohexyl moieties, or constraining in a planar phenanthrene system resulted in compounds that were less effective inhibitors of ADP-induced platelet aggregation. In contrast, variation of the heterocycle moiety revealed a much less stringent SAR and many 5- and 6-membered heterocycles were found to effectively substitute for the oxazole ring of 2 and 3. The diphenylmethyl moiety functioned as an effective isostere for 4,5-diphenylated heterocycles since 13aad showed similar platelet inhibitory activity to 3. With the exception of the 3,4,5-triphenylpyrazole derivative 13g, compounds presenting the (m-ethylphenoxy)acetic acid side chain discovered with 3 demonstrated enhanced potency compared to the analogously substituted alkanoic acid derivative. The structure-activity findings led to a refinement of a model of the nonprostanoid PGI2 mimetic pharmacophore.

Nonprostanoid prostacyclin mimetics. 5. Structure-activity relationships associated with [3-[4-(4,5-diphenyl-2-oxazolyl)-5- oxazolyl]phenoxy]acetic acid.

cis-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phenoxy]acetic acid (3) was previously identified as a nonprostanoid prostacyclin (PGI2) mimetic that potently inhibits ADP-induced aggregation of human platelets with an IC50 of 0.18 microM. As part of an effort to further explore structure-activity relationships for this class of platelet inhibitor and to provide additional insight into the nonprostanoid PGI2 mimetic pharmacophore, the effect of constraining the cis-olefin moiety of 3 into various ring systems was examined. Incorporation of the cis-olefin of 3 into either an oxazole (26) or an unsubstituted pyrazole (35) heterocycle provided compounds that are equipotent with progenitor 3. However, the oxazole 11f, which is isomeric with 26, inhibits ADP-induced human platelet aggregation in vitro with an IC50 of 0.027 microM, 6-fold more potent than 3, 26, or 35. These results suggest that the central oxazole ring of 11f is functioning as more than a simple scaffold that provides optimal stereodefinition for interaction with the PGI2 receptor. The nitrogen atom of the central heterocycle of 11f is postulated to engage in hydrogen-bond formation with a donor moiety in the PGI2 receptor protein, an interaction not available to 26 due to the markedly different topology. In support of this contention, the crystal structures of 11f and 26 contain strong intermolecular hydrogen bonds between the carboxylic acid hydrogen atom and the nitrogen atom of the central oxazole ring. Although 11f and 26 are exact isosteres and could, in principle, adopt the same molecular packing arrangement in the solid state, this is not the case, and the intermolecular hydrogen-bonding interactions in 11f and 26 are accommodated by entirely different molecular packing arrangements. Incorporation of the olefin moiety of 3 into a benzene ring provided a compound, 40, over 60-fold weaker with an IC50 of 11.1 microM. The affinities of 11f, 26, 31, 32, and 40 for the human platelet PGI2 receptor, determined by displacement of [3H]iloprost, correlated with inhibition of platelet function. The solid-state structures of 11f, 26, 31, 32, and 40 were determined and revealed that the more potent compounds 11f and 26 adopt a relatively planar overall topography. In contrast, the central phenyl ring and the phenoxy ring of the weakly active compound 40 are rotated by 53 degrees from planarity. The chemical shifts of the protons of the phenoxy rings of 3, 11f, 18, 26, 31, 32, and 40 suggest that in solution 3, 11f, 18, and 26 adopt a planar conformation while 40 does not.(ABSTRACT TRUNCATED AT 400 WORDS)

Diagnostic microspheres: an overview.

Diagnostic methods have become increasingly complex and frequently involve the use of agents that must meet the same approval criteria as drugs. The search for diagnostic contrast agents has spread from X-ray to other imaging modalities, especially to magnetic resonance imaging (MRI) and ultrasound. A wide variety of methods have been used to develop microencapsulated agents, from liposomal entrapment to use of biodegradable polymers. Various scientific and technological advancements have been made in the research and development of diagnostic microspheres. Diagnostic microspheres can be used to understand the human body functions in both healthy and sick people. For example, they allow the detection of malignancies vs. benign tissue changes. Diagnostic microspheres give useful clinical information for various diseases, are very stable, and have proven efficacy in the quantitative measurement of blood flow to an organ. This review discusses various aspects of diagnostic microspheres, such as the choice of contrast agents and radioactive molecules, and their applications in blood flow measurements and organ imaging.

End-stage renal disease in Indo-Asians in the North-West of England.

BACKGROUND: The incidence of end-stage renal disease (ESRD) in England is increasing. There is a higher incidence of ESRD in British Indo-Asians than in the White population. AIM: To determine to what degree the increasing demand for renal replacement therapy in the UK is due to Indo-Asian patients. To study the presentation to renal services of Indo-Asian patients with ESRD and report any inequalities in initial treatment of Indo-Asian patients with ESRD compared to their White counterparts. DESIGN: Prospective, inception cohort study. METHODS: Consecutive adult patients with ESRD who started renal replacement therapy between 1 April 2000 and 31 December 2001 in all 14 renal units serving an area from North Cheshire to South Cumbria, including Greater Manchester and Lancashire, were recruited and interviewed. RESULTS: Of the 578 patients, 9.5% were Indo-Asian. The annual acceptance rate for renal replacement therapy was 342 per million population in Indo-Asians, compared with 91 per million population in the White population ( p < 0.001). Indo-Asian patients with ESRD were younger (median age 51 years vs. 60 yrs, p = 0.006) and more socially deprived (81% vs. 36.5% in the 5th Carstairs quintile, p < 0.001). A greater proportion of Indo-Asian patients with ESRD presented late to specialist renal services (31% vs. 19%, p = 0.03). Once adjusting for their younger age, atherosclerotic renovascular disease and/or hypertensive nephropathy was more prevalent in Indo-Asian patients (OR 4.9; p = 0.03). There was no difference in the initial mode of maintenance dialysis or the perception of choice the patients felt they had, based on their ethnicity. DISCUSSION: There is a silent epidemic of ESRD in Indo-Asian patients in the North-West, possibly vascular in aetiology, in which specialist intervention is late. This suggests that Indo-Asian patients should be prioritized for early intervention strategies to reduce the burden of ESRD.

Poly-epsilon-caprolactone microspheres and nanospheres: an overview.

Poly-epsilon-caprolactone (PCL) is a biodegradable, biocompatible and semicrystalline polymer having a very low glass transition temperature. Due to its slow degradation, PCL is ideally suitable for long-term delivery extending over a period of more than one year. This has led to its application in the preparation of different delivery systems in the form of microspheres, nanospheres and implants. Various categories of drugs have been encapsulated in PCL for targeted drug delivery and for controlled drug release. Microspheres of PCL either alone or of PCL copolymers have been prepared to obtain the drug release characteristics. This article reviews the advancements made in PCL-based microspheres and nanospheres with special reference to the method of preparation of these and their suitability in developing effective delivery systems.

Partial nephrectomy in cystic partially differentiated nephroblastoma.

Cystic partially differentiated nephroblastoma (CPDN) is an uncommon renal neoplasm in children. It is now recognized as a tumor with low but definite malignant potential. The authors report a patient that was treated with partial nephrectomy and chemotherapy with successful outcome. The literature on CPDN is briefly discussed.