Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 µm, and 2.98 µm; respectively. Our results provide fundamental data for the application of SLNs in pulmonary delivery system of budesonide.

Risk factors for infection with Foot-and-Mouth Disease virus in a cattle population vaccinated with a non-purified vaccine in Iran.

In this study, we estimated the level of Foot-and-Mouth (FMD) virus infection in a cattle-dense north-western province of Islamic Republic of Iran and analyzed putative risk factors for FMD infection. Calves (6-24 months of age) from all 17 districts of West Azerbaijan were tested for antibodies against non-structural proteins (NSP-Ab) of FMD virus. A proportional stratification with a minimum of 30 epi-units was applied for 3 different husbandry systems: villages, dairy and mixed farms. Within an epi-unit, 30 calves were sampled. For the interpretation of ELISA test results, we used the 50% inhibition (50PI) cut-off as per producer's instructions and created one at 75% inhibition (75PI) based on the lowest point of the histogram of PI results. This approach resulted in three categories of outcomes; negative (N), low-positive (LP) and high-positive (HP). A generalized mixed-effect model for binary outcomes was used for analysing putative risk factors and was run for both cut-off values. A total of 8378 calves from 202 villages, 51 dairy farms and 28 mixed farms were eligible for analysis. The percentage of calves testing positive (LP+HP) was 53.7% (95% Confidence interval (CI): 52.6%-54.8%), with 39.6% (95% CI: 38.6-40.7%) testing HP (n=3309) while 14.1% (95% CI: 13.5-15.0%) of calves tested LP (n=1188). Of 281 epi-units sampled, all calves sampled tested negative in only 2 epi-units (0.7% (95% CI: 0.1-2.5%)) and more than 25 calves tested positive in 29 epi-units (10.3% (95% CI: 7.0-14.5%)). Outcomes of regression modelling using the 50 PI cut-off indicated that, for each month increase in age, the odds of testing positive increased 1.01 times (95% CI: 1.00-1.03). The odds of calves testing NSP-positive increased 1.46 times (95% CI: 1.22-1.77) for calves residing in epi-units that had experienced clinical FMD in the 12 months preceding this study. The odds of calves owned by livestock owners who traded livestock testing positive were 1.4-1.6 times higher than those owned by persons not engaged in trading while the odds for calves testing positive in dairy herds was 1.62 (95% CI: 1.10-2.35) times higher compared with calves in villages. The results of the model using the 75 PI cut-off value resulted in comparable estimates, with the age-effect becoming more evident. These results have confirmed widespread FMD infection and were used in developing a risk-based control strategy on FMD, in line with Stage 1 of the Progressive Control Pathway for FMD (PCP-FMD).

Preparation, characterization and optimization of glipizide controlled release nanoparticles.

The purpose of the present study was to develop glipizide controlled release nanoparticles using alginate and chitosan thorough ionotropic controlled gelation method. Glipizide is a frequently prescribed second generation sulfonylurea which lowers the blood glucose in type-two diabetics. Quick absorption of the drug from the gastrointestinal tract along with short half- life of elimination makes it a good candidate for controlled release formulations. Alginate-chitosan nanoparticles (ACNP) are convenient controlled delivery systems for glipizide, due to both the release limiting properties of the system, and the bioadhesive nature of the polymers. In the present study, glipizide loaded alginate-chitosan nanoparticles (GlACNP) were prepared, and the particle characteristics including particle size (PS), zeta potential (ZP), entrapment efficiency (EE%), loading percent (LP), and mean release time (MRT), as well as the morphology of the nanoparticles, the drug-excipient compatibility, and the release kinetics along with the drug diffusion mechanism were evaluated. The results suggested that ionotropic controlled gelation method offers the possibility of preparing the nanoparticles in mild conditions in an aqueous environment, and can lead to the preparation of particles with favorable size, controlled release characteristics, and high entrapment efficiency, serving as a convenient delivery system for glipizide. The particle and release characteristics can be efficiently optimized using the Box-Behnken design. Based on the findings of the present study, it is expected that this novel formulation be a superior therapeutic alternative to the currently available glipizide delivery systems.

Preparation and characterization of a sustained release buccoadhesive system for delivery of terbutaline sulfate.

Terbutaline sulfate exhibits extensive first pass metabolism and a short elimination half life which makes frequent oral administration of the drug inevitable. A novel buccoadhesive controlled delivery system of the drug can easily overcome the problem. A two-layered core tablet composed of a fast release layer made of mannitol, lactose, PEG and the drug attached to a sustained release layer composed of drug, varying ratios of HPMC, Carbomer 934 (CP), and lactose capped with a buccoadhesive cup coated with an impermeable backing layer was developed. Buccoadhesive cup initially optimized for bioadhesion strength using HPMC and CP with various ratios. Drug transport through buccal membrane indicated a high permeability coefficient (0.00105 cm/sec). All tablets were acceptable with regard to drug contents, thickness, weight variations, hardness and drug content uniformity. The CP:HPMC 2:1 mixture showed the best mucoadhesion properties and was selected as excipient for the cup layer. Swelling index was higher for formulations containing greater amount of lactose and lower percentage of polymers. Fast release layer released its entire content within 15 min while sustained release layer lasted for 12 h. Drug release controlled by a combination of diffusion and chain relaxation mechanism.

Development of novel budesonide pellets based on CODES(TM) technology: In vitro/in vivo evaluation in induced colitis in rats.

BACKGROUND AND THE PURPOSE OF THE STUDY: Budesonide is the drug of choice for treatment of active inflammatory bowel disease (IBD). The aim of this study was to develop budesonide pellets based on a novel colon drug delivery system (CODES). METHODS: Pellet cores containing lactulose or mannitol were prepared by extrusion/spheronization and coated with an acid soluble polymer (Eudragit E100), hydroxypropylmethyl cellulose (HPMC) and an enteric coat (Eudragit FS 30D) sequentially. In vitro drug release of coated pellets was studied using USP dissolution apparatus type II in buffers of pH 1.2 (2 hrs), pH of 7.4 (4 hrs) and pH of 6.8 containing 8% rat cecal contents (RCC) (18 hrs). The efficacy of the optimized formulation (containing 50% lactulose coated with Eudragit E (30% w/w) and Eudragit FS 30D (12% w/w)) was evaluated against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. RESULTS: The results of the kind of bacteria in vitro dissolution tests indicated absence of drug release in pHs of 1.2 and 7.4 and controlled release in buffer of pH 6.8 containing RCC. It was found that release rate was controlled by the type and amount of polysaccharide and the thickness of the acid soluble layer. The prepared formulation showed promising results in alleviating the conditions of experimental model of colitis. CONCLUSION: The results of this study suggest that pellets based on CODES technology could be useful for colonic delivery of budesonide.

Development and validation of a rapid HPLC method for simultaneous analysis of budesonide and its novel synthesized hemiesters in colon specific formulations.

A simple and reliable reversed-phase high performance liquid chromatographic (HPLC) method was developed, validated and applied for determination of budesonide and its novel synthesized hemiesters in colon specific formulations and dissolution media. The method was employed on a µ-Bondapak C(18) column (250 mm × 4.6 mm, 5 µm) at ambient temperature. The mobile phase consisted of acetonitrile: monobasic potassium phosphate containing orthophosphoric acid (55:45, pH 3.2) at a flow rate of 1 ml/min. The UV detection wavelength was set at 244 nm and 50 µL of sample was injected into the HPLC system. Dexamethasone was used as the internal standard. The retention times for internal standard and budesonide were 4.5 and 7.2 min, respectively. The method was linear in the concentration range of 1-20 µg/ml of budesonide (R(2)>0.999). Limit of detection and limit of quantitation were 0.05 and 0.5 µg/ml, respectively. The method presented the requisite accuracy, selectivity, sensitivity and precision and showed good resolution for separation of the drug and related derivatives in the presence of excipients. The proposed method was successfully used for analysis of the drug and its derivatives in dissolution media and oral colon specific formulations prepared in our laboratory with enough reproducibility.

Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects.

BACKGROUND AND THE PURPOSE OF THE STUDY: The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated. METHODS: The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC(0-72), AUC(0-8), C(max) and T(max). Similarity factor, dissolution efficiency (DE), and mean dissolution time (MDT) was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT) or fraction of the drug dissolved (FRD) vs fraction of the drug absorbed (FRA). RESULTS: Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC(0-8), and C(max) of each two formulations in each bioequivalence studies were within the acceptable range of 80-125%. Differences were not observed between the untransformed T(max) values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50) did not reflect their in vivo properties. MAJOR CONCLUSIONS: Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in-process quality control of amiodarone tablet formulations.

Development and validation of a new HPLC method for determination of lamotrigine and related compounds in tablet formulations.

A simple HPLC method was developed and validated for quantitation of lamotrigine and its related substances which may coexist in solid pharmaceutical dosage forms. The HPLC separation was achieved on a C18 mu-Bondapack column (250 mm x 4.6 mm) using a mobile phase of acetonitrile-monobasic potassium phosphate solution (35:65, v/v) containing orthophosphoric acid to adjust pH to 3.5 at a flow rate of 1.5 ml/min. The UV detector was operated at 210 nm, and column temperature was adjusted at 40 degrees C. The method was validated for specificity, linearity, precision, accuracy, robustness and limit of quantitation. The degree of linearity of the calibration curves, the percent recoveries of lamotrigine and related substances, the limit of detection and quantitation, for the HPLC method were determined. The method was found to be simple, specific, precise, accurate, and reproducible. The method was applied for the quality control of commercial lamotrigine tablets to quantify the drug and its related substances and to check the formulation content uniformity.

High performance liquid chromatographic determination, pharmacokinetic and comparative bioavailability studies of cisapride.

A sensitive and specific reversed phase HPLC method was developed to quantitate plasma levels of cisapride in order to conduct comparative bioavailability studies. The drug and internal standard was extracted from plasma with heptane-isoamyl alcohol (95:5 v/v) and back extracted with sulfuric acid. The acidic layer was then re-extracted with the same extracting solvent. The separated organic layer was evaporated to dryness under nitrogen and the residue reconstituted with acetonitrile. Analysis was performed on a C-8 Sil-X-10 HPLC column, with a mobile phase of acetonitrile, water, and triethylamine (75:25:0.01) and UV detection at 215 nm. The standard curve covering the concentration range 5-160 ng/ml was linear (r(2)=0.9992), relative errors were within +/-10% and the CV% ranged from 1.34 to 11.82. The in vivo study was carried out in 12 healthy volunteers according to a single dose, two-sequence, cross over randomized design. The bioavailability was compared using the total area under the plasma level versus time curve (AUC(0-34,) AUC(0- infinity )), peak plasma concentration (C(max)) and time to C(max) (T(max)). No statistically significant difference was found between the AUC(0- infinity ) or C(max) values of the test (cisapride) and reference (Propulsid). It was, therefore, concluded that the generic cisapride was bioequivalent with the innovator formulation.

Insulin-sparing effect of hydroxychloroquine in diabetic rats is concentration dependent.

To study the effect of hydroxychloroquine (HCQ) on glucose and insulin homeostasis, healthy rats were dosed with 160 mg x kg (-1) x day(-1) of HCQ orally, and streptozocin-induced diabetic rats received 80, 120, and 160 mg x kg(-1) x day(-1) of HCQ, while controls received normal saline. Ten days after treatment with HCQ, healthy animals were challenged intravenously with insulin or glucose, while diabetic rats were given only an i.v. injection of insulin. In healthy rats, the areas within and under the glucose concentration - time curve following insulin and glucose challenge were estimated. In diabetic animals, the areas under the curve for both the percent change in serum glucose from baseline (AUG) and the percent change in serum insulin from baseline (AUI) were used as pharmacodynamic end points. In healthy rats, HCQ did not influence fasting serum glucose concentrations or glycemic profiles following i.v. administration of glucose or insulin. In diabetic rats, AUG and AUI were increased dependent on blood HCQ concentrations. The normal homeostatic mechanisms responsible for insulin-glucose regulation may compensate for possible HCQ-induced reduction of insulin metabolism in healthy rats. The HCQ dose- or concentration-effect relationships for glucose and insulin were linear over the range of HCQ concentrations tested. It is concluded that HCQ significantly elevated insulin blood concentration resulting in reduced glucose levels in a concentration-dependent fashion in diabetic rats. HCQ may have therapeutic potential in the treatment of type I and type II diabetes.

Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats.

To elucidate the mechanism by which hydroxychloroquine (HCQ) affects glucose metabolism, the effect of this drug and its enantiomers on insulin metabolism was studied using the cytosolic fraction of liver homogenates from healthy and diabetic rats. Eadie-Hofstee plots were monophasic suggesting that only a one-component enzyme system is involved in insulin degradation in the fraction used. Reaction velocity (V) vs substrate concentration plots were consistent with a Vmax model. HCQ caused a significant reduction in Vmax and Vmax/Km values in both healthy (Vmax, 3.63 +/- 0.46 vs 1.97 +/- 0.13, ng/min/mg; protein P < 0.001; and Vmax/Km 0.265 +/- 0.015 vs 0.112 +/- 0.004, ml/min/g protein) and diabetic rats (Vmax, 0.718 +/- 0.06 vs 0.360 +/- 0.024, ng/min/mg protein; and Vmax/Km, 0.05 +/- 0.002 vs 0.023 +/- 0.001, ml/min/g protein). Significant reduction in the V was observed in the presence of racemic (rac)-, R-, or S-HCQ. Ranking of the inhibitory potency was HCQ > S = R except at highest examined concentration (20 mg/mL) which was HCQ > S > R. In conclusion, the effect of HCQ on insulin degradation appears to be, in part, through inhibition of cytosolic insulin metabolizing enzyme. The effect is not stereoselective except at high concentrations. The R- and S-HCQ may have synergistic effects on inhibition of insulin degradation.

Effect of experimental diabetes mellitus and arthritis on the pharmacokinetics of hydroxychloroquine enantiomers in rats.

PURPOSE: To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. METHODS: The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. RESULTS: Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 +/- 0.15 and 1.3 +/- 0.19 l/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 +/- 0.32 and 1.93 +/- 0.34 l/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. CONCLUSIONS: Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.

A needs index for mental health care.

The study aimed to develop a mental illness needs index to help local managers, district purchasers and national policy makers in allocating resources. Formulae were developed by regression analysis using 1991 census data to predict the period prevalence of acute psychiatric admission from electoral wards. Census variables used were chosen on the basis of an established association with mental illness rates. Data from one English Health Service region were analysed for patterns common to wards at hospital catchment area level and patterns common to district health authorities at regional level. The North East Thames region was chosen as the setting for the study, with 7096 patients being admitted during 1991. In most, but not all, catchment areas reasonable prediction of the pattern of admission prevalence was possible using the variables chosen. However, different population characteristics predicted admission prevalence in rural and urban areas. Prediction methods based on one or two variables are thus unlikely to work in both settings. A Mental Illness Needs Index (MINI) based on social isolation, poverty, unemployment, permanent sickness and temporary and insecure housing predicted differences in admission prevalence between wards at catchment area level better than Jarman's Underprivileged Area (UPA) score [1] and between districts at regional level better than the UPA score and comparably to the York Psychiatric Index [2] (adjusted r2 at regional level (MINI 0.82, UPA 0.53, York index 0.70). District admission prevalence rates vary by a factor of three between rural and inner city areas; this difference may not fully reflect the variation in the cost of providing care. It did not prove possible to incorporate factors related to bed availability in the models used; reasons for this are discussed. Data covering other aspects of mental health care in addition to hospital admission are needed for more satisfactory modelling.

A one year prospective study of the effect of life events and medication in the aetiology of schizophrenic relapse.

BACKGROUND: We set out to determine whether and to what degree life events independent of illness increase the risk of relapse in schizophrenia following withdrawal from medication in the previous 6 months, either by triggering a relapse in the following 4 weeks or by acting cumulatively over time. METHOD: Seventy-one patients fulfilling DSM-III-R criteria for schizophrenia with chronic illness were followed for 48 weeks and assessed on the LEDS scale. Half were treated with regular neuroleptic medication and half had been recently withdrawn from medication. A subgroup was randomised double-blind to treatment or placebo. RESULTS: A proportional hazards regression model showed that life events made a significant cumulative contribution over time (P < 0.05) to the risks of relapse and that ceasing medication made an independent contribution. The risk of relapse increased in proportion to the number of life events but no interaction between medication status and events could be detected, i.e. life events were not more closely associated with relapse on medication than off medication. For those of the sample exposed to the mean rate of life events during the study period, it was estimated that 23% of the relapse risk could be attributed to life events, and for those with twice the mean rate of events, 41%. In contrast, patients who continued on regular medication had 80% less risk of relapse than those who had been withdrawn from medication either by choice or under double-blind controlled conditions. CONCLUSIONS: A contribution of life events to the risk of relapse in schizophrenia was confirmed by this study but the hypothesis that life events trigger relapse was not supported, nor was the hypothesis that life events are more relevant to relapse in patients on maintenance medication than in patients off medication.

Towards the development of a multi-axial classification of people with learning difficulties.

The complexity of need experienced by people with learning disabilities might best be described by a multi-axial classification. The data routinely collected for a register of people with learning disabilities were analysed to see whether factors that might discriminate between individuals could be identified. Three factors were identified. The factor scores were used in a cluster analysis. A ten-cluster model formed from these factors made empirical sense. The present investigation indicates that a multi-axial classification is feasible and may be useful. However, the results cannot be applied beyond the data set used for its development at the present time. Ultimately, it will be necessary to collect additional information in order to calibrate the factor scores.

Rate of CD4 cell decline and prediction of survival in zidovudine-treated patients.

OBJECTIVE: To investigate the relationship between survival and the rate of CD4 cell decline before and in the first year following initiation of zidovudine (ZDV) therapy. DESIGN: Retrospective observational study. SETTING: Hospital-based HIV clinics within the Riverside District Health Authority in London. PATIENTS: Patients (total, 1415) with AIDS (n = 476), symptomatic (n = 687) or asymptomatic (n = 194) HIV-1 infection, or of unknown clinical status (n = 58), who first received ZDV between June 1986 and October 1991. INTERVENTION: The majority of patients received ZDV at an initial dose of 200 mg every 6 h or 250 mg twice daily. The median duration of follow-up after receipt of ZDV was 17 months (range, 2-54 months). MAIN MEASUREMENTS: CD4 cell counts prior to and following initiation of ZDV; rate of decline of log-transformed CD4 cell count before ZDV therapy and during the first year of therapy; survival. RESULTS: As of 31 December 1991, 432 patients had died. Patients with the highest rate of log CD4 decline before initiation of ZDV (< or = -0.06 log cells per month) as well as in the first year of ZDV therapy (< or = -0.08 log cells per month) had a much poorer 3-year survival from initiation of ZDV (23 and 40.5%, respectively) compared with patients with no decline or an increase in their CD4 count before (39.0%) or after (72.3%) ZDV therapy. In a series of multivariate analyses, a high rate of log CD4 decline in the first year of ZDV therapy (< or = -0.08 log cells per month) was predictive of poor survival, after adjustment for age and clinical status at initiation of ZDV and most recent CD4 count. In contrast, rate of CD4 decline before ZDV, presence of an initial CD4 rise and the magnitude of change in the rate of CD4 decline following ZDV were no longer significantly associated with outcome. CONCLUSIONS: In this retrospective study, the rate of CD4 decline in the first year of ZDV therapy, but not the occurrence of an initial CD4 rise was predictive of survival, suggesting that the early CD4 response may be a poor measure of the impact of ZDV. Patients with a high rate of CD4 decline despite ZDV therapy represent a subgroup of patients with a poor prognosis who might benefit from alternative or combination antiretroviral therapies.

Progressive CD4 cell depletion and death in zidovudine-treated patients.

Preliminary evidence suggests that a CD4 cell count < 50 cells/mm3 is associated with a particularly poor short-term prognosis, and is both necessary and sufficient for death associated with HIV infection. We sought to validate these findings in a cohort of 1,415 zidovudine (ZDV)-treated patients, with advanced HIV infection, and to examine more closely the profile of CD4 cell decline over the 2 years prior to death. As of December 31, 1991, 432 patients had died. The cumulative 2 year survival of patients once their CD4 cell count fell to < or = 50 cells/mm3 (median survival = 17.3 months) was substantially shorter at 25.7%, than from when their CD4 cell counts first fell within the range 51-100/mm3 (51.4%); 101-150/mm3 (67.3%); or 151-200/mm3 (76.5%). The percent of patients with a CD4 count < 50 cells/mm3, increased from 33% at 24 months prior to death to 58% at 12 months and 86% at 1 month. Patients with a CD4 count > or = 50 cells/mm3 in the month prior to death, were significantly older (p < 0.001) and had higher CD4 cell counts (p < 0.05) at initiation of ZDV compared to those with a CD4 count < 50 cells/mm3. There were no important differences in HIV risk category, duration of ZDV therapy or use of PCP prophylaxis between the two groups. These findings highlight the importance of more intensive monitoring of patients with CD4 counts < 50 cells/mm3, since life-threatening opportunistic infections are more likely to supervene at this stage. A CD4 count < 50 may also be a useful surrogate endpoint for survival in clinical trials.

Operative survival and 40 year follow up of surgical repair of aortic coarctation.

OBJECTIVE: To study early and late mortality after surgical correction of coarctation of the aorta. DESIGN: Data on 223 patients operated on at the Westminster Hospital, London, between 1946 and 1981, were collected and updated by questionnaire. PARTICIPANTS: All 223 patients recorded as undergoing operation for aortic coarctation up to the end of 1981. Fifteen of 197 survivors were lost to follow up; most of them were patients from overseas. OUTCOME AND RESULTS: The early mortality (within one month of operation) was 12% overall, 2.6% for elective surgery, and 0% for the 77 patients undergoing surgery since 1968. Survivors were followed up for a total of 3288 patient years; in 27 follow up lasted more than 30 years. In a few it reached 40 years. Twenty two patients died during this period, 18 from causes that could be attributed to coarctation or its repair. Mortality was highest more than 20 years after the operation. CONCLUSION: Repair increased life expectancy in patients with aortic coarctation. Late problems caused by persistent hypertension or recoarctation became apparent in long term survivors. The increased risk of late mortality associated with the duration of preoperative hypertension was not statistically significant. There were no deaths from cerebrovascular accidents. (In an earlier necropsy series cerebrovascular accidents accounted for 11.8% of deaths.) The incidence of deaths from aneurysms resembled that in the earlier necropsy series.

Models for forecasting hospital bed requirements in the acute sector.

STUDY OBJECTIVE: The aim was to evaluate the current approach to forecasting hospital bed requirements. DESIGN: The study was a time series and regression analysis. The time series for mean duration of stay for general surgery in the age group 15-44 years (1969-1982) was used in the evaluation of different methods of forecasting future values of mean duration of stay and its subsequent use in the formation of hospital bed requirements. RESULTS: It has been suggested that the simple trend fitting approach suffers from model specification error and imposes unjustified restrictions on the data. Time series approach (Box-Jenkins method) was shown to be a more appropriate way of modelling the data. CONCLUSION: The simple trend fitting approach is inferior to the time series approach in modelling hospital bed requirements.