Management of peri-prosthetic joint infection and severe bone loss after total hip arthroplasty using a long-stemmed cemented custom-made articulating spacer (CUMARS).

BACKGROUND: There is little evidence on techniques for management of peri-prosthetic infection (PJI) in the context of severe proximal femoral bone loss. Custom-made articulating spacers (CUMARS) utilising cemented femoral stems as spacers was described providing better bone support and longer survival compared to conventional articulating spacers. We retrospectively report our experience managing PJI by adaptation of this technique using long cemented femoral stems where bone loss precludes use of standard stems. METHODS: Patients undergoing 1st stage revision for infected primary and revision THA using a cemented long stem (> 205 mm) and standard all-polyethylene acetabulum between 2011 and 2018 were identified. After excluding other causes of revision (fractures or aseptic loosening), Twenty-one patients remained out of total 721 revisions. Medical records were assessed for demographics, initial microbiological and operative treatment, complications, eradication of infection and subsequent operations. 2nd stage revision was undertaken in the presence of pain or subsidence. RESULTS: Twenty-one patients underwent 1st stage revision with a cemented long femoral stem. Mean follow up was 3.9 years (range 1.7-7.2). Infection was eradicated in 15 (71.4%) patients. Two patients (9.5%) required repeat 1st stage and subsequently cleared their infection. Three patients (14.3%) had chronic infection and are on long term suppressive antibiotics. One patient (4.8%) was lost to follow up before 2 years. Complications occurred in seven patients (33%) during or after 1st stage revision. Where infection was cleared, 2nd stage revision was undertaken in 12 patients (76.5%) at average of 9 months post 1st stage. Five (23.8%) CUMARS constructs remained in-situ at an average of 3.8 years post-op (range 2.6-5.1). CONCLUSIONS: Our technique can be used in the most taxing of reconstructive scenarios allowing mobility, local antibiotic delivery, maintenance of leg length and preserves bone and soft tissue, factors not afforded by alternative spacer options.

Effect of feeding level on luteal function and progesterone concentration in the vena cava during early pregnancy in gilts.

This study assessed the effect of feeding level on progesterone concentration in the caudal vena cava during early pregnancy in gilts. Twenty-four Landrace gilts were allocated to either a high (2.8±0.02) or a low (1.5±0.01 kg day⁻¹) feeding level at Day 0 of pregnancy. Serial blood samples were collected every 15 min for 3 h before and 3 h after feeding on Days 6 and 9 of pregnancy. Embryo survival and development as well as in vitro luteal progesterone production were assessed at Day 10 of pregnancy. Progesterone concentration in the vena cava was pulsatile with gilts on the high feeding level having more pulses compared with Low gilts on Day 9 of pregnancy (P<0.05). On Day 6 the number of pulses did not differ significantly between treatments; however, the average progesterone concentration in the vena cava tended to be higher in the gilts on the high feeding level (P<0.10). Embryo survival at Day 10 was 92±3% for High gilts compared with 77±3% for Low gilts (P<0.05). No difference in embryo development between the treatments was seen. There was no difference between treatments in in vitro secretion of progesterone by luteal tissue. In conclusion, a high plane of nutrition positively affects progesterone secretion by the ovaries in early pregnancy.

Effects of pre-weaning energy substitutions on post-weaning follicle development, steroid hormones and subsequent litter size in primiparous sows.

The present study investigated the effects of pre-weaning energy substitutions on follicular development, endocrine characteristics and subsequent litter size in primiparous sows. Sows were fed a standard lactation diet (14.1 DE MJ/kg) and then allocated to a Control (C, n = 24), Fat (F, n = 23), Sugar (S, n = 23) or post-weaning Regumate (positive control; R, n = 22) treatment at 9 days before weaning of the C, F and S treatments. During the treatment period (8 days), 1 kg of the lactation diet was substituted with 1 kg of a fat-rich (F, 23.85 DE MJ/kg) or sugar-rich (S, 15.75 DE MJ/kg) substitution for F and S sows, respectively. For the R treatment, sows were weaned 8 days earlier than other treatments and fed a lactation diet at 3.5 kg with two doses of altrenogest as topdressing from 1 day before weaning until the day on which the other sows were weaned. The F treatment aimed to increase energy intake, and the S treatment aimed to elevate post-prandial glucose and insulin concentrations. Weaning-to-ovulation interval tended to be reduced in the S treatment compared with C (p = 0.06) and F (p = 0.08) treatments. Body weight (BW) loss during the treatment period, post-weaning follicle development, plasma oestradiol and pre-weaning leptin did not differ among C, F and S sows, although BW loss was lower and leptin was higher in the R treatment. Post-ovulatory progesterone concentration in the S treatment was higher (p < 0.05). Sows in the S and R treatments had a greater proportion of litters with larger litter sizes (p < 0.05). The outcome suggests that increasing circulating insulin and glucose concentrations during late lactation or a week of metabolic recovery positively improves subsequent litter size in primiparous sows.

Effects of pre-weaning dietary substitutions on plasma insulin and glucose profiles in primiparous sows.

The objective of this study was to investigate the effects of substituting 1 kg of a standard lactation diet with 1 kg of a sugar-rich (15.75 DE MJ/kg) or fat-rich (23.85 DE MJ/kg) diet during late lactation on blood glucose and insulin changes in primiparous sows. During a 4-week lactation period, 21 primiparous sows were fed to appetite with a standard lactation diet (14.10 DE MJ/kg). At 9 days before weaning, sows were assigned to a control (C, n = 7), fat (F, n = 6) or sugar (S, n = 8) treatment. During the treatment period (from 8 days before weaning until weaning), 1 kg of the lactation diet was substituted with 1 kg of a sugar-rich or fat-rich diet for S and F sows. At 3 days before weaning, serial blood samples were collected for a total of 228 min around feeding to establish pre- and postprandial plasma glucose and insulin concentrations. Preprandial plasma glucose and insulin concentrations did not differ between treatments (p > 0.05); however, mean plasma glucose and insulin concentrations were higher for S compared to F (p < 0.05) and intermediate for the C sows. Postprandial plasma concentrations of glucose and insulin were higher for the S sows than for C and F sows (p < 0.05). Sow body weight loss during late lactation did not differ between treatments (p > 0.05). The results from our study suggest that a sugar-enriched diet during the last week of lactation elevates circulating glucose and insulin concentrations and may potentially improve post-weaning fertility in primiparous sows.

Detection of a direct carbon dioxide effect in continental river runoff records.

Continental runoff has increased through the twentieth century despite more intensive human water consumption. Possible reasons for the increase include: climate change and variability, deforestation, solar dimming, and direct atmospheric carbon dioxide (CO2) effects on plant transpiration. All of these mechanisms have the potential to affect precipitation and/or evaporation and thereby modify runoff. Here we use a mechanistic land-surface model and optimal fingerprinting statistical techniques to attribute observational runoff changes into contributions due to these factors. The model successfully captures the climate-driven inter-annual runoff variability, but twentieth-century climate alone is insufficient to explain the runoff trends. Instead we find that the trends are consistent with a suppression of plant transpiration due to CO2-induced stomatal closure. This result will affect projections of freshwater availability, and also represents the detection of a direct CO2 effect on the functioning of the terrestrial biosphere.

Undernutrition during early follicle development has irreversible effects on ovulation rate and embryos.

This study assessed carry-over effects of energy level during the early antral phase and subsequent follicular phase on follicle recruitment and ovulation rate. Gilts (n=45) were fed a standard diet to a low (L, ~1.2kg day(-1)) or high (H, ~2.7kg day(-1)) level during the early antral (luteal) phase, and subsequently fed a H or L feed level during the follicular phase, resulting in four treatment groups (HH, HL, LH and LL). Follicle size at the end of the luteal phase was greater for gilts fed a high feed level previously (3.3vs3.0mm; P<0.05). During the follicular phase, high feeding increased follicle size at Day 5 (6.9vs6.2mm; P<0.005) and plasma oestradiol concentration (P<0.05). Nevertheless, a low feed level during the luteal phase reduced ovulation rate (14.4vs13.2; P<0.05) and embryo number (12.6vs10.5; P<0.05), and this was not counteracted by feed level during the follicular phase. Plasma progesterone concentration after ovulation was lower for LL gilts than for other treatments (P<0.05). These results indicate that undernutrition during early antral follicle development may have a residual effect on follicle recruitment and quality.

Incorporating model quality information in climate change detection and attribution studies.

In a recent multimodel detection and attribution (D&A) study using the pooled results from 22 different climate models, the simulated "fingerprint" pattern of anthropogenically caused changes in water vapor was identifiable with high statistical confidence in satellite data. Each model received equal weight in the D&A analysis, despite large differences in the skill with which they simulate key aspects of observed climate. Here, we examine whether water vapor D&A results are sensitive to model quality. The "top 10" and "bottom 10" models are selected with three different sets of skill measures and two different ranking approaches. The entire D&A analysis is then repeated with each of these different sets of more or less skillful models. Our performance metrics include the ability to simulate the mean state, the annual cycle, and the variability associated with El Niño. We find that estimates of an anthropogenic water vapor fingerprint are insensitive to current model uncertainties, and are governed by basic physical processes that are well-represented in climate models. Because the fingerprint is both robust to current model uncertainties and dissimilar to the dominant noise patterns, our ability to identify an anthropogenic influence on observed multidecadal changes in water vapor is not affected by "screening" based on model quality.

Direct ovarian-uterine transfer of progesterone increases embryo survival in gilts.

This study employed a unilateral ovariectomy model to investigate the relevance of the local supply of progesterone (ovary) compared with the systemic supply of progesterone, in terms of embryo survival in the ipsilateral uterine horn as opposed to the contralateral uterine horn. Thirty gilts were unilaterally ovariectomised (ULO) during the luteal stage of their first oestrous cycle. Half of the ULO gilts were fed at 1.2 maintenance requirement (M), while the other half were fed at 2.4M. Across ULO gilts 0.8 more embryos survived in the ipsilateral horn compared with the contralateral horn at Day 35 of gestation (P<0.05). In ULO gilts on the 2.4M feed level the difference (+1.3; P<0.05) between the ipsi- and contralateral horn was more pronounced than on the 1.2M feed level (+0.4; NS). The higher feed level reduced circulating levels of systemic progesterone on Day 5 of pregnancy but not embryo survival at Day 35. However, post-implantation embryo survival was lower on the low feed level. In conclusion, these data indicate that local progesterone supply from the ovaries to the uterus contributes to the probability of embryo survival.

External control of 20th century temperature by natural and anthropogenic forcings.

A comparison of observations with simulations of a coupled ocean-atmosphere general circulation model shows that both natural and anthropogenic factors have contributed significantly to 20th century temperature changes. The model successfully simulates global mean and large-scale land temperature variations, indicating that the climate response on these scales is strongly influenced by external factors. More than 80% of observed multidecadal-scale global mean temperature variations and more than 60% of 10- to 50-year land temperature variations are due to changes in external forcings. Anthropogenic global warming under a standard emissions scenario is predicted to continue at a rate similar to that observed in recent decades.

Does a dedicated hip fracture unit improve clinical outcomes? A five-year case series.

INTRODUCTION: The aim of the study was to establish whether a dedicated hip fracture unit, geographically separate from the local major trauma centre, could improve clinical outcomes for patients sustaining proximal femoral fragility fractures. MATERIALS AND METHODS: This study was a retrospective case series, using data collected from Brighton and Sussex University Hospitals NHS Trust's submissions to the National Hip Fracture Database between 1 April 2011 and 16 September 2016. The outcomes measured were mortality, length of hospital stay, time from admission to surgical intervention and return to premorbid residence. Patients were compared before and after reconfiguration of services into a separate dedicated hip fracture unit geographically distinct from the major trauma centre. RESULTS: A total of 2117 patients (2178 injuries) were managed before the existence of the hip fracture unit, while 660 patients (673 injuries) were treated within the hip fracture unit. During the five-year study period, the 30-day mortality rate (pre-hip fracture unit 5.47% vs hip fracture unit 3.13%, P = 0.014), variance in the length of hospital stay (P < 0.001), mean time to surgical intervention (P = 0.044) and return to premorbid residence were significantly improved. An immediate 12-month comparison demonstrated significantly improved variance in length of hospital stay (P = 0.020) and return to premorbid residence (P = 0.015). DISCUSSION: The reconfiguration of services significantly reduced variance in length of stay, enabling accurate resource planning in future. Multiple incremental improvements in service provision, in addition to the hip fracture unit, may explain the lower mortality observed. CONCLUSION: While further research is required, replication of the hip fracture unit service model may potentially afford significant clinical and financial gains.

Mixing gilts in early pregnancy does not affect embryo survival.

There is general acceptance that mixing sows during the first 3 weeks of gestation is detrimental to embryo development and survival. However, there is a paucity of data describing the influence of group housing and remixing during the first 14 days of gestation on pregnancy outcomes. Using 96 purebred maternal (Large White)/terminal (Duroc) line gilts, the current study determined the effects of regrouping, and the timing of regrouping, during the pre-implantation period on embryo mortality. The study was conducted in 2 blocks, with 12 gilts allocated to each of 4 treatments in each block. At 175 days of age, the combination of PG600 and 20 min of daily physical boar contact was used to stimulate puberty, with boar contact resuming 12 days after first detection of oestrus and gilts receiving two artificial inseminations (AIs), 24 h apart, at their second oestrus. After their first AI gilts were allocated to one of four treatment groups (n=12 gilts/treatment). Gilts in one treatment group were housed individually in stalls (STALL). The remaining gilts continued to be housed in their pre-AI groups and were either not remixed (NOMIX), or remixed to form new groups on day 3/4 (RMIXD3/4) or day 8/9 (RMIXD8/9) of gestation (day 0=day of first detection of second oestrus and first insemination). Group-housed gilts were housed in groups of 6, with a space allowance of 2.4 m2/gilt. All gilts were fed once a day (2.2 kg/gilt). Reproductive tracts were collected on day 26.6+/-0.13 of gestation, and the number of corpora lutea (CL) and viable embryos counted. Pregnancy rate was similar across all treatments, averaging 94.5% across the four treatment groups. The number of embryos present on day 26 of gestation was unaffected by housing treatments (P>0.05); gilts in the STALL, NOMIX, RMIXD3/4 and RMIXD8/9 groups possessed 13.2+/-0.67, 12.9+/-0.66, 14.1+/-0.46 and 13.8+/-0.57 embryos, respectively. Similarly, embryo survival rates were 0.91+/-0.04, 0.85+/-0.04, 0.91+/-0.02 and 0.87+/-0.05 for the STALL, NOMIX, RMIXD3.4 and RMIXD8/9 groups, respectively (P>0.05). In conclusion, the current data indicate that individually housing gilts immediately after their first AI does not improve embryo survival. There also appear to be no adverse effects on embryo development or survival when group-housed, mated gilts are remixed during the first 10 days of gestation.

Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study.

BACKGROUND: Studies have shown that response to a given chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer is superior to that in patients previously treated with other regimens. This finding raises the question of whether it is necessary and ethical to study the effects of new anticancer agents in untreated patients. Such studies appear to be the best test for drug development, but there has been no evaluation of whether survival of untreated patients, whose cancer is sensitive to established drugs, is adversely affected in trials of new drugs. PURPOSE: This randomized study of untreated patients with extensive-stage small-cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anticancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. METHODS: Eighty-six patients were randomly assigned to receive, as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) every 3 weeks--or the phase II drug menogaril (200 mg/m2) every 4 weeks. Treatment after induction therapy varied, depending on patient response, but nonresponders and those with disease progression received salvage chemotherapy--etoposide (120 mg/m2 on days 1, 2, and 3) and cisplatin (60 mg/m2 on day 1), repeated every 3 weeks. RESULTS: Of the 43 patients on CAV, 42% responded (eight complete responses and 10 partial responses); 5% of the 43 on menogaril responded (two partial responses) (P = .0001). Twelve (22%) of 54 patients responded to salvage chemotherapy (five complete responses and seven partial responses). Within 3 months from start of treatment, twelve patients died--3 patients in the CAV group and nine patients in the menogaril group (P = .12). The estimated median survival was 37 weeks with menogaril and 45 weeks with CAV (P = .28). At 6 months, survival was 76.7% for the CAV group and 67.4% for the menogaril group. At 12 months, survival rates were 24.4% and 27.9%, respectively. Confidence intervals (95%) for the differences between the proportions surviving in the two groups were -9%-28% at 6 months and -25%-14% at 12 months. Use of CAV resulted in significantly higher occurrence of severe and life-threatening treatment-related complications (P = .002). CONCLUSION: The confidence intervals for the differences in survival are too wide to conclude that evaluation of a new drug in untreated patients with extensive-stage small-cell lung cancer is or is not harmful. The data do suggest, however, that use of this study design may have no adverse effect on survival.

Possible mediators of the "living" radical polymerization.

The stable radicals derived from different compounds were detected in process of styrene autopolymerization. The nitroxide radicals are produced from nitrosocompound, hindered hydroxylamine, nitrophenols and nitroanisoles. The phenoxyl radicals are formed from quinine methides, and naphtoxyl radicals are generated from 2-nitro-1-naphtol. The radicals are identified, the kinetics of their formation and follow-up evolution are studied. These radicals can participate in process of living radical polymerization as the mediators and can effect significantly on kinetics of polymerization and structure of the resulting polymer.

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

PURPOSE: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). PATIENTS AND METHODS: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. RESULTS: The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. CONCLUSION: The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE: Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkin's lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS: Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS: Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION: Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.

Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen.

The formation of eutectic systems between ibuprofen (ibu) and seven terpene skin penetration enhancers was studied and, by using the eutectic systems as donors, the effects of melting point depression of the delivery system on transdermal delivery were investigated. A range of ibu:terpene binary mixtures were melted together, cooled, and recrystallised. Composition/melting point phase diagrams were determined by DSC and FT-IR analysis was used to investigated the nature of the interaction. Permeation of ibu across human epidermal membrane from the eutectic system was measured and compared to the flux from a saturated aqueous solution across skin and skin pretreated with the terpenes. The eutectic, i.e. minimum, melting points of these systems ranged from 32 degrees C for ibu:thymol 40:60 (% w/w) to -13 degrees C for ibu:1,8-cineole 40:60 (% w/w) compared to 76 degrees C for ibu alone. FT-IR studies indicated that only the terpenes which formed hydrogen bonds with ibu produced eutectic systems. Each set of ibu:terpene eutectic systems produced a significant (t-test, p = 0.05) increase in flux compared to a saturated aqueous solution applied to untreated and to terpene pretreated skin. For example, ibu:thymol 40:60 (% w/w) produced a flux of 150 micrograms/cm2/h, 5.9 times the flux from a saturated aqueous solution with thymol pretreated skin and 12.7 times the flux from a saturated aqueous solution across non-pretreated skin. In conclusion, a hydrogen bonding interaction is the primary mechanism by which some terpenes form binary eutectic mixtures with ibu. The resultant melting point depression of the delivery system is correlated with a significant increase in transdermal permeation.

Efficacy and tolerability of controlled-release trazodone in depression: a large multicentre study in general practice.

A double-blind, parallel-group study was carried out to compare the efficacy and tolerability of a controlled-release tablet formulation of trazodone with the standard trazodone tablet. Three hundred and forty-seven general practice patients with depressive symptoms were recruited into the trial. Patients were randomly allocated to receive either 1 controlled-release trazodone (150 mg) tablet at night or 1 standard trazodone (150 mg) tablet at night for a period of 6 weeks. Assessments of efficacy, tolerability and compliance were made at study entry and after 1, 2, 4 and 6 weeks of study medication. Seventy-seven patients withdrew from the study of whom 44 were in the standard trazodone tablet group and 33 were in the controlled-release trazodone tablet group. There were no statistically significant differences between treatment groups in any of the measures of efficacy (global severity, global improvement and Hamilton Depression Rating Scales 17- and 21-item). Major improvements in patients' condition were shown in all efficacy measures by the end of the study in comparison with study entry. Treatment differences were small but were numerically in favour of the controlled-release tablet formulation. As expected, a greater proportion of side-effects were reported during the first 2 weeks of treatment in both groups. Treatment differences, revealed in a five symptom adverse event checklist used throughout the study, were small, although in favour of the controlled-release tablet in the majority of cases, but not statistically significant.

A phase II trial of intermittent leukocyte interferon and high dose chlorambucil in the treatment of non-Hodgkin's lymphoma resistant to conventional therapy.

Thirteen patients with advanced non-Hodgkin's lymphoma who previously failed conventional chemotherapy protocols were treated with a combination of alpha-interferon (IFN) 6,000,000 units i.m. days 1-5 and 8, plus chlorambucil (CLB) 16 mg/m2 days 5-9 repeated every 4 weeks. There were five complete responses (CRs) and one partial response (PR) (46% total responses) with mean duration of remission of 456+ days. Responses were obtained in low and intermediate grade lymphomas. Toxicity was acceptable and easily managed. It is unlikely that IFN alone using this low dose intermittent schedule is responsible for the remissions. The combination of the two agents appears to be an effective treatment modality. IFN may be functioning as a biological response modifier when used in combination with a cytotoxic agent.

Mechanistic study into the enhanced transdermal permeation of a model beta-blocker, propranolol, by fatty acids: a melting point depression effect.

Transdermal permeation of propranolol through human skin in the presence of fatty acid (lauric, capric) penetration enhancers has been investigated. Thermal analysis showed that binary mixtures of propranolol with either fatty acid were not simple mechanical mixtures of the two components. Propranolol formed 1:1 molar addition compounds with both lauric and capric acids; the addition compound produced from propranolol and lauric acid (m.p. 79 degrees C) also developed eutectic systems with both propranolol (m.p. 54 degrees C) and lauric acid (m.p. 16 degrees C). Similarly, the addition compound made from propranolol and capric acid (m.p. 97 degrees C) formed eutectic systems with propranolol (m.p. 83 degrees C) and capric acid (m.p. 15 degrees C). Infrared analyses indicated that the addition compounds were fatty acid salts of the beta-blocker. The nature of the species permeating through human epidermal membranes from binary mixtures of propranolol with the fatty acids was investigated using a novel attenuated total reflectance Fourier transform infrared method. There was no clear difference in permeation rates of the fatty acids compared with the beta-blocker, suggesting that the permeating species was the intact addition compound. The influence of melting point depression of the beta-blocker fatty acid systems on transdermal permeation was predicted from a mathematical model; predicted and experimentally determined data correlated well thus providing an alternative explanation as to the mode of action of these permeation enhancers.