Patient-physician discordance in goals of care for patients with advanced cancer.

Background: Shared decision-making at end of life (eol) requires discussions about goals of care and prioritization of length of life compared with quality of life. The purpose of the present study was to describe patient and oncologist discordance with respect to goals of care and to explore possible predictors of discordance. Methods: Patients with metastatic cancer and their oncologists completed an interview at study enrolment and every 3 months thereafter until the death of the patient or the end of the study period (15 months). All interviewees used a 100-point visual analog scale to represent their current goals of care, with quality of life (scored as 0) and survival (scored as 100) serving as anchors. Discordance was defined as an absolute difference between patient and oncologist goals of care of 40 points or more. Results: The study enrolled 378 patients and 11 oncologists. At baseline, 24% discordance was observed, and for patients who survived, discordance was 24% at their last interview. For patients who died, discordance was 28% at the last interview before death, with discordance having been 70% at enrolment. Dissatisfaction with eol care was reported by 23% of the caregivers for patients with discordance at baseline and by 8% of the caregivers for patients who had no discordance (p = 0.049; ϕ = 0.20). Conclusions: The data indicate the presence of significant ongoing oncologist-patient discordance with respect to goals of care. Early use of a simple visual analog scale to assess goals of care can inform the oncologist about the patient's goals and lead to delivery of care that is aligned with patient goals.

Are all piglets born lightweight alike? Morphological measurements as predictors of postnatal performance.

Birth weight (BiW) of pigs is a commonly used predictor of postnatal performance; however, it has been suggested that morphological measurements may be more reflective of the intrauterine environment and thus better predictors of postnatal growth. The aim of this study was to determine 1) whether morphological measurements, including ponderal index (PI), body mass index (BMI), and abdominal circumference (AC), could be used as predictors of postnatal performance and 2) if so, would they be better predictors than BiW and 3) would the same predictors apply to pigs of different BiW at different stages of their growth? Morphological measurements, BiW, and BW at d 28 and 70 were available for 731 pigs from experiments conducted over a 2-yr period. A series of linear models was used to determine predictors that affected growth performance from birth to d 28 and from d 28 to 70. For both light (LBiW; ≤1.25 kg) and normal BiW pigs (NBiW; 1.60 to 2.00 kg), BiW was not the best predictor of performance ( > 0.05); different variables for the growth periods considered applied to pigs with different BiW. For LBiW pigs BMI ( < 0.001) and AC ( = 0.0202) were the best predictors for d 1 to 28, and AC ( = 0.0317) and PI ( = 0.0450) were the best predictors from d 28 to 70, with pigs with a larger AC and higher PI/BMI more likely to have higher ADG pre- or postweaning. In contrast, the best predictor variables for NBiW pigs were AC ( = 0.0482) for d 1 to 28 and crown-rump length (CRL; = 0.0138) for d 28 to 70. Focusing on LBiW pigs with low ADG, BMI was the best predictor ( < 0.05) of growth for pre and postweaning, whereas for LBiW pigs with high ADG the best predictors were AC ( = 0.00132) from d 1 to 28 and BiW ( = 0.00601) from d 28 to 70, with increasing BMI, AC, and BiW associated with greater ADG. For NBiW pigs with high preweaning ADG, the best predictor consisted solely of AC ( 0.0210), but no morphological predictor variables were significant for NBiW pigs with low preweaning ADG. For d 28 to 70, the best predictor for NBiW pigs with low ADG was CRL ( = 0.0171), but for high ADG no predictor variables were significant. The present study showed that the morphology of piglets is more important than BiW when predicting the postnatal growth of pigs; however, which measurement is the most important depends on both the BiW and stage of growth. For small-sized pigs, these morphological measures may be considered as a decision-making tool by farmers when trying to identify potential poor performers.

Animal and management factors influencing grower and finisher pig performance and efficiency in European systems: a meta-analysis.

A meta-analysis on the effects of management and animal-based factors on the performance and feed efficiency of growing pigs can provide information on single factor and interaction effects absent in individual studies. This study analysed the effects of such factors on average daily gain (ADG), feed intake (FI) and feed conversion ratio (FCR) of grower and finisher pigs. The multivariate models identified significant effects of: (1) bedding (P<0.01), stage of growth (P<0.001) and the interaction bedding×lysine (P<0.001) on ADG. ADG was higher on straw compared with no bedding (710 v. 605 g/day). (2) FI was significantly affected by stage of growth (P<0.01), bedding (P<0.01), group composition (P<0.05), group size (P<0.01), feed CP content (P<0.01), ambient temperature (P<0.01) and the interaction between floor space and feed energy content (P<0.001). Pigs housed on straw had a lower FI in comparison with those without (1.44 v. 2.04 kg/day); a higher FI was seen for pigs separated by gender in comparison with mixed groups (2.05 v. 1.65 kg/day); FI had a negative linear relationship with group size, the CP content of the feed and ambient temperature. (3) Stage of growth (P<0.001), feed CP (P<0.001) and lysine content (P<0.001), ambient temperature (P<0.001) and feed crude fibre (CF) content (P<0.01) significantly affected FCR; there were no significant interactions between any factors on this trait. There was an improvement in FCR at higher ambient temperatures, increased feed CP and lysine content, but a deterioration of FCR at higher CF contents. For ADG, the interaction of bedding×lysine was caused by pigs housed without bedding (straw) having higher ADG when on a feed lower in lysine, whereas those with bedding had a higher ADG when on a feed higher in lysine. Interaction effects on FI were caused by animals with the least amount of floor space having a higher FI when given a feed with a low metabolisable energy (ME) content, in contrast to all other pigs, which showed a higher FI with increased ME content. The meta-analysis confirmed the significant effect of several well-known factors on the performance and efficiency of grower and finisher pigs, the effects of some less established ones and, importantly, the interactions between such factors.

A meta-analysis to identify animal and management factors influencing gestating sow efficiency.

A meta-analysis on the effects of management and animal-based factors on the reproductive efficiency of gestating sows can provide information on single-factor and interaction effects that may not have been detected in individual studies. This study analyzed the effects of such factors on the number of piglets born alive per litter (BA), piglet birth weight (BiW) and weaning weight (WW), and number of piglets born alive per kilogram of sow feed intake during gestation (BA/FI). A total of 51 papers and 7 data sources were identified for the meta-analysis, out of which 23 papers and 5 sets of production data were useable (a total of 121 treatments). The information gathered included the dependent variables as well as information regarding animal, management, and feed characteristics. While a number of factors were individually significant, the multivariate models identified significant effects only of 1) floor type (P=0.003), sow BW at the end of gestation (P=0.002), and housing (stalls vs. loose; P=0.004) on BA; as floor type and housing were confounded, they were included in 2 separate models. The BA was higher on solid (12.1) in comparison to partly slatted (11.4) and fully slatted floors (10.2); 2) sow gestation environment (P=0.017) and gestation feed allowance (P=0.046) on BiW, with BiW of pigs higher for sows kept outdoors rather than indoors (1.75 versus 1.49 kg); 3) parity number (P=0.003) and feed intake during gestation (P=0.017) on WW; in addition there was an interaction between parity number×feed ME and parity number×feed CP content of feed during gestation on WW, with the positive effects of feed ME and CP contents seen during early rather than later parities; and 4) floor type (P=0.019) and feed crude fiber (P=0.003) for BA/FI with a greater number for those kept on solid floors (5.11) versus partially and fully slatted floors (4.07 and 4.05). The meta-analysis confirmed the significant effect of several well-known factors on the efficiency of gestating sows and, importantly, the interactions between these factors. In addition, the effects of some less established factors were noted, such as floor type. The results may contribute towards the improvement of efficiency of gestating sow systems by better understanding of the various factors that influence this.

High specification starter diets improve the performance of low birth weight pigs to 10 weeks of age.

Piglets born with low birth weights (LBiW) are likely to be lighter at weaning. Starter regimes tailored for pigs of average BW therefore may not be optimal for LBiW nursery performance. The objective was to determine if LBiW pigs benefit from a high specification starter regime and the provision of extra feed (additional allowance of last phase diet of the starter regime) in comparison to a standard commercial regime. Additionally, the effect of starter regime on performance of normal birth weight (NBiW) pigs at weaning was determined and compared to that of LBiW pigs. Finally, the cost effectiveness of the treatments was determined. The experiment was therefore an incomplete 2 × 2 × 2 factorial design, as the provision of extra feed was given only to LBiW pigs (n = 6 replicates per treatment; 5 pigs per replicate). Treatments comprised birth weight (LBiW or NBiW), starter regime (high specification [HS] or standard starter [SS]), and extra feed 3 quantity (yes [YF] or no [NF], for LBiW pigs only; feed 3 corresponded to the last phase diet of the starter regime). At weaning (d 28), pigs were randomly assigned within each birth weight category to treatment groups. Nutritional treatments were fed ad libitum on a kilogram/head basis for approximately 3 wk followed by a common weaner diet fed ad libitum until d 70. Starter regime (P = 0.019), feed 3 amount (P = 0.010), and their interaction (P = 0.029) had an effect on ADG of LBiW pigs from d 28 to 49, with pigs on HS followed by YF (HY) performing best. An improvement in feed conversion ratio (FCR) was noted between d 28 and 49 for pigs fed the additional feed 3 (P = 0.030); between d 49 and 70, the only residual effect seen was of starter regime (P = 0.017) on ADG. In contrast, there was no significant effect of starter regime from d 28 to 70 on ADG, ADFI, or FCR of NBiW pigs. By d 49 and 70, LBiW pigs on regime HY weighed the same as NBiW pigs (d 70 BW; 30.0 vs. 30.6 kg; P = 0.413), with similar growth rates from d 28 to 70 (0.570 vs. 0.533 kg/d; P = 0.137). Despite highest feed cost for regime HY at US$12.30 per pig, its margin over feed was greatest ($23.40). Conversely, regime SS gave the best margin over feed for NBiW pigs at $22.70 per pig. In conclusion, a postweaning feeding regime formulated for LBiW pigs improved the ADG and FCR to the end of the nursery phase enabling them to achieve the same weight as NBiW. Targeting the provision of the high quality expensive regime only to light pigs will ensure maximum growth and increased profitability.

Too late to catch up: a high nutrient specification diet in the grower phase does not improve the performance of low birth weight pigs.

Low birth weight pigs are on a different growth trajectory from their normal birth weight littermates and as a consequence they may need to be fed differently, if they are to show compensatory gain. The objective of the experiment was to determine if low birth weight pigs will respond to a higher AA: energy diet, in a manner similar to the response of normal birth weight pigs whose BW gain has been previously reduced as a result of feed restriction. The experiment was a 3 × 2 factorial with 180 pigs and 6 replicates. Treatments were comprised of 3 BW categories (NU = normal birth weight fed unrestrictedly [1.7 to 2.0 kg], NR = normal birth weight but fed restrictedly from d 49 to 63 and L = low birth weight [ ≤ 1.2 kg]) and 2 diet specifications given from d 63 to 91 (high or standard AA: energy ratio). In period 1 (d 0 to d 49), pigs were selected within 24 h of birth and cross fostered into litters by birth weight (11/12 piglets). Pigs were weaned at d 28 and kept in their litters until d 49. In period 2 (d 49 to 63), litters were split to form 2 treatment groups consisting of 5 pigs each: NR pigs received restricted amounts of feed (600 g/d) with the remaining NU and L pigs fed ad libitum on a conventional diet. The aim was for NR and L pigs to have the same BW by d 63. In period 3 (d 63 to 91), groups within litter were randomly allocated to a high or standard AA:energy ratio diet. Body weight on d 63 was 25.8, 21.2, 21.8 kg (0.381 SED) for NU, NR and L pigs respectively; by d 91 there was no difference in the BW of NU and NR pigs (P > 0.05), but L pigs still weighed less (P < 0.001). There was a significant effect of BW category and diet specification during period 3 on the ADG and G:F of pigs (P < 0.05), with NR pigs exhibiting higher ADG and G:F than L and NU pigs. For G:F only, there was a tendency towards significance for an interaction (P = 0.057) with NU and NR pigs having an improved G:F on the high specification diet, but L pigs did not. Average daily feed intake was similar for all BW categories and diets from d 63 to 91. However, both L and NR pigs consumed more feed than NU pigs relative to their BW, but only NR exhibited higher ADG than NU pigs. This suggests that a higher specification diet post weaning may not improve the performance of low birth weight pigs. However, previously restricted normal birth weight pigs were able to exhibit compensatory growth and were more efficient when fed a higher specification diet.

Athletic activity after lower limb arthroplasty: a systematic review of current evidence.

In this systematic review, our aim was to explore whether or not patients are able to return to athletic activity following lower limb joint replacement. We also investigated any evidence as to whether participation in athletic activity post-joint replacement increases complications and reduces implant survival. A PubMed, Embase and Sports Discus search was performed using the MeSH terms 'Sport', 'Athletic', 'Athlete', 'Physical', 'Activity', 'Arthroplasty', 'Total Hip Replacement', 'Hip Resurfacing', 'Total Knee Replacement', 'Unicompartmental Knee Replacement' and 'Unicondylar Knee Replacement'. From this search, duplications were excluded, the remaining abstracts were reviewed and any unrelated to the search terms were excluded. The remaining abstracts had their full papers reviewed. Following joint replacement, participation in sporting activity is common principally determined by pre-operative patient activity levels, BMI and patient age. The type of joint replaced is of less significance. Total time spent performing activity does not change but tends to be at a lower intensity. There is little evidence in the literature of an association between high activity levels and early implant failure.

Management strategies to improve the performance of low birth weight pigs to weaning and their long-term consequences.

Performance of pigs from birth to slaughter is a result of a complex interaction of factors, with the early stages of a pig's life likely to affect lifetime performance. During the preweaning stage, piglets are reliant on the sow for nutrition, and sibling competition is likely to affect growth, in particular for low birth weight (LBiW) piglets. The objective of the experiment was to determine the effect of litter composition (littermate weight) and milk supplementation during lactation on the performance of LBiW pigs to weaning and the long-term consequences of treatment to slaughter. The experiment was a 2 × 2 factorial with littermate weight (normal or LBiW) and provision of supplementary milk from d 1 to 28 (yes or no) as factors. A total of 265 piglets were selected within 24 h of birth and cross-fostered to create 2 litter types (LOW = LBiW pigs [≤ 1.25 kg] only and MX = both LBiW and normal birth weight pigs [1.6 to 2.0 kg]); half of the litters within a type were supplemented with milk and the other half were not. The behavior of litters given milk was recorded to identify milk consumption patterns. Piglets were weaned at d 28 and kept in their litters until d 70 and then subsequently housed in mixed groups until slaughter. No difference was observed at any stage in the ADG of pigs given access to supplementary milk or not (P > 0.05) nor was there any significant interaction between milk provision and litter composition (P > 0.05). However, LOW litters drank significantly more supplementary milk than MX litters (P < 0.001). There was a significant effect of litter type on ADG from d 14 to 28, with LBiW pigs in LOW litters performing better than those in MX litters (0.252 versus 0.217 kg/d; P < 0.05). At weaning, LBiW piglets in LOW litters weighed over 500 g more than those in MX litters (P < 0.05). In MX litters there was a significant interaction between birth weight and supplementary milk on the CV of BW from d 14 to slaughter (P < 0.05). In conclusion, grouping LBiW piglets with similar sized littermates preweaning can improve preweaning performance by reducing competition from heavier littermates; however, this advantage does not persist after weaning. Although supplementary milk does not improve LBiW pig performance before or after weaning, it affects their drinking behavior and can reduce the variation in the BW of LBiW piglets in mixed litters to slaughter.

Identification of risk factors associated with poor lifetime growth performance in pigs.

During the production period from birth to slaughter there are some pigs that grow markedly slower, despite conditions that seem to support the growth of their contemporaries. This reduction in growth inevitably leads to weight variation within a group, causes difficulties with management, and results in system inefficiencies. By understanding the factors that contribute to poor growth, the performance of these slow growing pigs might be improved, thereby decreasing the overall variability at slaughter. The aim of this paper was to analyze the factors associated with poor growth performance in pigs from birth to slaughter, determine the effect of piglet birth weight (BiW) and weaning weight (WW) on lifetime growth, and investigate the capacity of small piglets to compensate for any BW deficit. Two industry databases, with individual data for approximately 40,000 and 90,000 pigs, respectively, and containing BW profiles and relevant variables, were analyzed. Body weight at birth, weaning, intermediate, and finishing stages were available as well as sex, month of birth, litter size information (number born alive and total born including still born), sow parity number, and length of gestation. Absolute and relative growth rates, based on adjusted BW for age, were calculated for each time interval and 3 types of analysis were performed: a logistic regression, a continuous linear plateau model, and a weight category analysis. For both datasets poor absolute and relative growth from birth to final BW was associated with low BiW (P < 0.001), low WW (P < 0.001), sex (P < 0.001), breed code (P < 0.001), and month of birth (P < 0.001). The linear plateau model suggested that the relationship between BiW and lifetime growth was not linear beyond 1.91 (database 1) or 1.84 (database 2) kg; the same applied to the relationship between WW at 21 d and final BW (FW) growth, which was not linear beyond 7.53 kg. Finally, the weight category analysis revealed that piglets with the lightest BiW were able to exhibit compensatory growth from BiW to FW with 74 (database 1) and 82% (database 2) moving at least 1 BW category. It is concluded that growth performance to slaughter is not solely reliant on pig BiW, with WW also playing a critical role. Additionally, piglets with BiW below the average are capable of some degree of compensatory growth; this provides the opportunity for managing them so as to improve their lifetime growth.

Litigation after hip and knee replacement in the National Health Service.

The results of hip and knee replacement surgery are generally regarded as positive for patients. Nonetheless, they are both major operations and have recognised complications. We present a review of relevant claims made to the National Health Service Litigation Authority. Between 1995 and 2010 there were 1004 claims to a value of £41.5 million following hip replacement surgery and 523 claims to a value of £21 million for knee replacement. The most common complaint after hip surgery was related to residual neurological deficit, whereas after knee replacement it was related to infection. Vascular complications resulted in the highest costs per case in each group.Although there has been a large increase in the number of operations performed, there has not been a corresponding relative increase in litigation. The reasons for litigation have remained largely unchanged over time after hip replacement. In the case of knee replacement, although there has been a reduction in claims for infection, there has been an increase in claims for technical errors. There has also been a rise in claims for non-specified dissatisfaction. This information is of value to surgeons and can be used to minimise the potential mismatch between patient expectation, informed consent and outcome.

One sensor fits all--a new approach in monitoring brain physiology.

Oxygen plays a pivotal role as a nutrient to the brain. Monitoring partial pressure of oxygen (ptO2) has been shown to correlate with outcome after brain injury if certain tissue-ptO2-goals can be achieved. Oxford Optronix has recently developed a new fiber-optic based sensor (MPBS) with a large tissue sampling volume and long-term stability up to 10 days. Direct comparison of the MPBS sensor with the Licox system was performed using an in-vitro and in-vivo model. No statistically significant differences between the MPBS and the Licox sensor in different settings were found. The response times to a sudden drop in ptO2 was faster for the MPBS than for the Licox probes (time of 80% signal change; 65 +/- 11 vs 110 +/- 14 s; p<0.05).

Hospital readmission among long-term ventilator patients.

STUDY OBJECTIVES: Patients experiencing prolonged periods of in-hospital mechanical ventilation have been described as long-term ventilator (LTV) patients. The purpose of this study was to document the incidence of hospital readmission and to identify risk factors for readmission for LTV patients up to 6 months after hospital discharge. DESIGN: This study was part of a larger prospective longitudinal descriptive study of posthospital outcomes for LTV patients. SETTING AND PARTICIPANTS: One hundred ninety-nine ICU patients admitted to a university medical center, Veterans Administration hospital, or small community hospital who required > 96 h of continuous in-hospital mechanical ventilation were enrolled. MEASUREMENTS AND RESULTS: Descriptive statistics, logistic regression, and survival analytic techniques were used. The 6-month hospital readmission rate was 38%. Readmission occurred most often within days 1 to 60 days (mean, 39.2 days) posthospital discharge. Predictive variables for readmission were the following: length of the index hospital stay; length of the index mechanical ventilation; and the need for oxygen at hospital discharge. Using survival analysis, the age category of 66 to 71 years was statistically significant for the relative risk of readmission within the first 30 days of the index hospital discharge. CONCLUSIONS: LTV patients should be considered at risk for hospital readmission. Further study examining the impact of closer follow-up in the first 60 days posthospital discharge is necessary in order to determine whether there is a more effective way of reducing the risk of readmission for LTV patients.

Outcomes of long-term ventilator patients: a descriptive study.

BACKGROUND: Long-term ICU patients who require prolonged mechanical ventilation are a growing segment of the in-hospital population. Despite recognition that this population is costly to care for no systematic research has been done on the characteristics, outcomes, and disposition of these patients after they leave the hospital. OBJECTIVE: To describe clinical and sociodemographic characteristics and outcomes of ICU patients who require long-term (5 days or more) mechanical ventilation while in the hospital. METHODS: A prospective, longitudinal descriptive design was used to study 57 ICU patients who required 5 days or more of continuous mechanical ventilation while in the hospital. Clinical and sociodemographic data were collected at the time of enrollment. Patients were followed up for up to 6 months after discharge from the hospital to ascertain disposition and morality. RESULTS: On average, patients had a hospital stay of almost 6 weeks and required mechanical ventilation for approximately 4 weeks; 43.9% of the patients died in the hospital. None of the patients discharged from the hospital were able to return home initially without assistance. By 6 months after discharge, more than 50% of the original sample and died, 9% resided in an institution, and 33% were living at home. CONCLUSIONS: A large percentage of ICU patients who require 5 days or more of mechanical ventilation die in the hospital, and many of those who live spend considerable time in an extended-care facility before they are discharged to their homes. These likely outcomes of patients who require long-term ventilation should be discussed with patients and their families to assist them in making informed decisions.

Paradoxical blood flow responses in the diabetic neuropathic foot: an assessment of the contribution of vascular denervation and microangiopathy.

Blood flow is abnormal in the diabetic neuropathic foot, and this may be of importance in the pathogenesis of complications. Arteriovenous shunting is increased, and blood flow through these channels may paradoxically decrease in response to local heating. Peak skin blood flow is also reduced in these patients. It is not known whether these blood flow abnormalities may reflect diabetic microangiopathy, or whether they simply reflect vascular denervation. The skin blood flow response to a local thermal stimulus was studied in four non-diabetic patients with a unilateral traumatic neuropathy and foot ulceration. All showed a decrease in skin blood flow (to 68% of basal) at the great toe during local heating in the neuropathic limb, in contrast to the normal limb, in which blood flow increased to 180% of basal. Peak skin blood flow was also greatly reduced in the neuropathic limb, being only 29% of the normal limb. Neuropathy alone can be responsible for abnormal skin blood flow responses in the neuropathic foot.

Influence of neuropathy on the microvascular response to local heating in the human diabetic foot.

1. The diabetic neuropathic foot exhibits excess arteriovenous anastomotic shunt flow due to a reduced sympathetic vasoconstrictor tone. Local axon reflexes (mediating postural vasoconstriction, for example) are preserved even in severe diabetic neuropathy. This excess shunt flow and its local neurogenic control may be important in the development of complications of the neuropathic limb. 2. The response of arteriovenous anastomoses to local heating was assessed in 13 diabetic patients with neuropathy (12 insulin-dependent), 10 diabetic control patients (seven insulin-dependent) and 10 normal control subjects. The aim was to study the local reflex control of arteriovenous flow when central sympathetic tone had been largely removed. 3. The change in skin blood flow on local heating to 44 degrees C was measured by using a laser Doppler flowmeter in standard environmental conditions with the foot at heart level. Two sites were assessed: (i) the plantar surface of the great toe (a site in which skin blood flow is dominated by arteriovenous shunt flow) and (ii) the dorsum of the foot (a site without anastomotic flow). 4. It was found that when heat was applied to the plantar surface of the great toe in the diabetic patients with neuropathy a paradoxical decrease in flow through arteriovenous anastomoses occurred, flow declining to 65% (P less than 0.05) of its resting value. This could be compared with an increase in flow over the same time period of 262% and 228% (P less than 0.01) in diabetic control patients and normal subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Duration of activity of the acid, methyl ester and amide of an orally active platelet aggregation inhibitory prostanoid in the rat.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene PGE1 (OI-PGE1) has been shown to be a more potent inhibitor of ADP-induced human platelet aggregation than PGE1. OI-PGE1 inhibits ex vivo ADP-induced platelet aggregation for 60 minutes after an oral dose of 20 mg/kg to rats. Present studies compare duration of ex vivo inhibition of ADP-induced platelet aggregation in the rat by OI-PGE1, its methyl ester and amide after administration by various routes. All oral (p.o.) and intraduodenal (i.d.) doses were 20 mg/kg and all intravenous (i.v.) doses were 1 mg/kg. OI-PGE1 and its methyl ester had the same duration of activity after i.v. (60 min.) and p.o. (60 min.) administration, however, the methyl ester, when administered i.d., had a longer duration of activity than the free acid i.d. (greater than 90 min. vs. 60 min.). OI-PGE1-amide had significantly longer duration than the acid or methyl ester after i.v. (greater than 120 min.), p.o. (greater than 240 min.) or i.d. (greater than 240 min.) administration. Present data suggest that in the rat (1) intestinal absorption of OI-PGE1-methyl ester is more efficient than it is for the free acid and (2) due to metabolic and/or distributional differences between OI-PGE1 and its amide, the amide has a much greater duration of activity.

Prostaglandin prodrugs III: Synthesis and biological properties of C9- and C15-monoesters of dinoprost (prostaglandin F2 alpha).

Methods are described for the synthesis of dinoprost C9- and C15-monoesters using protective groups. Esters at C9 were synthesized by acylation of dinoprost 11,15-bis(tetrahydropyran-2-yl)ether followed by acid-catalyzed protective group removal. Esters at C15 were synthesized by initial formation of the protected intermediate, dinoprost 9,11-n-butylboronate, followed by acylation and hydrolytic protective group removal. Many esters were active in vivo in the hamster antifertility screen. Plasma hydrolysis studies showed that the C15-esters were more readily cleaved than the C9-esters. In vivo studies in the rat showed that both the C9- and C15-esters resulted in urinary excretion of 5 alpha, 7 alpha-dihydroxy-11-ketotetranorprosta-1,16-dioic acid in amounts comparable to those obtained after dosing with dinoprost, indicating that ester hydrolysis occurred in vivo.