Cost and mortality data of a regional limb salvage and hyperbaric medicine program for Wagner Grade 3 or 4 diabetic foot ulcers.

We obtained costs and mortality data in two retrospective cohorts totaling 159 patients who have diabetes mellitus and onset of a diabetic foot ulcer (DFU). Data were collected from 2005 to 2013, with a follow-up period through September 30, 2014. A total of 106 patients entered an evidence-based limb salvage protocol (LSP) for Wagner Grade 3 or 4 (WG3/4) DFU and intention-to-treat adjunctive hyperbaric oxygen (HBO2) therapy. A second cohort of 53 patients had a primary lower extremity amputation (LEA), either below the knee (BKA) or above the knee (AKA) and were not part of the LSP. Ninety-six of 106 patients completed the LSP/HBO2with an average cost of USD $33,100. Eighty-eight of 96 patients (91.7%) who completed the LSP/HBO2had intact lower extremities at one year. Thirty-four of the 96 patients (35.4%) died during the follow-up period. Costs for a historical cohort of 53 patients having a primary major LEA range from USD $66,300 to USD $73,000. Twenty-five of the 53 patients (47.2%) died. The difference in cost of care and mortality between an LSP with adjunctive HBO2therapy vs. primary LEA is staggering. We conclude that an aggressive limb salvage program that includes HBO2 therapy is cost-effective.

Glycosylated hemoglobin and hyperbaric oxygen coverage denials.

Some Medicaid and Medicare fiscal intermediaries are denying hyperbaric oxygen (HBO2) therapy for diabetic foot ulcer (DFU) patients if the glycosylated hemoglobin (HbA1c) > 7.0%. We performed multiple PubMed searches for any diabetic wound healing clinical trial that documented HbA1c and had a wound healing endpoint. We scrutinized 30 peer-reviewed clinical trials, representing more than 4,400 patients. The average HbA1c from the intervention side of the studies was 8.6% (7.2% - 9.9%) and the control/sham side was 8.3% (6.0% - 10.6%). Twelve studies made a direct attempt to link HbA1c and wound healing. Four retrospective studies and one prospective cohort study assert that lower HbA1c favors wound healing, but review of the studies reveal design flaws that invalidate these conclusions. In total, 25 studies showed no direct correlation between HbA1c levels and wound healing. There was no randomized controlled trial (RCT) data demonstrating that HbA1c < 7.0% improves diabetic wound healing. In every study reviewed, wounds healed with high HbA1c levels that would be considered poorly controlled by the American Diabetes Association (ADA). Frequently, patients lack optimal blood glucose control when they have a limb-threatening DFU. The evidence supports that denying hyperbaric oxygen to those with HbA1c > 7.0% is unfounded.

Memorable objects are more susceptible to forgetting: Evidence for the inhibitory account of retrieval-induced forgetting.

Retrieval of target information can cause forgetting for related, but non-retrieved, information - retrieval-induced forgetting (RIF). The aim of the current studies was to examine a key prediction of the inhibitory account of RIF - interference dependence - whereby 'strong' non-retrieved items are more likely to interfere during retrieval and therefore, are more susceptible to RIF. Using visual objects allowed us to examine and contrast one index of item strength -object typicality, that is, how typical of its category an object is. Experiment 1 provided proof of concept for our variant of the recognition practice paradigm. Experiment 2 tested the prediction of the inhibitory account that the magnitude of RIF for natural visual objects would be dependent on item strength. Non-typical objects were more memorable overall than typical objects. We found that object memorability (as determined by typicality) influenced RIF with significant forgetting occurring for the memorable (non-typical), but not non-memorable (typical), objects. The current findings strongly support an inhibitory account of retrieval-induced forgetting.

Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females.

INTRODUCTION: Ibandronate is a potent, nitrogen-containing bisphosphonate that is licensed as a once-monthly oral preparation and is currently in clinical development as a novel intermittent intravenous (i.v.) injection in osteoporosis. Ibandronate pharmacokinetic (PK) data were used to develop a PK model that could ultimately be incorporated into a PK pharmacodynamic (PD) model to assist the ibandronate development program through computer-assisted trial design. This manuscript reports the use of non-linear mixed-effects modeling to characterize the PK of ibandronate, to examine the possible influence of ethnicity on the disposition of ibandronate and to develop an appropriate population PK model for ibandronate. METHODS: A retrospective, cross-study population PK analysis was performed using PK data from five phase I studies with i.v. ibandronate (0.125 - 2.0 mg) conducted in Caucasian and Japanese healthy male volunteers, postmenopausal Caucasian women without osteopenia and postmenopausal Japanese women with osteopenia. The following covariates were investigated to establish their influence on the central volume of distribution (V1) and drug clearance (CL): age, body weight, gender, disease status (healthy versus osteopenic), creatinine clearance (CLCR), and ethnicity (Japanese versus Caucasian). Serum concentrations of ibandronate were quantified by GC-MS or ELISA, and data were modeled using non-linear mixed-effects modeling implemented by the software program NONMEM. RESULTS: The PK of ibandronate was adequately described by a linear 3-compartment model. Disease status, body weight, gender and CLCR significantly influenced ibandronate CL (10 34%) and the latter 3 also influenced V1 (20 29%). Ethnicity was not a determinant for ibandronate PK in the final model. Although gender was the most influential covariate, differences in V1 and CL between the sexes were modest (29 and 34%, respectively) and the overall effects on ibandronate exposure (Cmax and AUC) were not clinically relevant. The final model described the observed PK of ibandronate well, and all PK parameters were estimated with an acceptable degree of precision (SE < 13%). CONCLUSION: The PK of i.v. ibandronate was well described by a linear 3-compartment population PK model that included disease status, body weight, gender and CLCR as covariates, but without greatly affecting ibandronate exposure (Cmax and AUC). Ethnicity did not influence ibandronate PK and was not included in the final model.

Pharmacokinetics and tolerance of romazarit after oral administration of ascending single doses to healthy human volunteers.

Forty-four healthy male volunteers participated in an investigation of the pharmacokinetics and tolerance of single oral doses of romazarit, a potential disease-modifying antirheumatic drug. The study design involved single oral doses in ascending sequence from 40 to 1500 mg. At each dosage 9 volunteers were studied, of whom 6 received romazarit and 3 received placebo capsules in a double-blind manner. Tolerance was assessed before and after each of the 57 romazarit and 27 placebo doses. Plasma and urinary concentrations of romazarit were measured by HPLC with UV detection. Model-independent pharmacokinetic analyses showed that romazarit was rapidly and extensively absorbed in a dose-proportional manner. Urinary recovery of drug related material was about 70% of the dose and almost all in the form of labile metabolites (probably acyl glucuronides). Clearance was faster (greater than 3 l/h) at doses below 700 mg, than in the range 700-1500 mg (1.7 l/h). It is suggested that two or more clearance mechanisms are present. One of these mechanisms is saturable and may involve a reversible ester glucuronide formation coupled with saturable tubular secretion of glucuronides. Romazarit was well tolerated in these healthy volunteers. There were two reports of stomach pain, one associated with vomiting. Changes in laboratory safety test results and in measurements of vital signs were similar in frequency and magnitude after romazarit and after placebo doses.

Recent developments in electronic medical records.

Human factors engineering principles will guide the development of future EMR systems. Physicians will use wireless palmtop computers to record patient data so that the computer does not come between the physician and patient in routine encounters. With few exceptions, the pieces for this type of system are available today, but not in one package. I believe EMR developers have recognized the ubiquity and power of the Internet. Because of advances in computers, software, and telecommunications reliability, solutions using thin-client technology will lower the cost of EMRs to physicians.

The representation of response effector and response location in episodic memory for newly acquired actions: evidence from retrieval-induced forgetting.

Information retrieval can cause forgetting for related but non-retrieved information. Such retrieval-induced forgetting (RIF) has been previously found for semantically and episodically related information. The current study used RIF to examine whether response effector and location are encoded explicitly in action memory. Participants learned unique touchscreen responses to ten novel objects. Correct actions to each object involved left-hand or right-hand pushing of one of four possible object buttons. After learning, participants practiced two of the ten object-specific sequences. Unpracticed actions could share hand only, button only, both hand and button, or neither hand nor button, with the practiced actions. Subsequent testing showed significant RIF (in retrieval accuracy and speed measures) for actions that shared hand only, button only, or both hand and button with the practiced action. The results have implications for understanding the representations mediating episodic action memory, and for the potential of RIF as a tool for elucidating feature-based representations in this and other domains.

A three-dimensional study of endometrial mitochondria during the menstrual cycle.

Three-dimensional reconstruction of endometrial mitochondria during the menstrual cycle in the woman has produced three mitochondrial populations. These populations are seen to change in size, in number, and in complexity of structure as the menstrual cycle progresses. Through reconstruction and statistical analysis, morphologic data seem to support histochemical data relating to anaerobic and aerobic metabolism in endometrial gland cells.

Do electronic mail discussion lists act as virtual colleagues?

Anesthesiology Discussion Group (ADG), an electronic mail (email) discussion list, has previously been shown to be a clinically oriented, cost-effective form of telemedicine. ADG is composed of an international collection of anesthesia providers. Discussions with colleagues are generally informal in nature and are examples of types of information-seeking behavior which frequently occur in hallways or lounges of a hospital or clinic. Information-seeking occurs when a health care provider searches for information which will be used to solve or satisfy a patient's problem or need. We surveyed practitioners who had previously submitted non-rhetorical, clinical questions to the group. After analysis of the questionnaire results, we conclude that ADG is a valuable resource used for information-seeking and is a clinically effective form of telemedicine. Many of the respondents indicated that they used ADG to obtain second opinions from the collective expertise of group members. Respondents also indicated that they were generally satisfied with the quality of responses and would not hesitate to use ADG for future clinical questions.

Using concept maps on the World-Wide Web to access a curriculum database for problem-based learning.

Development of medical school curriculum databases continues to be challenging. Representation of the instructional unit is becoming increasingly difficult due to characteristics of the problem-based learning (PBL) curricula. Curriculum databases may be used to store materials for the PBL curricula, and also to provide a delivery mechanism for those materials. However, in order to take advantage of the curriculum database as a tool for PBL, methods for accessing the curriculum database that are better suited to the information needs of students, faculty, and administrators must be developed. Concept maps are directed graph representations of conceptual relationships, and may be used to represent the content of a curriculum database. In this paper, we describe a Web application that uses Java-based concept maps was the user interface to a curriculum database.

Cost-effective clinical uses of wide-area networks: electronic mail as telemedicine.

Electronic mail (E-mail) is widely used as a means of communication in the medical community. E-mail is clearly inexpensive when compared to two-way, fully interactive, real-time, video telemedicine. By content analysis of 200 consecutive messages, we show E-mail to be a low-cost use of computer networks, supporting a wide range of physician decision-making.

Metabolism of calcium antagonist Ro 40-5967: a case history of the use of diode-array u.v. spectroscopy and thermospray-mass spectrometry in the elucidation of a complex metabolic pathway.

1. The calcium antagonist, Ro 40-5967, is metabolized to a multitude of products by the rat and drug-related material is excreted predominantly via the bile. 2. Diode-array u.v. spectroscopy, following reverse phase h.p.l.c. separation of the partially purified metabolites, has been used to classify these compounds into six spectral classes which have been correlated with different metabolic reactions. 3. Connection of a mass spectrometer directly to the h.p.l.c. equipment by a thermospray interface, produced useful mass spectra. These, together with the u.v. spectra, enabled the structures of many metabolites to be elucidated. 4. Confirmation of structural assignments was provided by n.m.r. spectra of the major metabolites. 5. Major metabolic pathways included N-demethylation (16% of the biliary metabolites), hydrolysis of the ester side-chain (32%), hydroxylation at 4- (19%) and 5- (29%) positions of the benzimidazole ring, aromatization of the tetrahydronaphthyl system (26%), loss of the benzimidazole (15%) and glucuronidation of hydroxyl groups (81%).

Chromatographic and immunochemical approaches to the analysis of the HIV protease inhibitor saquinavir in plasma.

The development of the HIV protease inhibitor saquinavir (Ro 31-8959) required a range of analytical methods for its measurement in biological fluids. This paper describes the development of isocratic, reverse-phase HPLC/UV methods for the routine measurement of plasma levels of the drug together with a more sensitive radioimmunoassay. The performance of the two assays is compared with that of an HPLC/MS/MS method previously published and has been shown to be satisfactory, with coefficients of variation of calibration standards and quality control samples within the usual outside limits of +/- 15%. The HPLC/UV method can be routinely applied for concentrations down to 10-20 ng/ml and a lower limit of quantification of 1 ng/ml from 1 ml of human plasma is possible. The radioimmunoassay was developed for the specific measurement of saquinavir concentrations in human, HIV-positive plasma samples and has a lower limit of quantification of 0.5-1.0 ng/ml. Some preliminary findings suggested that it might not be specific in rat plasma and no attempts have been made to quantify any nonclinical samples with this technique. If still greater sensitivity is required, recourse can be made to the HPLC/MS/MS assay.

Metabolism of the calcium antagonist, mibefradil (POSICOR, Ro 40-5967). Part III. Comparative pharmacokinetics of mibefradil and its major metabolites in rat, marmoset, cynomolgus monkey and man.

1. The metabolism of mibefradil has been examined in rat, marmoset, cynomolgus monkey and man after single and multiple oral administration. 2. Metabolites typically represent between 50 and 80% of the circulating drug-related material after single oral doses of mibefradil to man, rat and marmoset. They arise by a combination of enzymatic processes: cytochrome P450-mediated oxidation at saturated and unsaturated carbon atoms, cytochrome P450-catalysed dealkylation and hydrolysis of the ester side-chain. 3. Plasma levels of mibefradil in the cynomolgus monkey are extremely low as a result of very efficient first-pass hydrolysis of its side-chain to give the corresponding alcohol. Steady-state concentrations of this metabolite are comparable with those of the parent drug in man and marmoset, but are relatively low in rat plasma. 4. Hydroxylation at the benzylic carbon of the tetrahydronaphthyl ring leads to further important metabolites in primates, whereas the products of O- and N-demethylation are found in small amounts in all four species. 5. Estimates of the exposure of the various species to the principal metabolites indicate that the choice of the rat, marmoset and cynomolgus monkey for the toxicological assessment of mibefradil was appropriate.

Biological properties of the angiotensin-converting enzyme inhibitor cilazapril.

Cilazapril is the monoethyl ester prodrug form of a potent, specific. long-acting antihypertensive inhibitor of angiotensin-converting enzyme (ACE). The biochemical and pharmacological properties of this compound have been compared with those of captopril and enalapril. In all test systems, cilazapril was the most potent and the longest acting. The active diacid of cilazapril was more potent than the corresponding diacid of enalapril in inhibiting the cleavage of angiotensin I and of Hip-His-Leu by ACE in vitro, in antagonising the angiotensin I-induced contractions of the isolated ileum of the guinea pig, in potentiating the vasodepressor responses to bradykinin, and in reducing the angiotensin I-induced rise in blood pressure of the rat. Parent drug absorption and diacid bioavailability in the rat were higher than for enalapril, and the inhibition of plasma ACE of longer duration. Single doses of cilazapril were more potent than enalapril in lowering the blood pressure of spontaneously hypertensive rats (SHR) and two-kidney renal hypertensive rats. On repeated daily oral dosing to SHR, both compounds had a cumulative antihypertensive effect. The acute antihypertensive effect was enhanced by simultaneous treatment with hydrochlorothiazide.

The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells.

Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.

(E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a selective and orally active inhibitor of tumor necrosis factor-alpha convertase.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), is a potent, orally active inhibitor of the TNF-alpha convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-alpha. Ro 32-7315 inhibited a recombinant form of TACE (IC(50) = 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-alpha release with IC(50) values of 350 +/- 14 nM (n = 5), 2.4 +/- 0.5 microM (n = 5), and 110 +/- 18 nM (n = 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-alpha with an ED(50) of 25 mg/kg. Treatment (days 0-14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebo-controlled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-alpha release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n = 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.