Impact of electronic chemotherapy order forms on prescribing errors at an urban medical center: results from an interrupted time-series analysis.

OBJECTIVE: To evaluate the impact of electronic standardized chemotherapy templates on incidence and types of prescribing errors. DESIGN: A quasi-experimental interrupted time series with segmented regression. SETTING: A 700-bed multidisciplinary tertiary care hospital with an ambulatory cancer center. PARTICIPANTS: A multidisciplinary team including oncology physicians, nurses, pharmacists and information technologists. INTERVENTION(S): Standardized, regimen-specific, chemotherapy prescribing forms were developed and implemented over a 32-month period. MAIN OUTCOME MEASURE(S): Trend of monthly prevented prescribing errors per 1000 chemotherapy doses during the pre-implementation phase (30 months), immediate change in the error rate from pre-implementation to implementation and trend of errors during the implementation phase. Errors were analyzed according to their types: errors in communication or transcription, errors in dosing calculation and errors in regimen frequency or treatment duration. Relative risk (RR) of errors in the post-implementation phase (28 months) compared with the pre-implementation phase was computed with 95% confidence interval (CI). RESULTS: Baseline monthly error rate was stable with 16.7 prevented errors per 1000 chemotherapy doses. A 30% reduction in prescribing errors was observed with initiating the intervention. With implementation, a negative change in the slope of prescribing errors was observed (coefficient = -0.338; 95% CI: -0.612 to -0.064). The estimated RR of transcription errors was 0.74; 95% CI (0.59-0.92). The estimated RR of dosing calculation errors was 0.06; 95% CI (0.03-0.10). The estimated RR of chemotherapy frequency/duration errors was 0.51; 95% CI (0.42-0.62). CONCLUSIONS: Implementing standardized chemotherapy-prescribing templates significantly reduced all types of prescribing errors and improved chemotherapy safety.

Hematopoietic SCT for adult T-cell leukemia/lymphoma: a review.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus type 1. The aggressive forms of the disease carry a poor prognosis with standard therapies. The role of high-dose treatment with blood and marrow transplantation has, therefore, been examined mainly by Japanese groups in the form of retrospective studies. In this study, we review the literature, discuss some of the challenges facing successful transplantation approaches and stress the need for more innovative studies including in the Western hemisphere.

Making EmOC a reality--CARE's experiences in areas of high maternal mortality in Africa.

OBJECTIVE: This paper describes the package of interventions undertaken by the CARE/AMDD program collaboration to increase the availability and quality of emergency obstetric care for 3 high maternal mortality countries in Africa. METHODS: Project implementation over 4 years focused on enhancing the capacity of 10 district hospitals in 3 countries - Tanzania, Rwanda and Ethiopia. Interventions were designed to create functional health facilities with trained and competent staff, working in an enabling environment supporting EmOC service delivery. RESULTS: By keeping a clear focus on EmOC, the project achieved modest improvements in services, even in the face of the considerable constraints of rural district hospitals. Availability and utilization of EmOC increased in Tanzania; the met need for EmOC increased slightly from 14% in year 1 to 19% in year 4, while in Rwanda it increased from 16% to 25% over 4 years. Case fatality rates (CFR) declined by 30-50% in all 3 countries. While still well below UN recommendations, in all 3 countries there was also a progressive increase in the cesarean section rates, a life saving obstetric intervention. CONCLUSIONS: The increases in met need and decreases in case fatality suggest that project interventions improved the quality and use of EmOC, a critical component for saving women's lives.

Improving availability of EmOC services in Rwanda--CARE's experiences and lessons learned at Kabgayi Referral Hospital.

OBJECTIVE: CARE's work in Rwanda was designed to improve the functional capacity of health facilities for the delivery of EmOC services. METHODS: The project supported a comprehensive package of focused interventions that included hospital renovations, provision of essential equipment, training of staff and improvement of management systems at the Kabgayi regional referral hospital. RESULTS: There was an increased level of preparedness for emergencies and ability to manage common obstetric complications according to evidence-based practices. These changes ultimately led to increased availability, quality and use of services as demonstrated by an increase in the demand for care of obstetric complications at the facility. The met need increased from 16% at the start of the project (2001) to 25% in 2004, while the cesarean rate remained essentially the same (1.9% and 3.2%) over the same time period. There were progressive declines in the case fatality rates from 2.2% in 2001 to 1.2% in 2004. CONCLUSION: CARE's experience indicates that progress towards reducing maternal mortality requires specific efforts that support and strengthen existing health systems to provide skilled care that can save women's lives.

Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids.

Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).

Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones.

A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC(50) = 0.14 microM)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED(50) = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC(50) = 0.10 microM) which shows excellent in vivo efficacy (ED(50) = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4-(1, 1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED(20) = 100 mg/kg; selectivity: MAP ED(20)/bladder ED(50) = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.

Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-Cyanoguanidine bioisosteres possessing in vivo bladder selectivity.

A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vivo. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was studied in vitro using isolated rat detrusor strips. Potent relaxants were evaluated in vivo in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arterial blood pressure (MAP) and heart rate as a measure of in vivo bladder selectivity. (R)-4-[3,4-Dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile (79) met our potency and selectivity criteria and represents an attractive development candidate for the treatment of UUI. Electrophysiological studies using isolated rat bladder detrusor myocytes have demonstrated that compound 79 produces significant hyperpolarization which is glyburide-reversed, thus consistent with the activation of K(ATP). The design, synthesis, structure-activity relationships (SAR), and pharmacological activity associated with this series of novel KCOs will be discussed.

Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and In vivo bladder instability in rat.

The effects of the ATP-dependent potassium channel agonists ZD6169, celikalim, and WAY-133537 on bladder contractile function were examined in vitro on isolated bladder strips and in vivo on spontaneous bladder contractions. All three compounds produced a concentration-dependent relaxation of isolated rat detrusor strips (IC50 values = 0.93, 0.03, and 0.09 microM, respectively for ZD6169, celikalim, and WAY-133537. Contractile inhibition by all three compounds was fully reversed by 6 microM glyburide. These compounds also effectively inhibited spontaneous bladder contractions in the rat hypertrophied bladder model of detrusor instability. We also examined the electrophysiological properties of WAY-133537 on isolated rat bladder detrusor myocytes. Myocytes had an average resting membrane potential of -40 mV. Under patch current-clamp conditions, WAY-133537 (0.3 and 1.0 microM, n = 4-5) produced a significant hyperpolarization of 21 and 26 mV, respectively. Hyperpolarization was reversed by the addition of 5 microM glyburide. In patch voltage-clamp studies, WAY-133537 (0.3 microM, n = 3) significantly increased outward current in response to both voltage step and ramp protocols consistent with activation of the ATP-dependent potassium channel. In the detrusor instability model, WAY-133537 and celikalim had similar oral potencies (ED50 = 0.13 and 0.3 mg/kg, respectively), whereas ZD6169 was less potent (ED50 = 2.4 mg/kg). The antihypertensive agent celikalim exerted effects on the bladder at doses that significantly reduced systemic blood pressure. In contrast, both WAY-133537 and ZD6169 inhibited bladder hyperactivity at doses that produced minimal changes in both mean arterial blood pressure and heart rate. These data suggest that both WAY-133537 and ZD6169 may be useful in the treatment of bladder instability at doses associated with minimal hemodynamic side effects.

Novel approaches in development for the treatment of pancreatic cancer.

Pancreatic adenocarcinomas are among the most resistant neoplasms to conventional chemotherapeutics. This has prompted intense investigations of novel non-cytotoxic agents based on new understandings of the molecular pathobiology of human malignancies. This review will focus on the potential uses of three new classes of agents: farnesyl transferase (FTPase) inhibitors, matrix metalloproteinase inhibitors (MMPI's) and antibodies to the HER-2/neu oncogene. When used as single agents, FTPase inhibitors and MMPI's may be cytostatic, helping to delay the growth of these cancers. All three classes of agents may have the greatest benefit when used in conjunction with traditional anticancer modalities. The biology of these agents will reviewed.

Recognition of AIDS by health personnel in rural south-Rwanda.

The ability of rural health personnel to recognise AIDS related symptoms and signs according to the WHO clinical case definition (CCD) and its modified Rwandan version was tested in 4141 clinically suspected cases in South-Rwanda. The sensitivities of these CCDs for AIDS in adults were 33% (36%), the specificities 78% (76%), and the positive predictive values (ppv) 46%. For AIDS in children the sensitivities of the CCDs were 13% (16%), the specificities 94% (90%), and the ppv 44% (38%). While the specificities did not differ from those found in studies conducted by trained physicians, the low sensitivities and predictive values demand improvement of the training of the health personnel to diagnose AIDS related symptoms and signs, especially where laboratory tests are not available.

PIP: In order to test the ability of health care workers in rural Rwanda to recognize the signs and symptoms of AIDS according to the World Health Organization clinical case definition (CCD) and to the slightly modified Rwandan version, serum samples and completed questionnaires were collected from all 4141 clinically-suspected cases of AIDS from 62 rural health centers and hospitals in Butare province during 1991. Of the 3669 patients older than 12 years, 964 met the CCD for adults, and 444 were seropositive. 1040 met the modified Rwandan version of the CCD, and 482 were seropositive. Of the 472 children, 35 met the CCD for children, with 16 seropositive. 53 met the Rwandan CCD, and 20 of these were seropositive. Sensitivities of the CCD and the Rwandan CCD, respectively, were 33 and 36% in adults and 13 and 16% in children. The respective specificities were 78 and 76% in adults and 94 and 90% in children. The positive predictive values were, therefore, 46% in adults and 44 and 38%, respectively, in children. These low sensitivity and positive predictive values will result in many cases of AIDS going undiagnosed. Whereas no single symptom had a sensitivity and specificity high enough to be used for diagnoses, an episode of herpes zoster is highly indicative of AIDS. Since this diagnosis is unequivocal, this strong association may prove useful in the diagnosis of AIDS. Because laboratory tests will remain unavailable in certain settings, health personnel must receive proper training to improve their ability to diagnose AIDS following the clinical case definition.

HIV infection among STD patients--Kigali, Rwanda, 1988 to 1991.

To follow the progression of HIV seropositivity among heterosexual adults at risk for HIV infection in the country of Rwanda prospectively, up to 100 patients with sexually transmitted diseases (STD) were tested each month from 1988 to 1991 at the health centre of Biryogo, which is located in a very crowded sector of the capital city, Kigali. Each patient had a blood sample tested anonymously for the presence of HIV antibodies. HIV seropositivity was defined as a reactive ELISA test combined to a reactive Western blot test. The overall HIV seropositivity among the 2058 subjects tested was 61%. It was higher (73%) among the 688 women tested as compared to the 1362 men tested (55%; P < 0.001). The per cent HIV seropositivity did not increase between 1988 and 1991, neither among the male nor among the female clinic attenders. However, the per cent seropositivity was higher in the older age groups, especially among the males. This exceedingly high proportion of HIV-infected STD patients in Kigali re-emphasizes the urgent need to include STD treatment, prevention and control among the priority actions for decreasing HIV transmission in African towns. Also, as the per cent seropositivities did not show any trend to increase over the 4-year period considered, we propose that our intensive HIV serosurveillance strategy among STD patients in Kigali be modified, since the plateau of HIV infection appears to have been attained in this particular high-risk population.

Infective and anti-infective properties of breastmilk from HIV-1-infected women.

Human immunodeficiency virus type 1 (HIV-1) is transmitted mainly by cell-to-cell contact. We postulated that transmission of HIV-1 through breastmilk could be favoured by the presence of infected cells, by deficiency of anti-infective substances in breastmilk, or both factors. 215 HIV-1-infected women were enrolled at delivery in Kigali, Rwanda; milk samples were collected 15 days, 6 months, and 18 months post partum. HIV-1 IgG, secretory IgA, and IgM were assayed by western blot, for the latter two after removal of IgG with protein G. In the 15-day and 6-month samples, we sought viral genome in milk cells by a double polymerase chain reaction with three sets of primers (gag, pol, and env). HIV-1 infection in the offspring was defined according to serological and clinical criteria. At 15 days, 6 months, and 18 months post partum, HIV-1 specific IgG was detected in 95%, 98%, and 97% of breastmilk samples, IgA in 23%, 28%, and 41%, and IgM in 66%, 78%, and 41%. In children who survived longer than 18 months, the probability of infection was associated with lack of persistence of IgM and IgA in their mothers' milk (adjusted chi 2 for trend, p = 0.01 for IgM and p = 0.05 for IgA). The presence of HIV-1-infected cells in the milk 15 days post partum was strongly predictive of HIV-1 infection in the child, by both univariate (p < 0.05) and multivariate analysis (p = 0.01). The combination of HIV-1-infected cells in breastmilk and a defective IgM response was the strongest predictor of infection. HIV-1 infection in breastfed children born to infected mothers is associated with the presence of integrated viral DNA in the mothers' milk cells. IgM and IgA anti-HIV-1 in breastmilk may protect against postnatal transmission of the virus.

Synthesis and selective class III antiarrhythmic activity of novel N-heteroaralkyl-substituted 1-(aryloxy)-2-propanolamine and related propylamine derivatives.

The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None of these compounds showed any class I activity. On the basis of the in vitro data, structure-activity relationships for the series are discussed. Two compounds, N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino] propoxy]phenyl]methanesulfonamide (12,WAY-123,223) and N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl] amino]methyl]-6-quinolinyl]-methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo. Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv). The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen. Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).

Computer-assisted design and synthesis of novel aldose reductase inhibitors.

The design and synthesis of phenalene 26 (AY-31,358), an unsubstituted analogue of a tolrestat/ICI-105,552 computer-generated hybrid (7), are reported. Compound 7 was designed by the superimposition of the putative low-energy conformers of tolrestat (1) and ICI-105,552 (6). The more rigid aldose reductase inhibitor sorbinil (2) was used as a template to help discern a common pharmacophore in the three inhibitors. Compound 26 was synthesized as a model and was evaluated as an inhibitor of bovine lens aldose reductase. It was found to exhibit good in vitro activity as well as some in vivo activity in the nerve. It was expected that introduction of the trifluoromethyl and methoxy substituents would enhance the biological activity of model compound 26. As a result of a positive Ames test with 26, however, work has now been directed toward modifying the template in a way so as to eliminate the mutagenicity with retention of biological activity.