Community Family Therapy: A Model for Family and Community Problem Solving and Development in South America

This article has a twofold purpose. First, it discusses theoretical and practice developments in both family therapy that include community, and in social work that emphasize acceleration toward social and community developmental welfare, but which should include microsystemic interventions. The authors contend that ethical family therapy and social work practice should use multimodal strategies, and suggest that the community family therapy (CFT) model is useful in addressing gaps in theoretical developments. Second, because the CFT model has not yet been adopted in South Africa, this article discusses evaluations of the CFT model by 3 groups of students for the model to be adopted with full understanding. These student groups are the 2010 cohort of final-year social work undergraduate students and the 2010 and 2011 cohort of postgraduate social work students at the University of KwaZulu Natal, Durban, South Africa. The article presents readers with some understanding of the CFT model, how its teaching has evolved through a learner-centered pedagogy, the merits and demerits of the model, and preconditions that may facilitate adoption of the model.     

Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study

The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.     

Oral bioavailability and pharmacokinetics of PAT-5A, a new insulin sensitizer in rats.

Pharmacokinetics of PAT-5A (a new thiazolidinedione derivative), a potent insulin sensitizing and lipid-lowering compound was studied in rats. A single dose of 3, 10, 30 and 100 mg/kg PAT-5A was given orally to Wistar rats for investigating the dose linearity in pharmacokinetics. In another study, a single intravenous bolus dose of PAT-5A was given to rats at 10 mg/kg dose following administration through the tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and concentration of PAT-5A in plasma was determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v. dosing and subjected to noncompartment pharmacokinetic analysis to obtain the values for the parameters. Both Cmax and AUC0-infinity appeared to increase proportionally to the administered oral doses. While the doses increased in the ratio of 1.0:3.3:10.0:33.3, the mean Cmax and AUC0-infinity increased in the ratio of 1.0:3.3:8.0:16.7 and 1:4.4:12.0:32.1, respectively. The systemic clearance and volume of distribution of PAT-5A in rats were 83.1 mL/h and 177.1 mL respectively after i.v. administration. Plasma concentrations declined monoexponentially following oral as well as intravenous administration and terminal half-life was about 1.4 h. There was no significant change in half-life with increase in oral doses. Absolute oral bioavailability of PAT-5A across the doses tested was in the range of 73-100% and this indicates that PAT-5A is neither a candidate for pre-systemic metabolism nor prone to absorption-related issues.     

Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential

Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.     

Impact of cremophor-EL and polysorbate-80 on digoxin permeability across rat jejunum: delineation of thermodynamic and transporter related events using the reciprocal permeability approach

The effect of Cremophor-EL (Cr-EL) and polysorbate-80 (PS-80) on the transepithelial permeability of digoxin (DIG) has been evaluated using the reciprocal permeability approach to delineate thermodynamic and transporter related events. Permeability data were corrected for solubilization using the micellar association constant (Ka) obtained from Papp data generated in the presence of the nonspecific ATPase inhibitor sodium orthovanadate. In the presence of mucosal Cr-EL, a concentration dependent decrease in serosal-mucosal (S-M) and increase in M-S transport was observed. Whilst serosal Cr-EL resulted in a reduction in S-M DIG transport, no impact on M-S transport was apparent. For PS-80, the presence of either serosal or mucosal surfactant led to a decrease in secretory (S-M) DIG transport, however no effect on absorptive transport was evident. The data confirm the potential P-gp inhibitory effects of Cr-EL, but suggest that in contrast to Cr-EL, PS-80 is not a potent inhibitor of P-gp and is incapable of increasing absorptive drug transport, at least in excised rat intestinal tissue and at the concentrations tested. The data are also consistent with the involvement of additional transporters (both apical and basolateral) in the intestinal permeability of DIG, although more definitive data is required to confirm this possibility.     

Lack of effect of sucralfate on the absorption and pharmacokinetics of rosiglitazone

The aim of the present study was to investigate the effect of sucralfate pretreatment on the pharmacokinetics of rosiglitazone following a single oral dose in healthy male volunteers. After an over night fast, and according to a randomized schedule, each volunteer (n = 9) received a single oral dose of rosiglitazone 8 mg (Avandia tablets, 4 mg x 2) with or without pretreatment of sucralfate 2 g (Recolfate tablets, 1 g x 2) in an open-label crossover study with a 2-week washout period. Plasma samples were collected over a period of 24 hours at regular intervals. Safety assessment included monitoring of the vital signs, blood parameters, and ECG. No statistically significant differences (p > 0.05) were observed for any of the calculated rosiglitazone pharmacokinetic parameters in the two treatment groups. The mean parameters, AUC0-infinity and Cmax, following rosiglitazone administration alone were 3825.02 ng x h/ml and 664.47 ng/ml, respectively, and for rosiglitazone administered after pretreatment with sucralfate were 4848.19 ng x h/ml and 624.88 ng/ml, respectively. The t(max) for rosiglitazone alone and for rosiglitazone after sucralfate treatments was 1.11 and 1.67 hours, respectively. The mean elimination half-life for rosiglitazone and rosiglitazone after sucralfate treatment was 4.35 and 4.51 hours, respectively. Fraction of rosiglitazone absorbed was calculated by the Wagner-Nelson method, and no statistically significant difference (p > 0.05) was observed for the two treatments. Since sucralfate pretreatment did not show any significant difference in the pharmacokinetics of rosiglitazone, no dose adjustment is warranted for rosiglitazone when it is administered with sucralfate.     

Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in rats

This study demonstrates the utility of an in vitro - in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX(2) inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX(2) selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10-100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78-96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.     

Use of plasma proteins as solubilizing agents in in vitro permeability experiments: correction for unbound drug concentration using the reciprocal permeability approach

The purpose of the present study was to explore the applicability of the reciprocal permeability approach to correct for changes in thermodynamic activity when in vitro permeability data are generated in the presence of plasma proteins. Diazepam (DIA), digoxin (DIG), and propranolol (PRO) permeability was assessed in the presence of bovine serum albumin (BSA) and bovine alpha-1-acid glycoprotein (AAG). The reciprocal permeability approach was subsequently employed to calculate the true permeability coefficient (Papp(corr)) and the operational protein association constant (nK(a)). For BSA binding, good agreement was observed between the Papp(corr) values and Papp values obtained in the absence of protein. For PRO and AAG, where binding affinity was high, deviation in the reciprocal permeability plots was evident suggesting ligand depletion at low drug/high protein concentrations. Bidirectional DIG permeability data in the presence of either BSA or AAG indicated that neither protein had an effect on the efflux transporters involved in DIG permeability. The data suggest that plasma proteins can be utilized in permeability experiments with no adverse effects on transporter function and that the reciprocal permeability approach can be used to correct permeability data for changes in unbound drug concentration.     

Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones.

A series of substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARgamma by 5a/5a maleate did not show any significant transactivation of PPARalpha or PPARgamma.     

Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management

Central venous catheter-related blood stream infection (CRBSI) is a major cause of morbidity and mortality in patients with end-stage renal disease treated with chronic hemodialysis. Risk factors include Staphylococcus aureus nasal colonization, longer duration of catheter use, previous bacteremia, older age, higher total intravenous iron dose, lower hemoglobin and serum albumin levels, diabetes mellitus and recent hospitalization. Symptoms that raise clinical suspicion of bacteremia in chronic hemodialysis patients are fevers and chills. When CRBSI is suspected, blood cultures should be obtained and empirical therapy with broad spectrum intravenous antibiotics initiated. The diagnosis of CRBSI is confirmed by isolation of the same microorganism from quantitative cultures of both the catheter and the peripheral blood of a patient that has clinical features of infection without any other apparent source. Gram-positive cocci, predominantly S. epidermidis and S. aureus, cause bacteremia in two-thirds of cases. Among the various approaches to management of CRBSI, removal and delayed replacement of the catheter, catheter exchange over a guidewire in selected patients, and the use of antimicrobial/citrate lock solutions have all been found to be promising for treatment and/or prevention; however, resolution of issues regarding selection, dose, duration and emergence of antibiotic-resistant organisms with chronic use of antibiotic lock solutions, as well as the safety of long-term use of trisodium citrate lock solutions, await further randomized, multicenter trials involving larger samples of hemodialysis patients.