Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity.

BACKGROUND: Although the use of highly active antiretroviral therapy in the treatment of HIV infection has led to considerable improvement in morbidity and mortality, unless patients are adherent to their drug regimen (i.e., at least 90 to 95% of doses taken), viral replication may ensue and drug-resistant strains of the virus may emerge. METHODS: The authors studied the extent to which neuropsychological compromise and medication regimen complexity are predictive of poor adherence in a convenience sample of 137 HIV-infected adults. Medication adherence was tracked through the use of electronic monitoring technology (MEMS caps). RESULTS: Two-way analysis of variance revealed that neurocognitive compromise as well as complex medication regimens were associated with significantly lower adherence rates. Cognitively compromised participants on more complex regimens had the greatest difficulty with adherence. Deficits in executive function, memory, and attention were associated with poor adherence. Logistic regression analysis demonstrated that neuropsychological compromise was associated with a 2.3 times greater risk of adherence failure. Older age (>50 years) was also found to be associated with significantly better adherence. CONCLUSIONS: HIV-infected adults with significant neurocognitive compromise are at risk for poor medication adherence, particularly if they have been prescribed a complex dosing regimen. As such, simpler dosing schedules for more cognitively impaired patients might improve adherence.

[Intermediate doses of cytosine arabinoside in the treatment of acute non-lymphoblastic leukaemia in children]. / Sredniowysokie dawki arabinozydu cytozyny w leczeniu dzieci z ostra bialaczka nielimfoblastyczna.

Between 1995-1997, at 7 centres of the Polish Paediatric Leukaemia/Lymphoma Study Group (PPLLSG) treatment was started in 102 children with acute non-lymphoblastic leukaemia. Sixty-two children treated according to the new protocol adjusted for risk factors were evaluated. Thirty-one patients belonged to standard risk and 23 to high risk group. Eight children were not evaluated due to early death. Out of 62 children, 44 (70,9%) achieved remission; in standard and high risk groups the rates of remission were 87,5% and 73%, respectively. Four-year event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS) probability in all patients were: 40,2%, 42% and 59% respectively, in standard risk group: 49,5%, 52,5%, 59,1%; in high risk group: 42%, 43,4% and 57,8%. In comparison with the previous period (1983-1994) EFS increased from 30% to 42%, which was statistically insignificant.

[Adverse reactions associated with the use of L-asparaginase during therapy of patients with nB non-Hodgkin's lymphoma. Report of the Polish Paediatric LeuKaemia/Lymphoma Study Group]. / Objawy niepozadane leczenia preparatami L-asparaginazy u chorych z nieziarniczym chloniakiem zlosliwym typu NB w oparciu o material Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków Zlosliwych u dzieci.

The aim of the study was to determine the side effects of asparaginase administration during treatment protocol for childhood non-Hodgkin's lymphoma (NHL). Drug adverse reactions occurred in 20/66 of patients (30,3%) treated in 9 centres in Poland between 1993 and 1998. The most common side effects were coagulation disturbances in 12/66 of the children (18,2%), which occurred due to reduced production of important coagulation factors. Six patients (9,1%) developed impairment of liver function (9,1%). Drug toxicity caused the modifications of treatment protocol in 12/66 (18,2%) of patients, mainly in the induction phase; 3 children died due to relapse of disease.

[Results of the treatment of myelodysplastic syndrome (MDS)obtained by the Polish Paediatric Leukaemia /Lymphoma Study Group]. / Wyniki leczenia zespolów mielodysplastycznych (MDS) uzyskane przez Polska Pediatryczna Grupe ds Leczenia Bialaczek i Chloniaków u dzieci.

Sixty children with MDS treated in six centres of the Polish Paediatric Leukaemia/Lymphoma Study Group in the period 1975-1999 were included in the study. In 20 children RAEB-T, in 13 RA, in 21 RAEB and in 6 CMML were diagnosed. Our own and literature data showed that BMT is the best therapy for children with MDS. We need a new comprehensive protocol for the diagnosis and treatment of children with MDS in Poland.

[Abdominal presentation of B-cell non-Hodgkin's lymphoma (B-NHL) - surgical treatment and its results. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Manifestacja brzuszna chloniaka B-komórkowego u dzieci - interwencja chirurgiczna i wyniki leczenia. Raport PPGLBC.

The aim of this study was to analyse the effect of LMB-89 protocol and surgical procedure at initial laparotomy on the outcome in children with abdominal B-cell NHL. The initial surgery intervention was: complete resection (20% pts), subtotal resection (20%), partial resection (4%), biopsy (36%). Postoperative complications occurred in 5 children. Complete recovery (CR) was achieved in 92% pts. There were 4% non responder patients. Two patients died before CR evaluation (tumour lysis syndrome; bleeding and multi organ failure after initial surgery). One patient died in CCR from sepsis probably influenced by the previous local operation. 10.8% patients relapsed. The estimate EFS for all patients with AB-NHL is 81%, 85% for stage III and 73% for stage IV. Major surgery in advanced stages is not recommended since it delays chemotherapy and fails to improve overall survival.

[G-CSF and GM-CSF in treatment of neutropaenia after chemotherapy in children with neoplasms]. / G-CSF i GM-CSF w leczeniu neutropenii po chemioterapii nowotworów u dzieci.

A total number of 608 cycles of G-CSF and/or GM-CSF was applied in 280 patients aged from 6 months to 20 years during neutropaenia associated with chemotherapy of children's neoplasms (NHL-124, NBL-42, RMS-36, Nephroblastoma-18, Osteosarcoma-17, Ewing's Sarcoma-14, Hepatoblastoma-6, Neurofibrosarcoma-6, PNET-5, Medulloblastoma-3, Fibrohistiocytoma-3, Angiosarcoma-2, other - 4). G-CSF - Neupogen (Filgastrim, Hoffman La Roche - 492 cycles) and GM-CSF - Leucomax (Molgramostim, Shering Plough - 116 cycles) were administered 5 mg/kg/day s.c. Forty one children with malignancies (NHL -21 cases, solid tumours -17) treated before cytokines were in use served as a control group. Our study demonstrated that G-CSF and GM-CSF therapy, gives a shorter period of neutropaenia, reduction of the number of febrile days, decreased frequency of infection and shortened its duration.

A new class of selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

[The analysis of failures in the treatment of children with non-B non-Hodgkin's lymphoma. Polish pediatric leukemia/lymphoma study group report]. / Analiza niepowodzen w leczeniu dzieci z nieziarniczym chloniakiem zlosliwym typu NB. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków zlosliwych u dzieci.

The aim of the study was to evaluate the results of treatment of 46 children with non B non-Hodgkin's Lymphoma registered in 7 centers of Polish Paediatric Leukaemia/Lymphoma Study Group from 1993 to 1998. The patients were treated according to BFM-90 protocol based on German regimen. The overall probability of event-free survival for the all children after 4 years of follow-up was 71%, for patients in stage III--65%, stage IV--70%. The achieved results were not as positive as in the BFM Study Group, what was related to: the great number of children with advanced stage of disease (54.3%), the late final diagnosis, the great number of recurrences (22.5%) and deaths caused by the toxicity of medication (6.5%) (infections, drug toxicity).

[The efficacy of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of solid tumors in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie guzów litych u dzieci. Raport PPG/LBC.

Total number of 306 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 146 children aged from 0.5-18 years during neutropenia associated with chemotherapy of solid tumours. Seventeen children with malignancies served as a historical control group. Our study have demonstrated after both G- and GM-CSF therapy shorter period of neutropenia, reduction of the number of febrile days and a decreased frequency of infectious complications and infection's duration.

[The effectiveness of G-CSF and GM-CSF in the adjunctive treatment of infections complicating chemotherapy of non-Hodgkin's lymphoma in children. Report of Polish Pediatric Leukemia/Lymphoma Treatment Group]. / Skutecznosc G-CSF i GM-CSF w leczeniu wspomagajacym zakazen wiklajacych chemioterapie nieziarniczych chloniaków zlosliwych u dzieci. Raport PPG/LBC.

Total number of 252 cycles of GM-CSF-Leucomax Sandoz (5 mg/kg/day s.c.) and/or G-CSF Filgrastim Hoffmann-La Roche (5-10 mg/kg/day s.c.) was applied in 124 children aged from 0.5-20 years during neutropenia associated with chemotherapy of non-Hodgkin's lymphoma (NHL). Twenty four children with NHL treated according to the same chemotherapy protocol but without G-CSF and GM-CSF served as a control group. Our study have demonstrated the good efficacy of both G-CSF and GM-CSF therapy. They shortened the period of neutropenia, reduced the number of febrile days, infection's duration and decreased the frequency of infectious complications.

Novel antagonists of platelet-activating factor. 2. Synthesis and structure-activity relationships of potent and long-acting heterofused [1,5]benzodiazepine and [1,4]diazepine derivatives of 2-methyl-1-phenylimidazo[4,5-c]pyridine.

The optimization of in vitro activity and oral potency and duration of action in vivo is described for three novel structural types of platelet-activating factor (PAF) antagonist: [1,5]benzodiazepines 5-12 onto which a variety of other heterocyclic rings were fused, pyrido[2,3-b][1,4]-diazepinones 13-26, and pyrazolo[3,4-b][1,4]diazepinones 27-46. Compounds 5-12 were prepared by elaboration of the [1,5]benzodiazepine-2-thiones 47 and 48, and 13-46 were prepared by cyclocondensation reactions of a variety of 2,3-diaminopyridine and 4,5-diaminopyrazole derivatives with ethyl 4'-(2-methylimidazo[4,5-c] pyrid-1-yl)benzoylacetate (53). The presence of imine-enamine tautomerism was observed in certain diazepine derivatives and is discussed. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. In addition, the duration of action in conscious dogs as measured by determining the oral dose of selected compounds required to inhibit completely PAF-induced whole blood aggregation ex vivo. The most potent compound was 1,6,7,8-tetrahydro-1,8-dimethyl-5-[4-(2-methylimidazo [4,5-c]pyrid-1-yl)phenyl]-7-oxo-3-(3-pyridyl) pyrazolo[3,4-b][1,4]diazepine (43, UK-91,473) (IC50 = 2.4 nM, ED50 = 0.01 mg/kg po), which was found to be significantly more potent in vivo (murine lethality) than the dihydropyridine PAF antagonist 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl- 4-[(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5- [N-(2-pyridyl)carbamoyl]pyridine (4, UK-74,505) (ED50 = 0.26 mg/kg po). Compound 43 also possessed a longer duration of action than compound 4 in the conscious dog at one-fourth of the dose. The crystal structure of compound 43, established by X-ray diffraction, is reported.

2(1H)-quinolinones with cardiac stimulant activity. 3. Synthesis and biological properties of 6-imidazol-1-yl derivatives.

A series of 6-imidazol-1-yl-8-methyl-2(1H)-quinolinones was synthesized and evaluated for cardiac stimulant activity in dogs. The majority of compounds were prepared from an appropriate 6-imidazol-1-yl-2(1H)-quinolinone precursor or by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide. Introduction of a range of 5-substituents into 6-(2,4-dimethylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (1) reduced inotropic activity in anesthetized dogs (percentage increase in dP/dtmax) although replacement of the 2-methyl group by iodo (10) or cyano (11) substituents was well tolerated. The 2-methyl-4-chloro (15) and 2-methyl-4-(methylthio) (22) derivatives displayed similar potency to 1 (40-50% increase in dP/dtmax, 10-12.5 micrograms/kg) and these compounds were 3-5 times more potent than milrinone. Introduction of iodo (14), cyano (16), or acetyl (17) substituents into the 4-position approximately halved inotropic activity. In conscious dogs, 11 (0.25 mg/kg) and 16 and 17 (0.125 mg/kg) produced similar increases in cardiac contractility (decrease in the QA interval) to 1 (0.125 mg/kg) and maximum responses were maintained for at least 3 h. Dose-related (25, 125, 250 micrograms/kg) cardiac stimulant activity was demonstrated by 17 and after the higher doses a marked response (approximately 30% increase in dP/dtmax) was still observed after 7 h, in contrast to milrinone. The substantial increases in cardiac contractility observed with 16 and 17 in the conscious dog were not accompanied by any tachycardia. These compounds also displayed an overwhelming selectivity for increasing the force of cardiac contraction (greater than 120% increase in dP/dtmax) rather than heart rate (5-10 beats/min decrease) in the Starling heart-lung preparation. As a result of this beneficial pharmacological profile, 6-(4-acetyl-2-methylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (17, UK-66,838) was selected for preclinical development studies.

2(1H)-quinolinones with cardiac stimulant activity. 2. Synthesis and biological activities of 6-(N-linked, five-membered heteroaryl) derivatives.

A series of 6-(N-linked, five-membered heteroaryl)-2(1H)-quinolinone derivatives was synthesized and evaluated for cardiotonic activity. Most compounds were prepared by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide or by condensation of a 2-amino-5-heteroarylbenzaldehyde or -acetophenone derivative with the ylide derived from triethyl phosphonoacetate. In anesthetized dogs, 6-imidazol-1-yl-8-methyl-2(1H)-quinolinone (3; 25 micrograms/kg) produced a greater increase in cardiac contractility (percentage increase in dP/dt max) than alternative 6-(five-membered heteroaryl)-substituted analogues (4-8). Introduction of 4-methyl (10) or 2,4-dimethyl (13) substituents into the imidazole ring of 3 produced a marked increase in inotropic activity, and these compounds were some 10 and 5 times more potent than milrinone. Most of these quinolinones also displayed positive inotropic effects (decrease in QA interval) in conscious dogs after oral administration (0.0625-1 mg/kg) and in many cases (3, 5-7, 9, 11, 13, 16) there was little difference in activities at both the 1- and 3-h time points. Compound 13 (62.5, 125, 250 micrograms/kg po) demonstrated dose-related cardiac stimulant activity which, in contrast to milrinone, was maintained over the whole 7-h test period. No changes in heart rate were detected at any dose level and compounds 3, 9, 10, and 13 also displayed high selectivity for the stimulation of cardiac contractile force rather than heart rate in the Starling dog heart-lung preparation. Increases in dP/dt max of approximately 50% were accompanied by heart rate changes of less than 10 beats/minute. Physicochemical measurements gave a log P of 1.64 for 13 with pKa values of 7.13 +/- 0.04 and 11.5 +/- 0.2 for the imidazole and quinolinone moieties, respectively. X-ray structural analysis of 13 showed the imidazole and quinolinone rings at 52 degrees to one another in close agreement with the minimum-energy conformation (30 degrees) suggested by PCILO calculations. 6-(2,4-Dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolinone (13, UK-61,260) is currently undergoing phase II clinical evaluation in congestive heart failure patients.

2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives.

A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones (1) was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolysis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 micrograms/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers (2, 4-6), and potency was maintained with either mono- (13, 15) or di- (16) alkylpyridinyl substituents. Introduction of a 4- (24) or 7- (25) methyl group into 3 reduced inotropic activity, whereas the 8-isomer (26) proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27) were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 X 10(-7) to 5 X 10(-4) M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.

Comparative physiology of rodent pulmonary macrophages: in vitro functional responses.

Since toxicological testing of inhaled materials frequently requires utilization of several species, we have investigated pulmonary macrophage (PM) functional responses and compared the rat model with other rodents. Two strains of rats, three strains of mice, and one strain each of hamster and guinea pig were used in this study. The numbers of recovered cells by bronchoalveolar lavage generally correlated with animal body weight. The one exception was the Syrian Golden hamster from which increased numbers of macrophages were recovered. Cellular differential data obtained from lavaged cytocentrifuge preparations demonstrated that PM's account for greater than 97% of recoverable free lung cells for all species except the guinea pig, which contains a resident population of eosinophils. Cell morphology studies indicated that hamster PM exhibited the highest proportion of ruffled PM and demonstrated the highest phagocytic activity, whereas mouse PM phagocytic activity was significantly reduced compared with the other three species. In addition, chemotaxis studies showed that rat PM migrated best to zymosan-activated, complement-dependent chemoattractants, whereas hamster PM demonstrated an enhanced chemotactic response to N-formyl peptides. The results of these studies suggest that the rat may be the most efficient species for clearing inhaled particles, whereas hamsters and guinea pigs may best respond to bacteria.