Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons.
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The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response. (+info)
Polypharmacy in general practice: differences between practitioners.
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BACKGROUND: Polypharmacy, the simultaneous use of multiple drugs, is associated with adverse drug reactions, medication errors, and increased risk of hospitalization. When the number of concurrently used drugs totals five or more (major polypharmacy), a significant risk may be present. AIM: To analyse the interpractice variation in the prevalence of major polypharmacy among listed patients, and to identify possible predictors of major polypharmacy related to the practice. METHOD: Prescription data were retrieved from the Odense Pharmacoepidemiological Database, and individuals subject to major polypharmacy were identified. The age- and sex-standardized prevalence rate of major polypharmacy was calculated for each practice in the County of Funen in Denmark (n = 173), using the distribution of age and sex of the background population as a reference. The practice characteristics were retrieved from the Regional Health Insurance System. Possible predictors of major polypharmacy related to the general practitioners (GPs) were analysed using backward stepwise linear multiple regression. RESULTS: A six-fold variation between the practices in the prevalence of major polypharmacy was found (16 to 96 per 1000 listed patients; median = 42). Predictors related to the practice structure, workload, clinical work profile, and prescribing profile could explain 56% of the variation. CONCLUSION: A substantial part of the variation in major polypharmacy between practices can be explained by predictors related to practice. (+info)
Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice.
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Phosphorylation of tyrosine residues on the epidermal growth factor (EGF) receptor (EGFr) is an important early event in signal transduction, leading to cell replication for major human carcinomas. CP-358,774 is a potent and selective inhibitor of the EGFr tyrosine kinase and produces selective inhibition of EGF-mediated tumor cell mitogenesis. To assess the pharmacodynamic aspects of EGFr inhibition, we devised an ex vivo enzyme-linked immunosorbent assay for quantification of EGFr-specific tyrosine phosphorylation in human tumor tissue specimens obtained from xenografts growing s.c. in athymic mice. When coupled with pharmacokinetic analyses, this measurement can be used to describe the extent and duration of kinase inhibition in vivo. CP-358,774 is an effective, orally active inhibitor of EGFr-specific tyrosine phosphorylation (ED(50) = 10 mg/kg, single dose). It has a significant duration of action, producing, on average, a 70% reduction in EGFr-associated phosphotyrosine over a 24-h period after a single 100 mg/kg dose. Inhibition of EGFr phosphotyrosine in an ex vivo assay format effectively estimates the potency and degree of inhibition of EGFr-dependent human LICR-LON-HN5 head and neck carcinoma tumor growth. Substantial growth inhibition of human tumor xenografts was achieved with p.o. doses of the compound (ED(50) = 10 mg/kg q.d. for 20 days). Combination chemotherapy with cisplatin produced a significant response above that of cisplatin alone with no detectable effects on body weight or lethal toxicity. Taken together, these observations suggest that CP-358,774 may be useful for the treatment of EGFr-driven human carcinomas. (+info)
Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.
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The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity. (+info)
Polypharmacy management in Medicare managed care: changes in prescribing by primary care physicians resulting from a program promoting medication reviews.
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OBJECTIVE: To examine the effects of medication reviews by primary care physicians on prescriptions written for elderly members of a Medicare managed care organization who were at risk for polypharmacy. STUDY DESIGN: Prospective study with follow-up survey. PATIENTS AND METHODS: We conducted a study in 1995 to demonstrate the prevalence of polypharmacy (defined as receiving 5 or more prescription medications during the 3-month study period) among elderly members of our managed care organization. Two years later, elderly members identified as being at risk for polypharmacy were sent a letter encouraging them to schedule a medication review with their primary care physician. Each primary care physician was provided with clinical practice guidelines on polypharmacy and patient-specific medication management reports. Patients and physicians were subsequently mailed a survey to assess the impact of the medication review program on prescribing practices. RESULTS: Of 37,372 elderly members screened, 5737 (15%) were at risk for polypharmacy. Of these, 2615 (46%) responded to the follow-up survey. Of the survey respondents, 1087 (42%) had gone to their primary care physician for a medication review. During the review, 96% of patients discussed their prescription medications and 72% discussed nonprescription medications they were taking. Twenty percent reported that their physician discontinued medications, 29% reported that the physician changed the dose of a medication, and 17% informed their physician about a new prescription or nonprescription medication they were taking. Of the 275 primary care physicians surveyed, 56 (20%) returned the questionnaire. Of these, 61% reported that the medication review program was "very" or "somewhat useful." Thirty-five percent reported discontinuing unnecessary medications, and 23% reported decreasing the frequency of dosing. Overall, 45% of physicians reported making at least one change in their prescribing to a member at risk for polypharmacy. CONCLUSIONS: Our program promoting medication reviews between primary care physicians and their elderly patients resulted in significant changes in prescribing by physicians. This type of program is likely to decrease the risk of polypharmacy among older members of a Medicare managed care organization. (+info)
Drug interactions and the statins.
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Drug interactions commonly occur in patients receiving treatment with multiple medications. Most interactions remain unrecognized because drugs, in general, have a wide margin of safety or because the extent of change in drug levels is small when compared with the variation normally seen in clinical therapy. All drug interactions have a pharmacokinetic or pharmacodynamic basis and are predictable given an understanding of the pharmacology of the drugs involved. Drugs most liable to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose-response curves; those having high first-pass metabolism or those with a single, inhibitable route of elimination. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interactions that can occur with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs. (+info)
Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels.
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Gabapentin has been administered in placebo-controlled studies with a thrice daily (T.I.D.) schedule, because of its short half-life. However, clinical efficacy does not seem strictly related to plasma levels: a twice daily (B.I.D.) schedule might therefore be possible. The aim of our study was to verify if the conversion from a T.I.D. to a B.I.D. regimen affected the efficacy and safety of gabapentin therapy. Out of 171 patients treated with add-on gabapentin, we selected 29 stable responders, who were followed for three months with a T.I.D. schedule and then switched to B.I.D. regimen for further three months. Seizure number, side-effects and trough plasma levels of gabapentin were collected during both periods. Gabapentin mean dose was 2117.2 mg/day. Mean number of seizures/months was: 4.2 at baseline, 1.0 during the T.I.D., and 0.9 during the B.I.D. period. Mean trough plasma level of gabapentin was 5.9 microgram/ml during the T.I.D. and 5.2 microgram/ml during the B.I.D. period. Twelve side-effects were reported by 11 patients during the T.I.D. and 6 by 5 patients during the B.I.D. period., sedation and vertigo were the most frequent in both. Results of our study suggest that gabapentin can be administered safely and effectively either with a T.I.D. and a B.I.D. regimen. (+info)
Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine.
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AIMS: To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR-related excess hospital stay in medical inpatients. METHODS: Structured data regarding patient characteristics, 'events' (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer-supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by 'event monitoring' to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. RESULTS: The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease-unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR-related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR-related excess hospital stay accounted for 8. 6% of hospital days. CONCLUSIONS: These data demonstrate the feasibility of the developed 'event monitoring' system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients. (+info)