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Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and scleroderma are immunologically mediated disorders that typically have multisystem involvement. Although clinically significant liver involvement is rare, liver enzyme abnormalities may be observed in up to 43% of patients. The biochemical abnormalities are typically mild and transient and the histologic abnormalities are usually nonprogressive. Such biochemical and histologic findings are typically ascribed to the primary rheumatologic condition and require no specific management. In a subset of patients with rheumatologic conditions and liver test abnormalities, further evaluation identifies a coexisting, primary liver disease or medication-related liver toxicity as the cause of the biochemical abnormality. Liver test abnormalities in patients with a coexisting primary liver disease are more likely to be persistent. In such cases, further workup using serologic tests, appropriate imaging studies and liver biopsy may be needed to accurately identify the cause of liver test abnormalities. This article reviews the spectrum of liver-related abnormalities associated with several rheumatologic diseases. Hepatotoxicity related to medications commonly prescribed in such conditions is also discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Although community pharmacists have historically been paid primarily for drug distribution and dispensing services, medication therapy management (MTM) services evolved in the 1990s as a means for pharmacists and other providers to assist physicians and patients in managing clinical, service, and cost outcomes of drug therapy. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA 2003) and the subsequent implementation of Medicare Part D in January 2006 for the more than 20 million Medicare beneficiaries enrolled in the Part D benefit formalized MTM services for a subset of high-cost patients. Although Medicare Part D has provided a new opportunity for defining the value of pharmacist-provided MTM services in the health care system, few publications exist which quantify changes in the provision of pharmacist-provided MTM services over time., Objectives: To (a) describe the changes over a 7-year period in the primary types of MTM services provided by community pharmacies that have contracted with drug plan sponsors through an MTM administrative services company, and (b) quantify potential MTM-related cost savings based on pharmacists' self-assessments of the likely effects of their interventions on health care utilization., Methods: Medication therapy management claims from a multistate MTM administrative services company were analyzed over the 7-year period from January 1, 2000, through December 31, 2006. Data extracted from each MTM claim included patient demographics (e.g., age and gender), the drug and type that triggered the intervention (e.g., drug therapeutic class and therapy type as either acute, intermittent, or chronic), and specific information about the service provided (e.g., Reason, Action, Result, and Estimated Cost Avoidance [ECA]). ECA values are derived from average national health care utilization costs, which are applied to pharmacist self-assessment of the "reasonable and foreseeable" outcome of the intervention. ECA values are updated annually for medical care inflation., Results: From a database of nearly 100,000 MTM claims, a convenience sample of 50 plan sponsors was selected. After exclusion of claims with missing or potentially duplicate data, there were 76,148 claims for 23,798 patients from community pharmacy MTM providers in 47 states. Over the 7-year period from January 1, 2000, through December 31, 2006, the mean ([SD] median) pharmacy reimbursement was $8.44 ([$5.19] $7.00) per MTM service, and the mean ([SD] median) ECA was $93.78 ([$1,022.23] $5.00). During the 7-year period, pharmacist provided MTM interventions changed from primarily education and monitoring for new or changed prescription therapies to prescriber consultations regarding cost-efficacy management (Pearson chi-square P<0.001). Services also shifted from claims involving acute medications (e.g. penicillin antibiotics, macrolide antibiotics, and narcotic analgesics) to services involving chronic medications (e.g., lipid lowering agents, angiotensin-converting enzyme [ACE] inhibitors, and beta-blockers; P<0.001), resulting in significant changes in the therapeutic classes associated with MTM claims and an increase in the proportion of older patients served (P<0.001). These trends resulted in higher pharmacy reimbursements and greater ECA per claim over time (P<0.001)., Conclusion: MTM interventions over a 7-year period evolved from primarily the provision of patient education involving acute medications towards consultation-type services for chronic medications. These changes were associated with increases in reimbursement amounts and pharmacist-estimated cost savings. It is uncertain if this shift in service type is a result of clinical need, documentation requirements, or reimbursement opportunities.

Study Objective: To assess the effectiveness of a community pharmacist-delivered cardiovascular case-management program by comparing body mass index (weight), systolic and diastolic blood pressure, and full lipid profile at the beginning of the program with these outcome measures at the end of the program., Design: Retrospective data analysis using billing data submitted between July 1, 2001, and October 31, 2004, with a pre-post design in which subjects served as their own controls., Setting: Manufacturing workplace in rural Iowa., Participants: Fifty-six workers with risk factors for cardiovascular disease (mean age 40.67 yrs), 37 had diabetes mellitus and 19 did not., Intervention: During visits to the workers, pharmacists provided education about cardiovascular disease, identification of drug therapy problems, and importance of routine blood pressure, pulse, and weight measurements; they communicated with participants' physicians as needed., Measurements and Main Results: The number of pharmacist visits/participant ranged from 1-13 (mean +/- SD 6.97 +/- 3.05). Outcome measures were weight, systolic and diastolic blood pressures, full lipid profiles (in patients with diabetes), and percentage of patients achieving treatment goal by the end of the 3 years. Statistically significant differences between the first and last visits were achieved for both systolic (124.12 +/- 11.07 and 120.36 +/- 14.39 mm Hg, respectively, p=0.016) and diastolic (80.4 +/- 9.01 and 77.43 +/- 9.14 mm Hg, respectively, p=0.019) blood pressure. The 19 patients without diabetes showed a statistically significant improvement in diastolic blood pressure (p=0.039), but the 37 patients with diabetes did not show a significant difference. A nonsignificant increase was seen in the percentage of patients with diabetes achieving low-density lipoprotein cholesterol (LDL) level goal between the first and last visits (p=0.06)., Conclusion: A cardiovascular case-management program delivered in the workplace to middle-aged working adults by community pharmacists improved blood pressure and reduced LDL levels. The program was not effective, however, in weight reduction.

Objectives: (1) Describe the structure of an outcomes-based method of pharmacist reimbursement for cognitive services, (2) outline the structure of an intervention program, (3) explain a mechanism to increase the provision of pharmacists. cognitive services, and (4) summarize findings from the first year of operations of this outcomes-based pharmacist reimbursement program (OBPR)., Methods: A cross-sectional descriptive study was completed using the claims submitted by pharmacists to summarize findings from the first year of operations of this OBPR. The program involves collaboration between pharmacy benefit managers (PBMs) and community pharmacists to improve medication use. Pharmacists were reimbursed for (1) converting therapeutic regimens to generic drugs or preferred formulary medications when a prescriber contact is required; (2) conducting patient education and follow-up after initiation of new medications, changes in drug therapy, or following an over-the-counter (OTC) consultation; and (3) resolving drug-therapy problems. An efficient, no-cost billing system was created. Pharmacies participating in this program are located in cities throughout Iowa, ranging in population from a few hundred to more than 100,000. The main outcome measures were descriptive statistics of prescriptions, intervention claims, and pharmacist participation in the program. Frequency distributions and descriptive statistics were used to summarize the first year of claims. Comparisons of averages were completed with t tests. Chi-square tests were used to compare frequency distributions., Results: Data analysis for the first year of operation, July 1, 2000, through June 30, 2001, showed that 11,326 enrollees obtained 124,768 prescriptions. The majority of individuals (n=8335, 74%) received some intervention service. The majority (90%) of intervention services were patient education and follow-up on new prescriptions or changes in prescriptions. More than 200 individuals had drug-related problems. There was variability in the level of service per pharmacy as the median number of intervention services was 30, while the mean was 113?188, among those providing any interventions., Conclusion: This unique system of outcomes-based pharmacist reimbursement permits community pharmacists to document and bill for cognitive services. It has demonstrated that PBMs and community pharmacists can work together to improve drug therapy, and it may reduce health care costs.

Additional structure-activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X = 2-4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Phe) (20), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(DL-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nM, respectively, and did not show any significant effect against other integrins (IC50 > 300 microM). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1-10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3-10 mg/kg. The peptide was released from some formulations over a period of 10-20 days. ZD7349 is currently undergoing pre-clinical investigation.

(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide (ZD6169) is a novel ATP-sensitive potassium channel opener. Bladder activity and selectivity after oral dosing were studied in conscious, normotensive rats and dogs by monitoring cystometric and cardiovascular (CV) parameters. The reference ATP-sensitive K+ channel opener cromakalim was also evaluated in this study. ZD6169 significantly reduced micturition frequency in rats (ED50 = 0.16 mg/kg), but its effect on CV parameters was minimal (ED20 = 30 mg/kg), yielding a selectivity dose ratio of 187. The duration of action was between 7 and 24 hr at doses of 0.3 and 3 mg/kg, but it was more than 24 hr at 10 mg/kg. The ED50 value for bladder activity in dogs was less than 1.0 mg/kg, and the ED20 value for CV activity was slightly greater than 15 mg/kg but less than 20 mg/kg; the selectivity ratio was greater than 15. A significant improvement in bladder compliance was noted in dogs with ZD6169, and the bladder activity in rats was blocked by i.v. glibenclamide (3 mg/kg). Cromakalim had a bladder profile similar to that of ZD6169 but appeared to be more selective for CV parameters. In conclusion, ZENECA ZD6169 is a unique ATP-sensitive K+ channel opener with in vivo selectivity of relaxing bladder smooth muscle. This agent has the potential for treating patients with urge incontinence.

ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM181,037 in spontaneously hypertensive rats. ZENECA ZM181,037 demonstrated a K+ channel-blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KCl, both the d- and l-enantiomer of ZENECA ZM181,037 antagonized the relaxation of cromakalim with mean pKB values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 mumol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in 86Rb+ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM181,037 is a blocker of the ATP-sensitive K+ channel (KATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM181,037, the lack of antihypertensive effect appears to result from its blocking activity on KATP in vascular tissues.

ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K+ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.

ICI 206,970 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which exhibited a calcium antagonist profile. The isolated rat aorta evaluation and dihydropyridine ligand [3H]-PN 200-110 binding studies demonstrated that ICI 206,970, like verapamil and nifedipine, inhibits vascular smooth muscle tone by inhibiting voltage-sensitive calcium channels. ICI 206,970 produced dose-related hypotensive, negative chronotropic, dromotropic, and coronary vasodilator responses after i.v. injection in anesthetized dogs. ICI 206,970, similar to calcium channel blockers and dissimilar to diuretics, produced an acute antihypertensive effect in spontaneously hypertensive rats (SHR), and significant protection against the development of myocardial hypertrophy in SHR after chronic oral treatment for 28 consecutive days. It is concluded that ICI 206,970 is a calcium channel blocker in addition to its novel eukalemic diuretic property.

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.