Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics.

Fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti-inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment-related changes in amino-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed-effects longitudinal kinetic-pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were -18, -22, and -22% (P1NP), and -7, -13, and -17% (OC), respectively. Changes with prednisone 5 and 10 mg were -15% and -18% (P1NP) and -10% and -17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.

FDA Advisory Meeting Clinical Pharmacology Review Utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment?

In the evolving discipline of quantitative systems pharmacology (QSP), QSP model (QSPM) applications are expanding. Recently, a QSPM was used by US Food and Drug Administration (FDA) clinical pharmacologists to evaluate the appropriateness of a proposed dosing regimen for a new biologic. This application expands the use-horizon for QSPMs into the regulatory domain. Here we retrace the evolution of the model and suggest a question-based approach to directing model scope, identifying applications, and understanding overall QSPM value.

Predicting nonlinear changes in bone mineral density over time using a multiscale systems pharmacology model.

A mathematical model component that extends an existing physiologically based multiscale systems pharmacology model (MSPM) of calcium and bone homeostasis was developed, enabling prediction of nonlinear changes in lumbar spine bone mineral density (LSBMD). Data for denosumab, a monoclonal antibody osteoporosis treatment, dosed at several levels and regimens, was used for fitting the BMD component. Bone marker and LSBMD data extracted from the literature described on/off-treatment effects of denosumab over 48 months [Miller, P.D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222-229 (2008)]. An indirect model linking bone markers to LSBMD was embedded in the existing MSPM, reasonably predicting nonlinear increases in LSBMD during treatment (24 months); LSBMD declines following discontinuation and increases upon treatment reinstitution. This study demonstrates the utility of MSPM extension to describe a phenomena of interest not originally in a model, and the ability of this updated MSPM to predict nonlinear longitudinal changes in the clinically relevant endpoint, LSBMD, with denosumab treatment.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e14; doi:10.1038/psp.2012.15; advance online publication 14 November 2012.

Spontaneous bacterial peritonitis from Streptococcus salivarius in a compromised host.

A seriously ill patient with cirrhosis and resistant ascites from hepatitis C and alcohol abuse abruptly deteriorated. He developed encephalopathic changes, abdominal pain and tenderness and was suspected of having spontaneous bacterial peritonitis. The peritoneal fluid contained many granulocytes and Steptococcus salivarius was isolated from the fluid.

Reversible galactorrhea and prolactin elevation related to fluoxetine use.

Fluoxetine, an antidepressant of the selective serotonin reuptake inhibitor class, may stimulate prolactin release by pituitary lactotrophs. A 71-year-old woman taking estrogen replacement therapy developed galactorrhea after initiation of fluoxetine for depression and was found to have an elevated prolactin level. Fluoxetine was discontinued with resolution of the patient's galactorrhea and normalization of her prolactin level.

Evidence for the involvement of blood flow-related mechanisms in the ovulatory process of the rat.

To elucidate whether any relationship exists between ovarian blood flow and ovulation rate, the effects on these parameters were examined in equine chorionic gonadotrophin/human chorionic gonadotrophin (eCG/HCG) (15I U/15I U) primed rats after bilateral ligation and severance of either the ovarian branch of the uterine artery and vein (UL), the ovarian artery and vein (OL) or both sites (UL+OL) in comparison to sham operations. Laser Doppler flowmetry demonstrated the presence of microcirculatory vasomotion and a reduction of blood flow after UL, OL and UL+OL performed during the intervals 0-3 h (78, 66 and 19% of pretreatment values respectively) and 6-9 h (68, 57 and 20%) after HCG. Experiments utilizing radioactive microspheres also indicated decreased ovarian blood flow by UL and OL. Ovulation rate was assessed 20 h after HCG in animals where ligations had been performed at 0, 3, 6 and 9 h after HCG. No ovulations were seen after UL+OL and significantly decreased ovulation rates ( approximately 50% of sham operated animals) were seen after UL at 0 and 3 h and after OL at 0, 6 and 9 h. Progesterone concentrations in blood 20 h after HCG were reduced by OL but not UL and ovarian weights were unaffected by ligation. It is concluded that acute blood flow reduction during the ovulatory interval reduces ovulation rate in the rat.

Acute infection with Sin Nombre hantavirus without pulmonary edema.

Acute infection with Sin Nombre virus has been associated with development of hantavirus cardiopulmonary syndrome (HCPS), a severe cardiopulmonary illness with respiratory failure and shock. We present two cases of Sin Nombre hantavirus infections that did not lead to marked pulmonary complications in two otherwise healthy young adults from Utah and California. Sin Nombre virus causes a wider spectrum of disease severity than has been previously reported.

Iliac vein compression syndrome from urinary bladder distension due to prostatism.

Urinary bladder distention is a rarely reported cause of iliac vein compression. We report a case of bilateral lower extremity and scrotal edema resulting from marked bladder distention. The bladder was readily palpable and a 4,100 cm3 postvoid residual urine volume was found. No other cause of lower extremity and scrotal edema was found. The patient improved after bladder drainage and transurethral prostatectomy (TURP) for moderate benign prostatic hypertrophy.

Clinical aspects of Campylobacter jejuni infections in adults.

Campylobacter jejuni is an almost ubiquitous, microaerophilic, gram-negative rod. Outbreaks have been associated with drinking raw milk or contaminated water and eating poultry. Campylobacter jejuni accounts for 3.2% to 6.1% of cases of diarrheal illness in the general population of the United States, and infected patients frequently present with abdominal pain and fever. Less frequently, C jejuni is responsible for bacteremia, septic arthritis, septic abortion, and other extraintestinal infections. Reactive arthritis, Reiter's syndrome, the Guillain-Barré syndrome, and pancreatitis may accompany or follow C jejuni enterocolitis. Campylobacter jejuni is an important cause of diarrheal illness and is a more commonly identified stool organism than Salmonella or Shigella species. Recurrent and chronic infection is generally reported in immunocompromised hosts.

Rheumatic manifestations of Campylobacter jejuni and C. fetus infections in adults.

Reports of the rheumatic manifestations of Campylobacter jejuni and C. fetus infections in adults are reviewed in order to determine the most common presentations and which individuals are at risk for rheumatic disease. Relevant English-language articles were identified through a Medline search and from bibliographies of identified articles. 105 articles were reviewed in detail. 29 cases of reactive arthritis or Reiter's syndrome following Campylobacter jejuni enteritis were identified. The knee is the most commonly involved joint and an average of 3.2 joints were involved in affected persons. HL-A B27 positive patients are more frequently affected and have higher erythrocyte sedimentation rates than HL-A B27 negative patients. Eight cases of septic arthritis and 4 cases of osteomyelitis caused by C. fetus or C. jejuni were identified, and these cases generally occurred in compromised hosts or in diseased joints.

Prosthetic hip infection and bacteremia due to Campylobacter jejuni in a patient with AIDS.

Campylobacter jejuni is a common enteric pathogen in healthy individuals and in patients with AIDS. It usually causes a self-limited diarrheal illness with fever and abdominal pain. We report what we believe is a unique case of C. jejuni osteomyelitis in a 60-year-old man who had hemophilia A, AIDS, and a hip prosthesis. He presented to the hospital with a 4-day history of fever and diarrhea and a 1-day history of hip pain. Findings on plain films and a bone scan were suggestive of osteomyelitis in the proximal femur. Cultures of blood and a hip aspirate yielded C. jejuni.

Contributions of the history, physical examination, and laboratory investigation in making medical diagnoses.

We report an attempt to quantitate the relative contributions of the history, physical examination, and laboratory investigation in making medical diagnoses. In this prospective study of 80 medical outpatients with new or previously undiagnosed conditions, internists were asked to list their differential diagnoses and to estimate their confidence in each diagnostic possibility after the history, after the physical examination, and after the laboratory investigation. In 61 patients (76%), the history led to the final diagnosis. The physical examination led to the diagnosis in 10 patients (12%), and the laboratory investigation led to the diagnosis in 9 patients (11%). The internists' confidence in the correct diagnosis increased from 7.1 on a scale of 1 to 10 after the history to 8.2 after the physical examination and 9.3 after the laboratory investigation. These data support the concept that most diagnoses are made from the medical history. The results of physical examination and the laboratory investigation led to fewer diagnoses, but they were instrumental in excluding certain diagnostic possibilities and in increasing the physicians' confidence in their diagnoses.

Assessment by patients of their health education needs.

One hundred ninety-two patients of three family practice clinics were surveyed about their health information needs. The largest gaps between present and desired knowledge were in cardiopulmonary resuscitation and immunizations. Other major differences concerned mind/body relationships, health risk reduction, coverage of health care costs and nonprescription medications. There was little knowledge discrepancy with regard to the problem for which the patients saw their physicians. This technique is recommended as a way for clinics to target their patient education efforts more effectively.