Pharmacologic treatment of type 2 diabetes: oral medications.

OBJECTIVE: To review the oral and injectable pharmacologic treatment options for type 2 diabetes. DATA SOURCES: A literature search was conducted using PubMed electronic database for studies published in English between 1993 and September 2014. Search terms included diabetes mellitus, type 2 diabetes, and the individual name for each antidiabetic medication reviewed. In addition, manual searches were performed for cross-references from publications. Package inserts, United States Food and Drug Administration (FDA) Web site, Institute for Safe Medication Practices Web site, American Diabetes Association Web site and scientific session poster presentations, and individual drug company Web pages were also reviewed. STUDY SELECTION AND DATA EXTRACTION: This review focused on information elucidated over the past 10 years to assist prescribers in choosing optimal therapy based on individual patient characteristics. Studies leading to the approval of or raising safety concerns for the antidiabetic medications reviewed in this article were included. DATA SYNTHESIS: In the past 10 years, there have been 4 novel oral antidiabetic medication classes and 9 new injectable agents and insulin products approved by the FDA for the treatment of type 2 diabetes as well as new information regarding the safety and use of several older antidiabetic medication classes. The distinctions were reviewed for each individual agent, and a comparison was completed if there was more than one agent in a particular therapeutic class. Using current information available, select investigational agents in phase III trials or those with a pending new drug application were highlighted. CONCLUSION: There are now 9 distinct oral pharmacologic classes and a variety of insulin and noninsulin injectable medications available for the treatment of type 2 diabetes. Metformin remains the first-line treatment option for most patients. When considering options for alternative or additional treatment, prescribers must weigh the benefits and risks using individual patient characteristics.

Pharmacologic treatment of type 2 diabetes: injectable medications.

OBJECTIVE: To review the oral and injectable pharmacologic treatment options for type 2 diabetes. DATA SOURCES: A literature search was conducted using PubMed electronic database for studies published in English between 1993 and September 2014. Search terms included diabetes mellitus, type 2 diabetes, and the individual name for each antidiabetic medication reviewed. In addition, manual searches were performed for cross-references from publications. Package inserts, United States Food and Drug Administration (FDA) Web site, Institute for Safe Medication Practices Web site, American Diabetes Association Web site and scientific session poster presentations, and individual drug company Web pages were also reviewed. STUDY SELECTION AND DATA EXTRACTION: This review focused on information elucidated over the past 10 years to assist prescribers in choosing optimal therapy based on individual patient characteristics. Studies leading to the approval of or raising safety concerns for the antidiabetic medications reviewed in this article were included. DATA SYNTHESIS: In the past 10 years, there have been 4 novel oral antidiabetic medication classes and 10 new injectable agents and insulin products approved by the FDA for the treatment of type 2 diabetes as well as new information regarding the safety and use of several older antidiabetic medication classes. The distinctions were reviewed for each individual agent, and a comparison was completed if there was more than one agent in a particular therapeutic class. Using current information available, select investigational agents in phase III trials or with a pending new drug application were highlighted. CONCLUSION: There are now 9 distinct oral pharmacologic classes and a variety of insulin and noninsulin injectable medications available for the treatment of type 2 diabetes. Metformin remains the first-line treatment option for most patients. When considering options for alternative or additional treatment, prescribers must weigh the benefits and risks using individual patient characteristics.

Mechanistic insights into the analgesic efficacy of A-1264087, a novel neuronal Ca(2+) channel blocker that reduces nociception in rat preclinical pain models.

UNLABELLED: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 µM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. PERSPECTIVE: The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.

Delayed lower urinary tract symptoms and erectile dysfunction after acute episode of coccidioidal meningitis.

We present an interesting case of a 27-year-old male with coccidioidal meningitis who developed permanent erectile dysfunction (ED) and lower urinary tract symptoms 3 months after initiation of therapy. The patient presented to the urology clinic with a complaint of a weak stream, urinary urgency and frequency, as well as enuresis which were only moderately controlled with anti-cholinergics. His ED responded well to phosphodiesterase-5 inhibitors. After an extensive review of the literature, this is the first report of delayed presentation of ED and lower urinary tract symptoms secondary to coccidioidal meningitis.

Orthotopic urinary diversion in the female patient.

Orthotopic reconstruction offers the most natural voiding pattern after radical cystecomty, allowing voluntary micturition through the intact native urethra. Several pathologic reviews have demonstrated that with careful selection of appropriate patients, a portion of the female urethra can be preserved for orthotopic reconstruction. Performing minimal dissection anteriorly, and avoiding injury of the pudendal innervations to the rhabdosphincter is crucial in maintaining the midurethral continence mechanism in female patients with neobladders.

Histologic comparison of pubovaginal sling graft materials: a comparative study.

OBJECTIVES: Little is known about the host response to the various biologic and synthetic graft materials used as substitutes for autologous fascia. We investigated the host response to sling graft materials in humans. METHODS: A total of 24 women undergoing sling revision had a portion of the graft material removed for comparative analysis. At exploration, the degree of graft preservation (integrity), encapsulation, infection, and fibrosis was quantified. A histopathologic analysis was performed by systematically examining each specimen for the inflammatory response, neovascularity, and host fibroblast infiltration. RESULTS: A total of 24 grafts were explanted at 2-34 months after implantation. The indications for removal were a lack of sling efficacy in 2, urinary retention in 9, and sling obstruction in 13. The types of graft material were polypropylene mesh (PPM) in 10, autologous fascia in 5, porcine dermis in 4, cadaveric dermis in 3, and cadaveric fascia in 2. No graft degradation had occurred in PPM material. Autologous and cadaveric fascia had the most demonstrable graft degradation. No encapsulation had occurred with autologous fascia or PPM. The porcine dermis was the most encapsulated. No host infiltration had occurred with the encapsulated porcine grafts, and only peripheral infiltration of fibroblasts had occurred in the cadaveric grafts. The PPM grafts had the greatest number of fibroblasts throughout the entire graft. Neovascularity was the most prevalent in mesh and was also present in the autologous fascia. Giant cells were seen in two mesh and two porcine grafts. CONCLUSIONS: The results of our study have shown that porcine dermis has the potential to encapsulate. The degree of host tissue infiltration was greatest with PPM, and no degradation of the mesh material had occurred with time.

The effects of isolated posterior compartment defects on lower urinary tract symptoms and urodynamic findings.

OBJECTIVES: To determine any significant patterns among subjective and/or objective storage or voiding variables in women with isolated rectoceles or posterior enteroceles. PATIENTS AND METHODS: We retrospectively reviewed the charts of 23 women with isolated posterior compartment defects. Patient histories, physical examination findings, catheterized postvoid residual urine volume (PVR) after uroflowmetry, and urodynamic evaluations were reviewed. Lower urinary tract symptoms (LUTS) were classed as pure storage (urgency, frequency, nocturia, etc.), pure voiding (hesitancy, straining, positional voiding, etc.), or mixed. RESULTS: The mean (range) age of the women was 67 (48-85) years. On physical examination, 15 women had a grade 3 defect, and eight a grade 2 defect. Thirteen women reported symptoms related to their prolapse (vaginal bulge, splinting with defecation): nine reported pure storage symptoms, one pure voiding symptoms, and 12 mixed symptoms; two women relied on catheterization for bladder emptying. Only one woman reported no LUTS. An elevated PVR (>100 mL) was found in 11 women (48%). Urodynamic studies were available for 17 women, and revealed detrusor overactivity in nine of them. There were low maximum urinary flow rates (Qmax < or = 15 mL/s) in 12 of the 17 women, and high voiding pressures at Qmax (P(det.Qmax) > or = 20 cmH2O) in 10. Both findings were present in seven of the 17 women. There was evidence of abdominal straining to void in nine of the 17 women. CONCLUSIONS: The overwhelming majority of women with isolated posterior compartment defects reported bothersome LUTS and most had abnormal urodynamic variables. The findings suggest that significant posterior prolapse defects can cause bladder outlet obstruction.

Histopathological evaluation of the uterosacral ligament: is this a dependable structure for pelvic reconstruction?

OBJECTIVE: To explore, by histological examination, whether the uterosacral ligament complex is an adequate support structure for vaginal vault suspension and other reconstructive procedures of the female pelvis. MATERIALS AND METHODS: We dissected 14 fresh hemipelves from seven adult female cadavers. The uterosacral complexes were excised from the pelvic sidewall immediately beneath the uterosacral pedicle. The specimens were stained with connective tissue-specific Movat stain and evaluated microscopically for the presence of collagen and/or elastin. RESULTS: Uterosacral tissue similar to that identified during pelvic reconstructive surgery was obtained in all cases. Six of the women had had a hysterectomy. A ligamentous structure with clearly aligned collagen and interspersed elastin was identified in only three specimens, two from one cadaver of a young woman who had not had a hysterectomy. The other specimens had an attenuated, poorly organized layer of collagen immediately beneath the peritoneum. CONCLUSION: We could not consistently identify normal ligamentous tissue in the uterosacral complexes. The overwhelming majority of specimens from women who had had a hysterectomy showed disorganized tissue with reduced cellularity. This reinforces doubts about the integrity of these tissues as structural supports in pelvic reconstructive surgery, particularly in elderly women who have had a hysterectomy.

Are patient symptoms predictive of the diagnostic and/or therapeutic value of hydrodistention?

INTRODUCTION: Hydrodistention (HD) has been utilized as a diagnostic and therapeutic tool in patients with refractory and diverse pelvic floor symptoms, including bladder pain with or without irritative bladder symptoms such as urinary urgency and urinary frequency. We sought to determine whether we could better define in whom HD was a more valuable intervention by stratifying patients according to presenting symptoms. MATERIALS AND METHODS: A retrospective review was performed on 185 patients who underwent HD at our institution by a single surgeon between 1/2002-8/2004. Subjects were placed into groups according to their symptoms. Group 1 (G1) patients reported pain with bladder filling that was relieved with emptying, group 2 (G2) reported constant pelvic pain unrelated to bladder filling or emptying, and group 3 (G3) reported urgency and frequency alone with no pain component. Anesthetic capacity, presence and severity of glomerulations post-distention, and follow-up at 1, 3, and 6 months were recorded for each patient. RESULTS: G1 included 40 patients with mean age of 42 (R = 16-77), G2 included 101 patients with mean age of 46 (R = 20-76), and G3 22 patients with mean age of 40 (R = 20-84). The mean anesthetic capacity was 715 ml, 725 ml, and 542 ml for G1, G2, and G3 respectively. ANOVA revealed a statistically significant reduction in the capacity of G3 when compared with the others (P = 0.0072). Glomerulations were present in 74% of G1, 72% of G2, and 86% of G3 patients. 61%, 33%, & 0% of G1 patients reported improvement at 1, 3, and 6 months respectively, 54%, 25%, & 7% of G2 patients reported improvement, and 50%, 19%, & 7% of G3 patients reported improvement. There were no statistically significant differences in the responses amongst the three groups. CONCLUSIONS: Although HD is frequently employed for patients with refractory pelvic pain and/or lower urinary tract complaints, results failed to identify any statistically significant differences in post-distention objective findings (anesthetic capacity, glomerulations) or therapeutic benefits when patients are categorized according to presenting symptoms.

Outcome of continence procedures in the pediatric patient: a single institutional experience.

PURPOSE: Achieving continence remains a major goal in the treatment of children with neurogenic and/or anatomical voiding dysfunction. We reviewed our experience with continence procedures in pediatric lower urinary tract reconstruction. MATERIALS AND METHODS: We reviewed the records of all pediatric patients who underwent continence procedures at our institution since July 1993. We reviewed the diagnosis, type of primary reconstructive procedure, concomitant procedure(s) and initial success rate. In cases of primary failure we noted the type of secondary continence procedure performed and the ultimate success rate. Success was defined as dry intervals of at least 4 hours when the patient was compliant with a catheterization or voiding regimen. RESULTS: Primary continence procedures were performed in 43 cases and secondary procedures were performed in 6 for a total of 49 continence procedures. The diagnoses included myelomeningocele in 22 patients, exstrophy in 12, epispadias in 3, bilateral single system ureteral ectopia in 3 and spinal cord injury in 3. A total of 32 primary procedures were performed concomitantly with or were preceded by bladder augmentation with creation of a catheterizable stoma. The remaining 11 patients underwent a continence procedure only. The diagnosis in these 11 patients was exstrophy in 5, epispadias in 3, with spinal cord injury in 2 and myelomingocele in 1. Mean followup was 35 months (range 1 to 95). Initial continence procedures included Young-Dees-Leadbetter bladder neck repair in 14 cases, of which 11 (79%) were initially successful, a urethral sling in 9 with 7 initial successes (78%), bladder neck division and closure in 7 with all successful (100%), collagen in 5 with 1 success (20%), other urethral lengthening procedure (eg Pippi Salle or Kropp) in 4 with 3 successes, (75%), combined urethral sling and Young-Dees-Leadbetter in 2 with 1 success (50%), and an artificial sphincter and fascial wrap in 1 each, which were successful. Of the 6 secondary procedures performed for primary failure collagen was injected in 4 and the bladder neck was divided and closed in 2. All were successful. CONCLUSIONS: Various lower urinary tract procedures can be performed to achieve successful continence in the pediatric population. At our institution all procedures had a reasonable success rate except primary collagen injection. Collagen injection and bladder neck division/closure proved to be reliable secondary procedures in cases of primary failure.

Predicting blood loss and transfusion requirements during radical prostatectomy: the significant negative impact of increasing body mass index.

PURPOSE: Radical retropubic prostatectomy (RRP) has been associated with significant blood loss and/or transfusion requirement. While still a concern, routine autologous blood donation has not been standard at our institution for more than a decade. We assessed recent blood loss and transfusion requirements in contemporary patients undergoing RRP and examined the possible predictive impact of preoperative variables. MATERIALS AND METHODS: A retrospective review of 436 consecutive patients who underwent RRP between July 1999 and December 2001 was performed with the primary purpose of analyzing estimated blood loss (EBL) and blood transfusion requirements as well as possible preoperative risk factors, including clinical demographic characteristics, body mass index (BMI), defined as weight in kg/height in m, comorbidities, American Society of Anesthesiologists classification and Charlson index score. RESULTS: A total of 436 consecutive patients with a mean age of 60 years (range 39 to 78) underwent RRP under general anesthesia. Mean American Society of Anesthesiologists class was 2.3 (range 1 to 3) and the mean BMI was 27.7 (range 18.2 to 44.3). Mean preoperative and postoperative hematocrit was 43.9% and 32.5%, respectively. Overall mean EBL was 603 cc (range 100 to 3500) and the transfusion rate was 4.8%. On multivariate analysis the only significant correlative predictor of EBL was BMI. There was a significantly lower EBL in patients with an acceptable BMI (less than 25) vs overweight (25 to 30) and obese (greater than 30) patients (p = 0.021). Likewise the rate of transfusion was significantly higher in the overweight (6.9%) and obese (5.6%) groups compared to the normal BMI group (1.9%) (p = 0.009). CONCLUSIONS: Our series demonstrates that blood loss during RRP continues to decrease. The respectable blood loss and low transfusion rates in this series were due to refinements in surgical technique rather than to perioperative modifications. To our knowledge the identification of BMI as a predictor of blood loss and transfusion is novel. These data serve as a benchmark for future comparisons and argue for continued refinements in techniques to decrease blood loss, particularly in overweight and obese patients.