Weight loss and complications of the banded Roux-en-Y gastric bypass: lessons learned from a prospective case control study.

OBJECTIVE: Obesity is a growing global health burden which is particularly challenging to manage. Bariatric surgery is considered the most effective means of sustained weight loss, and Roux-en-Y gastric bypass is considered the most effective treatment for morbid obesity. The additional benefit of placing a non-adjustable band to form a banded Roux-en-Y gastric bypass has gained interest as a measure to improve weight loss; however, comparative data are few, and complications can be high. METHODS: We conducted a prospective case-control study of 484 patients aged 18 and over who received either banded Roux-en-Y gastric bypass with a non-adjustable silastic ring or Roux-en-Y gastric bypass. Patients were followed up for five years and evaluated for weight loss, percentage excess weight loss (%EWL), BMI, and band-related complications. RESULTS: No significant difference was detected in %EWL or BMI between BRYGB and RYGB. The mean raw weight loss, %EWL, and BMI for BRYGB verse RYGB were as follows: 27.49 SD (17.11) kg verse 34.46 SD (18.18) kg, 65.7% SD (30%) verse 62.2% SD (37%), and 32.33 SD (6.9) kg/m2 verse 32.43 SD (7.2) kg/m2. A total of 80 (21.7%) patients had the non-adjustable band removed for complications. CONCLUSION: There is little difference in weight-loss results when comparing BRYGB to RYGB and non-adjustable bands may cause significant complications.

Spontaneous haemorrhage of chronic varicose ulceration causing ischaemic colitis.

Venous ulcers are common and account for the majority of lower limb chronic wounds. Complications may be serious in nature and although haemorrhage is rare, it may be rapidly fatal. The case of a female patient who presented with a spontaneous varicose ulcer haemorrhage causing hypovolaemic ischaemic colitis is described. This case exemplifies the need to identify and manage the development of venous insufficiency before progression to chronic wounds or other disease burdens which may be fatal or life-altering.

Risk factors for recurrence in colorectal cancer: a retrospective analysis in a regional Australian hospital.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed malignancy in Australia. Up to a third of patients who have undergone surgery with curative intent for colorectal cancer will have a recurrence of disease leading to significant morbidity and mortality. Regional Australians have disproportionately worse outcomes. AIM: To identify factors associated with recurrence in colorectal cancer patients treated at a regional Australian hospital. METHODS: This study is a retrospective cohort analysis. Consecutive patients who have undergone curative resection at a regional public and private hospital by three surgeons from a single surgical practice for either rectal cancer or colon cancer were included. Prognostic indicators of recurrence were examined via both univariate and multivariate time-to-event analyses. RESULTS: Three hundred nine patients were included with 43 recurrences. Thirty presented with distant metastases, seven presented with locoregional recurrence and six presented with locoregional as well as distant recurrence. In univariable analysis, higher rates of recurrence were associated with tumour type, higher AJCC summary stage, higher preoperative levels of CA19-9, perineural invasion, lymphovascular invasion, <12 nodes examined, positive lymph nodes and emergency surgery status. On multivariable analysis recurrence remained associated with tumours with a mucinous and/or signet cell component, positive nodes and <12 lymph nodes examined. CONCLUSION: A combination of patient and treatment factors are relevant in determining the risk of recurrence for stage I-III colorectal cancer. This study emphasises the importance of histology in determining risk, particularly the number of nodes examined. CEA 19-9 may also be a useful pre-operative predictor of recurrence.

A case of multifocal stroke-the first presentation of underlying ovarian malignancy.

Ischaemic stroke is a rare manifestation of hypercoagulability induced by underlying malignancy. It is proposed that paraneoplastic non-bacterial thrombotic endocarditis (NBTE) is the most common cause, predisposing to the formation of friable valvular lesions composed of platelets and fibrin that embolize commonly. Pancreas, gallbladder, stomach, colon and gynaecological malignancies have all been associated with NBTE. We describe a female patient who presented to our facility with syncope and limb weakness. Magnetic resonance imaging of the brain revealed ischaemic strokes in both the anterior and posterior circulation. Further investigation revealed a pelvic mass that was biopsy proven to be ovarian malignancy. Prognosis is heavily reliant on disease stage, thus diagnostic clues suggesting the possibility of underlying malignancy in the presentation of stroke should prompt a thorough investigation to exclude malignancy.

A case of splenic artery pseudoaneurysm rupture presenting as rectal bleeding in a regional hospital.

Splenic artery pseudoaneurysm is a rare phenomenon most associated with chronic pancreatitis or previous trauma. Complications can include erosion and rupture into local structures, a situation that carries a reported mortality of 10-40%. A 58-year-old male with chronic alcoholic pancreatitis and a known splenic artery pseudoaneurysm presented to the emergency department of a regional hospital with rectal bleeding and sepsis. Computed tomography revealed a peri-splenic mass communicating with the splenic flexure. The patient was taken for an emergency splenectomy and left hemicolectomy and was confirmed to have rupture of the splenic artery aneurysm into the large bowel. This case presented with comparable features reported in the literature and demonstrates that access to emergency specialist surgical services in a regional setting offers the capability to manage rare, life threatening surgical emergencies.

Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia.

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel.

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113µg while Day 60 values ranged from 284 to 454µg. Daily LNG release ranged from 129 to 684µg on Day 1 and 2-91µg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131µg/day or 37-66µg/day for DPV, and either 96-150µg/day or 37-57µg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.

Controlling levonorgestrel binding and release in a multi-purpose prevention technology vaginal ring device.

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine - a lead candidate antiretroviral microbicide - for combination HIV prevention and hormonal contraception.

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring.

Acceptability and preferences for vaginal dosage forms intended for prevention of HIV or HIV and pregnancy.

This paper reviews key issues found to affect acceptability and preferences for vaginal products to prevent HIV infection or HIV and pregnancy. We focus on the interplay between the biological and physico-chemical aspects of formulation and the social and behavioral issues that may affect use. The need for an HIV prevention product that women can use is driven by women's increased biological and social vulnerability to HIV infection, and thus social and behavioral research on microbicide acceptability has been conducted alongside, as well as separate from, the earliest product development efforts. Some acceptability and preference issues are specific to a product's dosage form, use-requirements, and/or use indications, while others pertain to any vaginal product used for prevention of HIV or pregnancy. Although most of the work cited here was published since 2010, it draws on a much longer trajectory of research.

Preclinical safety evaluation.

Before pharmaceutical products are evaluated in humans, it is essential that they undergo a rigorous safety assessment using in vitro models and studies in preclinical species. Once products progress into the clinic, additional preclinical studies are needed to support further clinical testing. Although regulatory guidelines provide a good framework for the types of studies that should be performed, there are some areas where it is unclear how these should be applied to microbicides, what study designs should be used, whether certain tests are relevant or if additional assays are appropriate. In this chapter we provide an overview of the key issues for the preclinical development of microbicides, and describe the purpose of each of the tests along with the key considerations to be taken into account when designing the individual safety studies as well as the overall preclinical program.

ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid], a novel nonpeptide delta receptor agonist, reduces myocardial infarct size without central effects.

A novel delta-receptor selective compound, ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having delta receptor selectivity using radioligand binding and had no apparent selectivity between delta receptor subtypes as determined by [(3)H] cyclic [D-Pen(2),D-Pen(5)]enkephalin (delta(1)) and [(3)H]Deltorphin II (delta(2)) competition binding. ARD-353 also showed selective delta receptor agonist activity in mouse-isolated vas deferens. There was no evidence of any seizure-like convulsions when ARD-353 was administered to mice either i.v. or p.o., implying minimal penetration of the blood-brain barrier. ARD-353 decreased infarct size in a left anterior descending coronary artery (LAD) occlusion model of myocardial infarction. In animals pretreated with ARD-353 (i.v.) and then subjected to 30 min of LAD occlusion followed by 90 min of reperfusion, infarct size was reduced in a dose-dependent manner compared with vehicle-treated controls. The effects of ARD-353 on infarct size were blocked by the delta(1)-opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the delta(1)-opioid receptor in the cardioprotective mechanism of ARD-353. ARD-353 (0.3 mg/kg i.v.) produced significant protection when administered 5 min and 12 and 48 h before ischemic insult or when given immediately after the ischemic insult (at the start of reperfusion). Given the lack of central nervous system effects and beneficial efficacy in the rat model of myocardial ischemia, it is felt that ARD-353 is the first nonpeptide delta-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.

DPI-221 [4-((alpha-s)-alpha-((2s,5r)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide]: a novel nonpeptide delta receptor agonist producing increased micturition interval in normal rats.

There is a wealth of information from animal models and clinical opioid-analgesic use that indicates a significant role for opioid receptors in the modulation of bladder activity. The novel benzhydrylpiperazine compound DPI-221 [4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide] was characterized as having delta receptor selectivity using radioligand binding (K(i) = 2.0 +/- 0.7 nM, delta receptor; 1800 +/- 360 nM, mu receptor; and 2300 +/- 680 nM, kappa receptor), and agonist activity was demonstrated in the mouse isolated vas deferens where DPI-221 inhibited electrically induced contractions with an IC(50) value of 88 +/- 7.5 nM. In the guinea pig isolated ileum, DPI-221 had no effect on electrically induced contractions at concentrations as high as 1 microM. Sterile saline was infused (7 ml/h) into the bladder of Sprague-Dawley rats, via a transmural catheter; DPI-221 (1.0 to 20 mg/kg p.o.) significantly increased the interval between micturition events, whereas peak void pressure was not significantly decreased by any dose of DPI-221. The micturition effects of 10 mg/kg p.o. DPI-221 were blocked by naltrindole, indicating a delta receptor mechanism of action. In isolated rat bladder strips, DPI-221 was ineffective at relaxing detrusor muscle precontracted with carbachol. The most crucial safety aspect of delta agonist administration is the incidence of seizure-like convulsions in rodents. DPI-221 produced no convulsions at doses up to 100 mg/kg p.o. in mice, although rapid bolus i.v. injection of 5 mg/kg produced convulsions in 3% of mice tested. These findings indicate a good safety profile for DPI-221 administered orally, with potent efficacy in modifying bladder activity.