The Impact of the Coronavirus Disease 2019 Pandemic on US Total Knee and Hip Arthroplasty Procedures in 2020.

Background: The coronoavirus disease 2019 (COVID-19) pandemic had profound impact on elective procedures in the United States. We characterized the longer-term decline and recovery of hip and knee arthroplasty procedures following the onset of the COVID-19 pandemic in the United States. Methods: We conducted a retrospective analysis of patients undergoing primary and revision total knee and hip arthroplasty (TKA and THA) in the United States between 2014 and 2020 using claims from a large national commercial payer data set contaivning deidentified information from patients with commercial health coverage. We calculated the percentage of cases lost by month using a forecast model to predict TKA and THA volumes in the absence of COVID-19. We then calculated the association between COVID-19 positivity rates and THA/TKA procedures by state and month. Results: There was a large initial decline in procedures, with primary TKA and THA volumes declining by 93.2% and 87.1% in April 2020, respectively, with revisions seeing more modest declines. Cases quickly recovered with volumes exceeding expected levels in summer months. However, cumulative 2020 volumes remained below expected with 9.7% and 7.5% of expected primary TKA and THA cases lost, respectively. Higher state COVID-19 positivity rates were associated with lower primary TKA, THA, and revision knee procedure rates. Conclusions: After the initial decline in March and April, knee and hip arthroplasty cases resumed quickly; however, by the end of 2020, the annual procedure volume had still not recovered fully. The loss in case volume within states was worse in months with higher COVID-19 positivity rates.

Astragalosides Supplementation Enhances Intrinsic Muscle Repair Capacity Following Eccentric Exercise-Induced Injury.

Astragalosides have been shown to enhance endurance exercise capacity in vivo and promote muscular hypertrophy in vitro. However, it remains unknown whether astragalosides supplementation can alter inflammatory response and enhance muscle recovery after damage in humans. We therefore aimed to evaluate the effect of astragalosides supplementation on muscle's intrinsic capacity to regenerate and repair itself after exercise-induced damage. Using a randomized double-blind placebo-controlled cross-over design, eleven male participants underwent 7 days of astragalosides supplementation (in total containing 4 mg of astragalosides per day) or a placebo control, following an eccentric exercise protocol. Serum blood samples and variables related to muscle function were collected prior to and immediately following the muscle damage protocol and also at 2 h, and 1, 2, 3, 5, and 7 days of the recovery period, to assess the pro-inflammatory cytokine response, the secretion of muscle regenerative factors, and muscular strength. Astragalosides supplementation reduced biomarkers of skeletal muscle damage (serum CK, LDH, and Mb), when compared to the placebo, at 1, 2, and 3 days following the muscle damage protocol. Astragalosides supplementation suppressed the secretion of IL-6 and TNF-α, whilst increasing the release of IGF-1 during the initial stages of muscle recovery. Furthermore, following astragaloside supplementation, muscular strength returned to baseline 2 days earlier than the placebo. Astragalosides supplementation shortens the duration of inflammation, enhances the regeneration process and restores muscle strength following eccentric exercise-induced injury.

Surgical stabilization of rib fractures versus nonoperative treatment in patients with multiple rib fractures following cardiopulmonary resuscitation: An international, retrospective matched case-control study.

BACKGROUND: The presence of six or more rib fractures or a displaced rib fracture due to cardiopulmonary resuscitation (CPR) has been associated with longer hospital and intensive care unit (ICU) length of stay (LOS). Evidence on the effect of surgical stabilization of rib fractures (SSRF) following CPR is limited. This study aimed to evaluate outcomes after SSRF versus nonoperative management in patients with multiple rib fractures after CPR. METHODS: An international, retrospective study was performed in patients who underwent SSRF or nonoperative management for multiple rib fractures following CPR between January 1, 2012, and July 31, 2020. Patients who underwent SSRF were matched to nonoperative controls by cardiac arrest location and cause, rib fracture pattern, and age. The primary outcome was ICU LOS. RESULTS: Thirty-nine operatively treated patient were matched to 66 nonoperatively managed controls with comparable CPR-related characteristics. Patients who underwent SSRF more often had displaced rib fractures (n = 28 [72%] vs. n = 31 [47%]; p = 0.015) and a higher median number of displaced ribs (2 [P 25 -P 75 , 0-3] vs. 0 [P 25 -P 75 , 0-3]; p = 0.014). Surgical stabilization of rib fractures was performed at a median of 5 days (P 25 -P 75 , 3-8 days) after CPR. In the nonoperative group, a rib fixation specialist was consulted in 14 patients (21%). The ICU LOS was longer in the SSRF group (13 days [P 25 -P 75 , 9-23 days] vs. 9 days [P 25 -P 75 , 5-15 days]; p = 0.004). Mechanical ventilator-free days, hospital LOS, thoracic complications, and mortality were similar. CONCLUSION: Despite matching, those who underwent SSRF over nonoperative management for multiple rib fractures following CPR had more severe consequential chest wall injury and a longer ICU LOS. A benefit of SSRF on in-hospital outcomes could not be demonstrated. A low consultation rate for rib fixation in the nonoperative group indicates that the consideration to perform SSRF in this population might be associated with other nonradiographic or injury-related variables. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

An unusual and challenging cause of small bowel bleeding: Isolated gastrointestinal blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disease that presents as cutaneous and extra-cutaneous vascular malformations, most commonly affecting the gastrointestinal (GI) tract. We report a case of adult onset BRBNS in an African American male with vascular lesions isolated to the jejunum without any cutaneous manifestations. Physicians should recognize that BRBNS can present without skin involvement and may have complications from visceral organ involvement. Treatment of BRBNS is mainly symptomatic and aims at preserving the GI tract as much as possible. BRBNS may also present as delayed recurrence after surgical or endoscopic interventions.

Applications of artificial intelligence in orthopaedic surgery.

The practice of medicine is rapidly transforming as a result of technological breakthroughs. Artificial intelligence (AI) systems are becoming more and more relevant in medicine and orthopaedic surgery as a result of the nearly exponential growth in computer processing power, cloud based computing, and development, and refining of medical-task specific software algorithms. Because of the extensive role of technologies such as medical imaging that bring high sensitivity, specificity, and positive/negative prognostic value to management of orthopaedic disorders, the field is particularly ripe for the application of machine-based integration of imaging studies, among other applications. Through this review, we seek to promote awareness in the orthopaedics community of the current accomplishments and projected uses of AI and ML as described in the literature. We summarize the current state of the art in the use of ML and AI in five key orthopaedic disciplines: joint reconstruction, spine, orthopaedic oncology, trauma, and sports medicine.

Effect of opioid treatment on clinical outcomes among cirrhotic patients in the United States.

BACKGROUND: Opioid medications are frequently used to address pain among patients with cirrhosis, including those on the liver transplant (LT) waitlist and after transplantation. However, opioid use has been associated with poor allograft outcomes and reduced transplant survival. We examined the impact of opioid use across the spectrum of advanced liver disease, from the initial hepatology consultation for cirrhosis through transplant referral, listing, and the post-LT process. METHODS: The study includes all patients referred for cirrhosis management in a single healthcare system in the United States. Data were extracted retrospectively through medical chart review. RESULTS: Of 414 patients included in the study, 104 (25%) were treated with opioid. Patients on opioids were more likely to be White, have body mass indices (BMI) >30, have HCV, suffer from hepatic encephalopathy, cigarette smokers, and use benzodiazepines concurrently. Higher doses of opioids were associated with multiple emergency department (ED). Eighty-nine underwent LT, including 20 opioid-treated patients. There was no difference found between the opioid and non-opioid groups with regard to allograft loss, ED visits, and hospital readmissions at 2 years post-LT follow-up. CONCLUSIONS: Opioid treatment was common among patients with cirrhosis. We did not find increased negative outcomes among opioid users across the spectrum of cirrhosis. However, the sample for LT patients was small.

Nicotine Supplementation Does Not Influence Performance of a 1h Cycling Time-Trial in Trained Males.

The use of nicotine amongst professional and elite athletes is high, with anecdotal evidence indicating increased prevalence amongst cycling sports. However, previous investigations into its effects on performance have not used high-validity or -reliability protocols nor trained cyclists. Therefore, the present study determined whether nicotine administration proved ergogenic during a ∼1 h self-paced cycling time-trial (TT). Ten well-trained male cyclists (34 ± 9 years; 71 ± 8 kg; O2max: 71 ± 6 ml ⋅ kg-1 ⋅ min-1) completed three work-dependent TT following ∼30 min administration of 2 mg nicotine gum (GUM), ∼10 h administration of 7 mg ⋅ 24 h-1 nicotine patch (PAT) or color- and flavor-matched placebos (PLA) in a randomized, crossover, and double blind design. Measures of nicotine's primary metabolite (cotinine), core body temperature, heart rate, blood biochemistry (pH, HCO3 -, La-) and Borg's rating of perceived exertion (RPE) accompanied performance measures of time and power output. Plasma concentrations of cotinine were highest for PAT, followed by GUM, then PLA, respectively (p < 0.01). GUM and PAT resulted in no significant improvement in performance time compared to PLA (62.9 ± 4.1 min, 62.6 ± 4.5 min, and 63.3 ± 4.1 min, respectively; p = 0.73), with mean power outputs of 264 ± 31, 265 ± 32, and 263 ± 33 W, respectively (p = 0.74). Core body temperature was similar between trials (p = 0.33) whilst HR averaged 170 ± 10, 170 ± 11, and 171 ± 11 beats ⋅ min-1 (p = 0.60) for GUM, PAT, and PLA, respectively. There were no differences between trials for any blood biochemistry (all p > 0.46) or RPE with mean values of 16.7 ± 0.9, 16.8 ± 0.7, and 16.8 ± 0.8 (p = 0.89) for GUM, PAT, and PLA, respectively. In conclusion: (i) nicotine administration, whether via gum or transdermal patch, did not exert an ergogenic or ergolytic effect on self-paced cycling performance of ∼1 h; (ii) systemic delivery of nicotine was greatest when using a transdermal patch; and (iii) nicotine administration did not alter any of the psycho-physiological measures observed.

On exercise thermoregulation in females: interaction of endogenous and exogenous ovarian hormones.

KEY POINTS: One in two female athletes chronically take a combined, monophasic oral contraceptive pill (OCP). Previous thermoregulatory investigations proposed that an endogenous rhythm of the menstrual cycle still occurs with OCP usage. Forthcoming large international sporting events will expose female athletes to hot environments differing in their thermal profile, yet few data exist on how trained women will respond from both a thermoregulatory and performance stand-point. In the present study, we have demonstrated that a small endogenous rhythm of the menstrual cycle still affects Tcore and also that chronic OCP use attenuates the sweating response, whereas behavioural thermoregulation is maintained. Furthermore, humid heat affects both performance and thermoregulatory responses to a greater extent than OCP usage and the menstrual cycle does. ABSTRACT: We studied thermoregulatory responses of ten well-trained ( V̇O2max , 57 ± 7 mL min-1  kg-1 ) women taking a combined, monophasic oral contraceptive pill (OCP) (≥12 months) during exercise in dry and humid heat, across their active OCP cycle. They completed four trials, each of resting and cycling at fixed intensities (125 and 150 W), aiming to assess autonomic regulation, and then a self-paced intensity (30-min work trial) to assess behavioural regulation. Trials were conducted in quasi-follicular (qF) and quasi-luteal (qL) phases in dry (DRY) and humid (HUM) heat matched for wet bulb globe temperature (WBGT) (27°C). During rest and exercise at 125 W, rectal temperature was 0.15°C higher in qL than qF (P = 0.05) independent of environment (P = 0.17). The onset threshold and thermosensitivity of local sweat rate and forearm blood flow relative to mean body temperature was unaffected by the OCP cycle (both P > 0.30). Exercise performance did not differ between quasi-phases (qF: 268 ± 31 kJ, qL: 263 ± 26 kJ, P = 0.31) but was 5 ± 7% higher during DRY than during HUM (273 ± 29 kJ, 258 ± 28 kJ; P = 0.03). Compared to matched eumenorrhoeic athletes, chronic OCP use impaired the sweating onset threshold and thermosensitivity (both P < 0.01). In well-trained, OCP-using women exercising in the heat: (i) a performance-thermoregulatory trade-off occurred that required behavioural adjustment; (ii) humidity impaired performance as a result of reduced evaporative power despite matched WBGT; and (iii) the sudomotor but not behavioural thermoregulatory responses were impaired compared to matched eumenorrhoeic athletes.

Multiday Pomegranate Extract Supplementation Decreases Oxygen Uptake During Submaximal Cycling Exercise, but Cosupplementation With N-acetylcysteine Negates the Effect.

Pomegranate extract (POMx) has been suggested as an ergogenic aid due to its rich concentration of polyphenols, which are proposed to enhance nitric oxide bioavailability, thereby improving the efficiency of oxygen usage and, consequently, endurance exercise performance. Although acute POMx supplementation improves aerobic exercise performance in untrained individuals, trained athletes appear to require chronic supplementation for a similar effect. Furthermore, the combination of POMx with a thiol antioxidant may prove more effective than POMx alone, due to the protective effects of thiols on nitric oxide. Thus, this study hypothesized that multiday POMx supplementation would decrease the oxygen uptake (VO2) required by trained cyclists to perform submaximal exercise and increase performance during a time trial, and that thiol (N-acetylcysteine [NAC]) cosupplementation would enhance these effects. Eight cyclists completed four 8-day supplementation periods: POMx only, NAC only, POMx + NAC (BOTH), and placebo. Following supplementation, they performed submaximal cycling and a 5-min time trial, with VO2 and muscle oxygen saturation (SmO2) being recorded. A three-way (POMx × NAC × Intensity) repeated-measures analysis of variance with a Fisher's least significant difference post hoc assessment was performed for dependent variables (p ≤ .05). VO2 during submaximal exercise was reduced with POMx versus placebo (-2.6 ml·min-1·kg-1, p = .009) and BOTH (-2.5 ml·min-1·kg-1, p < .05) and increased with NAC (+1.9 ml·min-1·kg-1, p < .03), despite no main effect of treatment on SmO2 or performance. It appears that POMx's high polyphenol content reduced the VO2 required during submaximal exercise. However, NAC cosupplementation annulled this effect; thus, NAC may interact with nitric oxide to reduce its bioavailability.

The effect of acute pomegranate extract supplementation on oxygen uptake in highly-trained cyclists during high-intensity exercise in a high altitude environment.

BACKGROUND: Recent research has indicated that pomegranate extract (POMx) may improve performance during aerobic exercise by enhancing the matching of vascular oxygen (O2) provision to muscular requirements. POMx is rich in ellagitannin polyphenols and nitrates (NO3-), which are both associated with improvements in blood flow and O2 delivery. Primarily, this study aimed to determine whether POMx improves performance in a cycling time trial to exhaustion at 100%VO2max (TTE100%) in highly-trained cyclists. In addition, we investigated if the O2 cost (VO2) of submaximal exercise was lower with POMx, and whether any changes were greater at high altitude where O2 delivery is impaired. METHODS: Eight cyclists exercised at three submaximal intensities before completing a TTE100% at sea-level (SEA) and at 1657 m of altitude (ALT), with pre-exercise consumption of 1000 mg of POMx or a placebo (PLAC) in a randomized, double-blind, crossover design. Data were analysed using a three way (treatment x altitude x intensity) or two-way (treatment x altitude) repeated measures ANOVA with a Fisher's LSD post-hoc analysis. Significance was set at p ≤ 0.05. The effect size of significant interactions was calculated using Cohen's d. RESULTS: TTE100% performance was reduced in ALT but was not influenced by POMx (p > 0.05). Plasma NO3- were 10.3 µmol greater with POMx vs. PLAC (95% CI, 0.8, 19.7,F1,7 = 7.83, p < 0.04). VO2 measured at five minutes into the TTE100% was significantly increased in ALTPOMx vs. ALTPLAC (+3.8 ml.min-1kg-1, 95% CI, -5.7, 9.5, F1,7 = 29.2, p = 0.001, ES = 0.6) but unchanged in SEAPOMx vs. SEAPLAC (p > 0.05). Submaximal VO2 values were not affected by POMx (p ≥ 0.05). CONCLUSIONS: The restoration of SEA VO2 values at ALT is likely driven by the high polyphenol content of POMx, which is proposed to improve nitric oxide bioavailability. Despite an increase in VO2, no change in exercise performance occurred and therefore this study does not support the use of POMx as an ergogenic supplement.

Hemorrhagic Cystitis in a Liver Transplant Recipient Secondary to BK Virus.

The association between BK virus infection and hemorrhagic cystitis (HC) in hematopoietic stem cell transplant (HSCT) recipients is well established. However, BK virus-associated HC has not been described in liver transplant (LT) recipients. We present a case of BK virus-associated HC in a LT recipient. Our patient presented with worsening liver function tests 2 years after transplantation and was found to have acute cellular rejection. He was treated with increased immunosuppression and subsequently developed hematuria. He was eventually diagnosed with BK virus-associated HC.

Management of Intrapleural Sepsis with Once Daily Use of Tissue Plasminogen Activator and Deoxyribonuclease.

BACKGROUND: Pleural infection remains a significant cause of morbidity, mortality, prolonged hospital stay, and increased healthcare costs, despite advances in therapy. Twice daily intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) initiated at the time of diagnosis has been shown to significantly improve radiological outcomes and decrease the need for surgery. OBJECTIVES: To analyze our experience with once daily tPA/DNase for intrapleural sepsis. METHODS: Data derived from consecutive patients with empyema and complicated parapneumonic effusion who received once daily intrapleural tPA/DNase between January 2012 and August 2014 were reviewed. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity, length of hospital stay, need for surgery, and adverse events. RESULTS: 55 consecutive patients (33 male; mean age ± SD, 54.6 ± 16.1 years) were treated with once daily intrapleural tPA/DNase for 3 days. The majority of the patients (n = 51; 92.7%) were successfully managed without the need for surgical intervention. The mean change in pleural opacity measured on chest radiograph at day 7 was -28.8 ±17.6%. The median amount of fluid drained was 2,195 ml. No serious adverse events requiring discontinuation of intrapleural medications were observed. The most common complication was pain requiring escalating doses of analgesics (n = 8; 15%). Compliance with the protocol was excellent. CONCLUSION: Early administration of once daily intrapleural tPA/DNase for 3 days is safe, effective, and represents a viable option for the management of empyema and complicated parapneumonic effusion.

Resolution mediator chemerin15 reprograms the wound microenvironment to promote repair and reduce scarring.

Disorders of cutaneous repair can cause disability or death given that skin functions as a protective barrier against the external environment. The inflammatory response triggered by tissue damage is thought to play both positive (e.g., pathogen-killing) and negative (e.g., scarring) roles in repair. Inflammatory resolution mediators such as chemerin15 (C15) control the magnitude and duration of the inflammatory response; however, their role in wound repair and scarring is unknown. Here, we show that the C15 precursor, chemerin, and its receptor, ChemR23, are both upregulated after skin damage and that the receptor is expressed by macrophages, neutrophils, and keratinocytes. Dynamic live-imaging studies of murine cutaneous wounds demonstrate that C15 delivery dampens the immediate intravascular inflammatory events, including platelet adhesion to neutrophils, an important event in driving leukocyte recruitment. C15 administration indirectly accelerates wound closure while altering fibroblast-mediated collagen deposition and alignment to reduce scarring. Macrophage recruitment is restricted to the immediate wound site rather than spilling extensively into the adjacent tissue as in control wounds, and macrophage phenotype in C15-treated wounds is skewed toward a less inflammatory phenotype with reduced iNOS, increased Arginase-1, and lower wound tumor necrosis factor α (TNF-α) expression. Modulation of inflammatory resolution pathways in acute and chronic wounds may therefore provide a novel therapeutic avenue to improve repair and reduce scarring.

Body mass index and acetabular component position in total hip arthroplasty.

INTRODUCTION: Correct acetabular component positioning during total hip arthroplasty affects the restoration of normal biomechanics, component wear and failure rates. This study examined whether a patient's body mass index (BMI) affects the accuracy of acetabular component placement in terms of the post-operative abduction angle. METHODS: This was a retrospective review of 102 total hip arthroplasties performed from May 2009 in a single institution. The acetabular abduction angle was measured on the post-operative radiographs of the included patients. Statistical analysis of variance and t-tests were performed using Microsoft Excel to compare the mean abduction angles of patients grouped according to their BMI. RESULTS: Comparison of the mean abduction angle between those with BMI < 25 and BMI > 25 showed a statistically significant difference (P = 0.003). Analysis of variance between all BMI groups was statistically significant (P = 0.01). Patients in the lowest centile of abduction angle had an average BMI of 28. Patients in the highest centile of abduction angle had an average BMI of 33. DISCUSSION: This study shows that patients with a normal BMI tend to have smaller abduction angles. Overweight or obese patients, on average, have a normal abduction angle but are more likely to have an 'open cup'. A number of factors unique to obese and overweight patient may contribute to an 'open cup' and less accurate cup placement.

Long term effects of denufosol tetrasodium in patients with cystic fibrosis.

RATIONALE: Denufosol stimulates chloride secretion independent of the chloride channel which is dysfunctional in cystic fibrosis (CF) and therefore has the potential to benefit CF patients regardless of genotype. OBJECTIVES: To assess the efficacy of denufosol in CF patients with mild lung function impairment age 5 years and older. METHODS: This multicenter, randomized, parallel group double-blind placebo-controlled trial was conducted at 102 CF care centers in Australia, Canada and the United States (NCT00625612) The active group (n=233) received 60 mg denufosol via inhalation three times daily The primary efficacy endpoint was change in FEV(1) in liters from Day 0 to week 48. MEASUREMENTS AND MAIN RESULTS: 685 patients were screened for the study and 466 patients (233 in each group) were randomized to study treatment. The adjusted mean change in FEV(1)was 40 mL for denufosol and 32 mL for placebo with a resulting treatment effect of 8 mL (95% CI -0.040, 0.056). The average rate of change in FEV(1) percent of predicted over 0 to 48 weeks was -3.04% for placebo vs. -2.30 for denufosol (a difference of 24% relative to placebo) among all patients. The incidence of pulmonary exacerbation was 26% vs. 21% for the placebo and denufosol groups with no differences in the time to first event. The study treatments were well tolerated and there was no evidence of systemic effects in any safety parameter assessed. CONCLUSIONS: In patients with CF treatment with denufosol for 48 weeks did not improve pulmonary function or reduce the incidence of pulmonary exacerbations.

Irritable bowel syndrome: a "mesh" of a situation.

The diagnosis of irritable bowel syndrome (IBS) frequently is made after the exclusion of a mechanical etiology for a patient's symptoms. This case demonstrates that IBS symptoms can be caused by a rare complication of a common surgery: mesh herniorrhaphy repair. The patient is a 50-year-old woman who underwent periumbilical Marlex mesh herniorrhaphy 13 years before presentation. After her operation, the patient developed constipation (approximately one bowel movement per week) alternating with diarrhea for approximately 10 years. An abdominal radiograph showed large amounts of stool, and after a normal colonoscopy the patient was diagnosed with IBS. The patient was treated with tegaserod (Zelnorm) and polyethylene glycol (MiraLAX), which did not palliate her symptoms. The patient presented with obstructive symptoms and physical findings of an incarcerated umbilical hernia. A computed tomography (CT) scan of the abdomen confirmed an umbilical hernia involving a segment of small bowel with surrounding fecalization of enteric contents. During operative repair, the patient was found to have Marlex mesh fully eroded into the lumen of the small bowel, causing a partial obstruction. The involved section of small bowel was resected, and during serial follow-up the patient had complete resolution of her IBS-like symptoms. A discussion follows regarding the implications of mesh migration, and questions are posed for future research.

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.

AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.

Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret.

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P<0.001) and 61% (P<0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P<0.01) and 66% (P<0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by approximately 70-90% (P<0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P<0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P<0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P<0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P>0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.

Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: a new use of silicon bioisosteres in medicinal chemistry.

The synthesis, physicochemical properties and pharmacological profiles of two novel silicon-containing p38 MAP kinase inhibitors are described.