Midodrine: Insidious development of urologic adverse effects in patients with spinal cord injury: A report of 2 cases

Midodrine, a prodrug, is converted after oral administration into its active drug, desglymidodrine, which acts as an α₁-adrenoceptor stimulant. Midodrine is prescribed for the treatment of neurogenic orthostatic hypotension in patients with spinal cord injury. By virtue of its α₁-adrenergic effects, midodrine causes an increase in the tone of the vesical sphincter, which may silently lead to progressive retention of urine, particularly in patients with spinal cord injury who void urine spontaneously. Further, midodrine may aggravate detrusor-sphincter dyssynergia, which can lead to hydroureteronephrosis. A 68-year-old man with C-4 tetraplegia was voiding urine satisfactorily through reflex detrusor contractions. He was prescribed midodrine (5 mg at 8:00am, 5 mg at 1:00pm, and 2.5 mg at 10:00pm) for postural hypotension. During the next 7 wk, this patient experienced severe leg spasms while passing urine, and the flow of urine became very slow. Intravenous urography showed bilateral hydroureteronephrosis, although an earlier study had revealed normal kidneys. Midodrine therapy was stopped, and intermittent catheterization 4 times a day, along with oral oxybutynin, was started. After midodrine was discontinued, the leg spasms during passage of urine and slowing of the urine stream coincident with the spasms disappeared completely. The patient was able to pursue activities of daily living without taking midodrine. A 40-year-old man with C-7 tetraplegia was passing urine spontaneously with no problem. For postural hypotension, he was prescribed midodrine (5 mg in the morning and 2.5 mg at lunchtime), fludrocortisone (100 μg daily), and ephedrine (15 mg by mouth, taken 10 min before getting up in the morning). Three months later, the patient presented with sweating. During the day, he would pass only small amounts of urine, but from evening onward, he would void large volumes of urine, and the sweating would diminish. Intravenous urography showed vesical diverticula; a postmicturition film revealed moderate residual urine. This patient was able to stop taking the second dose of midodrine, but he required midodrine and ephedrine in the morning to enable him to get up without feeling dizzy. After the noon midodrine dose was stopped, the patient’s sweating diminished by late afternoon. During the morning hours, however, he continued to sweat and had difficulty passing urine. Intermittent catheterization was not possible in the community setting, and the patient remains under close follow-up. These cases illustrate that patients with cervical spinal cord injury who void spontaneously may develop insidious urologic adverse effects after taking midodrine for postural hypotension. When patients with spinal cord injury develop urologic adverse effects while taking midodrine, the drug should be stopped, and other pharmacologic agents (eg, fludrocortisone) and nonpharmacologic methods should be prescribed for management of orthostatic hypotension. If a patient continues to require midodrine to control postural hypotension, intermittent catheterization combined with antimuscarinic therapy (eg, oxybutynin) should be recommended instead of spontaneous voiding.     

Comparative Studies of Lamivudine-zidovudine Nanoparticles for the Selective Uptake by Macrophages

The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGAPoloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs.     

Number and location of venous valves within the popliteal and femoral veins: a review of the literature

Although deep venous insufficiency is common and important, the anatomy of deep vein valves is poorly understood. The aim of this study was to investigate the location, number and consistency of venous valves in the femoral and popliteal veins in normal subjects. A detailed literature search of PubMed was performed. Abstracts and selected full text articles were scrutinised and relevant studies published between 1949 and 2010 reporting anatomical details of deep vein valves were included. From 7470 articles identified by the initial search strategy, nine studies with a total of 476 legs were included in this review. All studies were cadaveric and subjects ranged from stillborn fetuses to 103 years of age. Studies suggested that femoral veins contain between one and six valves, and popliteal veins contain between zero and four valves. Deep vein valves were consistently located in the common femoral vein (within 5 cm of the inguinal ligament), the femoral vein (within 3 cm of the deep femoral vein tributary) and in the popliteal vein near the adductor hiatus. Valves are consistently located at specific locations in the deep veins of the leg, although there is often significant variability between subjects. Further anatomical and functional studies using new imaging modalities available should target these areas to identify whether certain valves play a more important role in venous disease. This may guide us in the development of new treatment options for patients with deep venous disease.     

The Importance of Early Carotid Endarterectomy in Symptomatic Patients

INTRODUCTION

Early carotid endarterectomy (CEA) in symptomatic patients may prevent repeat cerebral events. This study investigates the relationship between waiting time for CEA and the incidence of repeat cerebral events prior to surgery in symptomatic patients.

PATIENTS AND METHODS

A prospective database of consecutive patients undergoing CEA between January 2002 and December 2006 was reviewed. Repeat event rates prior to surgery were calculated using Kaplan–Meier analysis and predictive factors identified using Cox regression analysis.

RESULTS

A total of 118 patients underwent CEA for non-disabling stroke, TIA and amaurosis fugax. Repeat cerebral events occurred in 34 of 118 (29%) patients at a median 51 days (range, 2–360 days) after the first event. The estimated risk of repeat events was 2% at 7 days and 9% at 1 month after first event (Kaplan–Meier survival analysis). Age (HR 1.059; 95% CI 1.014–1.106; P = 0.009] was identified as a predictor of repeat events. Patients underwent surgery at median 97 days (range, 7–621 days) after the first event. Eleven of 60 (18%) patients waiting ≤?97 days for surgery and 23 of 58 (40%) patients waiting >?97 days had repeat events. (P = 0.011, chi-squared test).

CONCLUSIONS

Delays in surgery should be reduced in order to minimise repeat cerebral events in patients with symptomatic carotid stenosis, particularly in the elderly population.     

Formulation development of ambroxol hydrochloride soft gel with application of statistical experimental design and response surface methodology

The purpose of present work was to develop ambroxol hydrochloride soft gel formulation with the application of statistical experimental design and response surface methodology (RSM). A two-factor, three-level (3(2)) full factorial design of experiment with RSM was run to evaluate the main and interaction effect of two independent formulation variables that included the amount of low-acetylated gellan gum and sodium citrate. The dependent variables included viscosity (Y(1)), amount of drug release at 10 min (Y(2)) and 30 min (Y(3)), and gelation time (Y(4)). In order to obtain a formulation having the maximum amount of drug release at 10 min and minimum gelation time, RSM optimization was used. The prepared formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. All the formulations showed a gelation time in the range of 6 to 48 min. The drug content in all the formulations was within limit (99.6 ± 1.56%). The viscosity of all the formulations was found in the range of 1872-12,182 cP. Dissolution studies of the formulations showed drug release in the range of 40.56-72.46% within 10 min and 80.2-100.5% within 30 min. Human evaluation tests revealed that all the gels possessed acceptable characteristics. This study showed that the soft gel formulation GA5, containing 0.3% of gellan gum and 0.4% of sodium citrate, has potential use as an immediate release soft gel for oral drug delivery. LAY ABSTRACT: The objective of this investigation was to develop a new, immediate-release, soft gel dosage form for ambroxol hydrochloride, an oral expectorant and mucolytic agent. This novel soft gel dosage form needs to be suitable for pediatric and geriatric patients as well as patients with dysphagia. A statistical technique was used for optimization of the gel formulation. The methodology, called a design of experiment with response surface methodology, evaluated several independent formulation variables, including the amount of two ingredients, low-acetylated gellan gum and sodium citrate. Their effects were studied by comparing physical properties of the gel such as viscosity, amount of drug release at 10 and 30 min, and gelation time. The final optimized formulation (0.3% of gellan gum and 0.4% of sodium citrate) was chosen to maximize the amount of drug release at 10 min, minimize gelation time, and optimize viscosity in a reasonable range. After this optimization exercise, the prepared ambroxol hydrochloride soft gel formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. Human evaluation tests revealed that all the gels possessed acceptable organoleptic characteristics.     

Exploration of Cold Extrusion for the Preparation of Enteric Minitablets of Isoniazid

The objective of the present work was to formulate the enteric minitablets of isoniazid by cold extrusion method. The minitablets were prepared using isoniazid, hydroxylpropylmethylcellulose phthalate and dibasic calcium phosphate. The minitablets were coated using hydroxypropylmethylcellulose phthalate. Full factorial design was adopted to optimize the formulation. The minitablets showed good flow and acceptable friability. The drug release was resisted in 0.1 N HCl for 2 h from the optimized batch. The optimized batch showed more than 90% of drug release in phosphate buffer in 15 min. Capsules containing rifampicin powder and enteric isoniazid minitablets showed complete drug release in acidic and alkaline media respectively. The process of cold extrusion appears to be an attractive alternative to by-pass the existing patents.     

Quality monitoring of soft-copy displays for medical radiography

As presentation of medical radiographic images on soft-copy displays (cathode ray tubes) becomes increasingly prevalent in electronic radiography, methods of quality assurance must be developed to ensure that radiologists can effectively transfer film-based reading skills. Luminance measurements provide the basis for evaluating the state of soft-copy displays. An integrated approach has been implemented at Mallinckrodt Institute of Radiology (MIR, Washington University, St Louis, MO) that facilitates measurement of geographically distributed soft-copy displays with centralized data logging, performance tracking, and calibration. MIR's central radiology image manager exercises the display station that drives the monitor, harvests the measurement data, stores the results, and submits the resulting data for additional processing. The luminance measurements are collected by a small, portable, photometric instrument designed at MIR that includes a serial port that is accessed via local area terminal service supported by the radiology image manager. The design details of the photometric instrument and example luminance characteristics of several soft-copy displays used at MIR are presented in this report.