Eran Lavy

Expandable gastroretentive dosage forms.

Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, and describes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies, relevant imaging techniques and pharmacokinetic-pharmacodynamic aspects of such delivery systems are also discussed.

Clinical manifestations of infectious canine cyclic thrombocytopenia

This paper describes five naturally occurring clinical cases of infectious canine cyclic thrombocytopenia that were the first serologically confirmed cases of Ehrlichia platys infection in Israel. In the USA this disease is considered subclinical, but the dogs in this study developed distinct clinical abnormalities. The signs observed by the owners included anorexia, lethargy, depression, weight loss and a mucopurulent nasal discharge. The principal findings on physical examination included lymphadenomegaly, pale mucous membranes, fever and the presence of ticks. The main abnormal haematological and biochemical findings included thrombocytopenia, the presence of giant platelets, low haematocrit, monocytosis and low albumin concentrations. All five dogs were less than two years of age, and four were purebred dogs, suggesting that these two factors may be associated with increased risk to infection and clinical disease. Two of the dogs were seropositive to E canis, a finding which is compatible with other reports, and which confirms that combined infections of E platys and E canis are common; it also suggests that E canis infections may contribute to the pathogenesis of E platys. The distinct clinical manifestation of the disease in these five dogs suggests that there may be a different, more virulent strain of E platys in Israel.

Canine spirocercosis: clinical, diagnostic, pathologic, and epidemiologic characteristics

The nematode Spirocerca lupi is a parasite of dogs with beetles of several species serving as intermediate hosts. The medical records of 50 dogs diagnosed with spirocercosis at the Hebrew University Veterinary Teaching Hospital (HUVTH) in Israel during 1991-1999 were retrospectively reviewed and compared to a control group (n=100). There was a seven-fold increase in the annual number of dogs diagnosed with spirocercosis during these years while the hospital caseload increased by 80%, indicating an emerging outbreak of this infection. Dogs from the greater Tel Aviv area were at the highest risk of being diagnosed with spirocercosis with 74% of the cases originating from this region compared to only 17% of the controls. The disease appeared to have a primarily urban pattern of distribution with a significantly higher percentage (P=0.025) of dogs from cities versus rural areas, as compared to the control group. Sixty-two percent of the cases were diagnosed during the colder months of December through April. The median age of infected dogs was 5 years, with dogs 1 year old or younger at the lowest risk of being diagnosed with spirocercosis. Large breeds were at a higher risk of infection in comparison to small breeds and the Labrador Retriever was significantly over represented (P=0.027) in the study group compared to the control population. The most common signs were vomiting or regurgitation (60%), pyrexia (24%), weakness (22%), respiratory abnormalities (20%), anorexia (18%), melena (18%) and paraparesis (14%). A caudal esophageal mass was identified by radiography in 53% of the dogs and spondylitis of the thoracic vertebrae in 33%. Fecal flotation was positive for S. lupi eggs in 80% of the dogs, and endoscopy was found to be the most sensitive diagnostic procedure and allowed diagnosis in 100% of the examined dogs. Fifty-three percent of the dogs were anemic and creatine kinase (CK) activities were elevated in 54%. Necropsy of 14 dogs revealed esophageal or gastric granulomas in 13 dogs, and an esophageal osteosarcoma in a single animal. Aortic aneurysms were found in six (43%) dogs. Out of 24, 15 dogs (63%) for which follow-up information was available died or were euthanized within 1 month of admission. The case-fatality rate decreased toward the end of the study period when improved therapy with avermectins became available.

Novel levodopa gastroretentive dosage form: in-vivo evaluation in dogs.

Due to its narrow absorption window, levodopa has to be administered continuously to the upper parts of the intestine in order to maintain sustained therapeutic levels. This may be achieved by a controlled release (CR) gastroretentive dosage form (GRDF). The aim of this work was to develop a novel GRDF, based on unfolding polymeric membranes, that combines extended dimensions with high rigidity, and to examine the pharmacokinetics of levodopa compounded in the GRDF. Levodopa CR-GRDFs were administered to beagle dogs pretreated with carbidopa. The CR-GRDF location in the gastrointestinal tract was determined by X-ray, and serial blood samples were collected and assayed for levodopa. Optimization of the pharmacokinetic profile of levodopa from the CR-GRDFs was carried out based on the in-vitro in-vivo correlation following modifications of the release rates (adjusted by various membrane thicknesses) and drug loads. The successful CR-GRDF maintained therapeutic levodopa concentrations (>500 ng ml(-1)) over 9 h. In comparison to non-gastroretentive CR-particles and oral solution, mean absorption time was significantly extended. These outcomes demonstrate that the CR-GRDF may be used to improve levodopa therapy and can be applied to extend the absorption of other narrow absorption window drugs that require continuous input.

Novel Gastroretentive Dosage Forms: Evaluation of Gastroretentivity and Its Effect on Riboflavin Absorption in Dogs

AbstractPurpose. The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drugs absorption properties. Methods. Dosage forms (DFs) with different dimensions and mechanical properties were administered to beagle dogs with acidic buffer (pH=1.5), whose gastric retention time (GRT) was then determined by X-ray pictures. Concurrent administration of radiopaque markers was used to assess the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin from a prototype GRDF was compared with a nongastroretentive controlled-release DF and to an oral solution of the drug. Results. Large DFs (≥2.5 × 2.5 cm) containing rigid frame had prolonged GRT (>4 h). Administration of 400 mL of acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional prolongation. The extended absorption phase (>48 h) of riboflavin administered in a GRDF led to 4-fold increased bioavailability. Conclusion. The combination of large dimensions with rigidity produce gastroretentivity that can be used to improve absorption properties of a model of narrow absorption window drugs in the gastrointestinal tract.

Retrospective study of 46 cases of feline haemobartonellosis in Israel and their relationships with FeLV and FIV infections

Forty-six cats with clinical haemobartonellosis were studied; 75 per cent of the cats of known age were two-and-a-half years old or younger, 50 per cent were intact males and 19.5 per cent were castrated males. The predominant signs of the disease were tachypnoea, lethargy, depression, anorexia, infestation with fleas, pale mucous membranes, icterus, emaciation, dehydration, splenomegaly, anaemia, leucocytosis, increased activities of alanine aminotransferase and aspartate aminotransferase, and azotaemia. Thirty-eight per cent of the cats that were tested for feline leukaemia virus (FeLV) antigen were positive, and 22 per cent of those tested for feline immunodeficiency virus (FIV) antibodies were positive. The prevalence of both FeLV and FIV was much higher than in the general Israeli cat population. The cats infected with both Haemobartonella felis and FeLV had a significantly lower body temperature, were more anaemic and the mean cell volume of their erythrocytes was greater than in the cats with haemobartonellosis alone.

Novel gastroretentive dosage forms: Evaluation of gastroretentivity and its effect on levodopa absorption in humans

AbstractPurpose. To design novel expandable gastroretentive dosage forms (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers. Methods. Thin (<0.07 cm), large-dimensioned (≥ 5 × 2.1 cm), multilayer dosage forms (DFs) with different rigid polymeric matrices and mechanical properties were folded into gelatin capsules and were administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa-GRDF were compared to Sinemet CR® in a crossover design. Results. The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity (≥ 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDFs rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR®. Conclusions. The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.

Furosemide Pharmacokinetics and Pharmacodynamics following Gastroretentive Dosage Form Administration to Healthy Volunteers

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage form (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate‐release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled‐release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the bodys counteractivity to the drug effect.

Evaluation of doramectin for the treatment of experimental canine spirocercosis.

The nematode Spirocerca lupi is primarily a parasite of dogs, which causes typical lesions of esophageal nodular granulomas, aortic aneurysms and spondylitis. In order to evaluate the therapeutic effect of doramectin on experimental canine spirocercosis, seven beagle dogs experimentally infected with 40 infectious S. lupi larvae (L(3)) were treated with doramectin. Treatment was commenced following endoscopic visualization of esophageal granulomas, and typical S. lupi eggs were detected in the feces. The treatment protocol included six treatments of doramectin (400 microg/kg subcutaneously) at 2 weeks intervals, followed by monthly injections until the disappearance of the esophageal granulomas or the end of the study (768 days post-inoculation). Eggs could not be found on fecal examinations 3-10 days after the first or second doramectin treatment. In addition, a gradual decrease in size of granulomas was noticed in all seven dogs during the course of the study. Esophageal granulomas had completely resolved in six of the seven dogs between day 35 and day 544 post-initial doramectin treatment, by day 35 in one dog (after three treatments), by day 43 in two dogs (after four treatments), by day 98 in one dog (after seven treatments), by day 460 in one dog (after 18 treatments) and by day 544 in another dog (after 21 treatments). In one dog, remnants of S. lupi granulomas could still be seen 544 days post-initiation of treatment with doramectin. Multiple subcutaneous injections of doramectin (400 microg/kg) were shown to be effective and safe in the treatment of canine spirocercosis.

Urethral obstruction in cats: Predisposing factors, clinical, clinicopathological characteristics and prognosis

Feline lower urinary tract diseases in general, and urethral obstruction (UO) in particular, are common clinical conditions in cats. The aims of this study were to identify risk factors for UO, to characterise clinical and clinicopathological signs, outcome and recurrence, as well as risk factors for mortality and recurrence. Eighty-two cats with UO were compared to 82 sex and time matched controls. The mean age of cats with UO was significantly lower compared to controls, while the mean body weight was higher. The proportion of indoors–outdoors cats was significantly lower in the study group compared to the control group, and the proportion of cats consuming only dry food was higher. Overall mortality was 8.5%. Ionised calcium was significantly higher in survivors compared to non-survivors, and the prevalence of hypocalcaemia was lower. Recurrence in 6 months and 2 years were 22% and 24%, respectively. Cats with recurrence had significantly lower urine pH at presentation.