Richard C Walovitch

• PhD
• Chief Scientific Officer at World Care Clinical

The debate over human visual perception and how medical images should be interpreted have persisted since X-rays were the only imaging technique available. Concerns over rates of disagreement between expert image readers are associated with much of the clinical research and at times driven by the belief that any image endpoint variability is proble...

Though many clinical trials rely on medical image evaluations for primary or key secondary endpoints, the methods to monitor reader performance are all too often mired in the legacy use of adjudication rates. If misused, this simple metric can be misleading and sometimes entirely contradictory. Furthermore, attempts to overcome the limitations of a...

The FDA has recently issued a draft Guidance Standard for Clinical Trial Imaging Endpoints, which focuses on how to perform registration trials with imaging as an end-point or using imaging to determine patient eligibility. Leading up to the release of the guidance document, a major question was how the FDA viewed the value proposition of a blinded...

The current cost of developing a successful drug is typically over a billion dollars, with the registration trial(s) determining the success or failure of the entire development program. Often the primary endpoint of these trials is a subjective assessment. For registration trials with subjective endpoints, a regulatory agency may require a blinded...

Primary efficacy and safety endpoints in clinical trials are often subjective assessments made by site personnel. For international confirmatory trials conducted over broad geographic regions and different clinical practice settings, variability in these subjective assessments can be substantial. Centralized endpoint assessment committees (EACs) of...

To determine if perfusion stress echocardiography (PSE) with Imagify (perflubutane polymer microspheres) is comparable to stress perfusion imaging using (99m)Tc single photon emission computed tomography (SPECT) for coronary artery disease (CAD) detection. PSE is a novel technique for evaluating myocardial perfusion. RAMP (real-time assessment of m...

Introduction RAMP (Realtime Assessment of Myocardial Perfusion Imaging) 1 and 2 showed that coronary artery disease (CAD) diagnosis with perfusion stress echocardiography (PSE) and perflubutane polymer microspheres in chest pain patients is as accurate as SPECT perfusion imaging. Hypothesis PSE provides incremental predictive value over clinical ri...

AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3...

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic micropar- ticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of adminis- tering AI-850 as a <30-min i.v. infusion without premedic...

We sought to determine whether analysis of the contrast signal from the radial artery is better able to reflect changes in left ventricular (LV) microbubble dynamics than the signal from the LV itself. Assessment of microbubble behavior from images of the LV may be affected by attenuation from overlying microbubbles and nonuniform background signal...

Amphiphilic gadolinium complexes were investigated as potential magnetic resonance imaging (MRI) contrast agents. A series of complexes was synthesized in order to study the effect of hydrophilic phosphodiester groups on albumin binding, relaxivity, and blood half-life in rats. Thus, compound 11a, a diethylenetriaminepentaacetato aquo gadolinium(II...

A new intravenous contrast agent, AI-700, was evaluated to determine whether a bolus injection could be used to detect myocardial perfusion abnormalities during acute ischemia by using 2-dimensional (2D) and 3-dimensional (3D) myocardial contrast echocardiography. 2D MCE was performed in 14 closed-chest dogs during coronary occlusion by using both...

To determine whether a synthetic ultrasonographic (US) contrast agent can be used to differentiate coagulation necrosis from untreated tumor immediately after radio-frequency ablative therapy. VX2 (adenocarcinoma) tumors (0.8-1.5-cm diameter) were implanted into 12 rabbits. Gray-scale and color Doppler US were performed with or without intravenous...

MR angiography is proving to be a useful clinical study for the diagnosis of vascular disorders of renal arteries. However, its utility in terms of stenosis characterization is still limited. Renal perfusion could provide supplemental information that could allow for a comprehensive evaluation of renal artery stenosis by MR imaging. MS-325 is a sma...

To assess the effectiveness of an intravascular contrast agent, MS-325, for enhancing the vascular signal in coronary MR angiograms, six minipigs were studied using a three-dimensional, gradient-echo sequence with retrospective respiratory gating. To suppress the myocardial signal, preparatory RF pulses were applied before data acquisition. With th...

To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents. Protein binding in human plasma was measured by means of ultrafiltration. T1 relax...

To evaluate the imaging performance and patient tolerance of a blood-pool contrast agent (MS-325) for magnetic resonance (MR) angiography. Imaging of peripheral and carotid vessels was performed in seven healthy volunteers in a phase I clinical trial of the gadolinium chelate MS-325. Each volunteer received an intravenous injection of 0.05 mmol/kg...

The authors evaluate MS-325, a new albumin-targeted magnetic resonance imaging (MRI) contrast agent, for its pharmacokinetics, biodistribution, and elimination characteristics in multiple animal species. Studies were performed in rats, rabbits, and nonhuman primates at intravenous doses ranging from 0.025 to 0.20 mmol/kg. Concentrations of MS-325 i...

This study was designed to optimize three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) sequences and to determine whether contrast-enhanced MRA could improve the accuracy of lumen definition in stenosed carotid arteries of minipigs. 3D TOF MRA was acquired with use of either an intravascular (n = 13) and/or an extravas...

99mTc-bicisate (99mTc-ECD) is a new brain perfusion imaging agent formulated from a radiochemically stable kit (Neurolite). A multicenter trial was conducted to determine the sensitivity and specificity of single photon emission computed tomography (SPECT) imaging with 99mTc-bicisate in the localization of ischemic stroke; 170 subjects were enrolle...

The structure-activity relationship in a series of analogues of 99mTc-bicisate (99mTc-N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester dihydrochloride, RP-217) is described using in vivo studies in rodent and primate models and in vitro studies in rodent and primate brain tissue. All analogues investigated were 99mTc-diamine dithiol diesters, whic...

A blinded read of images obtained with 99mTc-bicisate and single photon emission computed tomography (SPECT) was conducted to determine if a relationship exists between the severity of abnormalities on SPECT brain images and the severity of cognitive impairment in patients with dementia of the Alzheimer type (DAT) and to examine the interreader agr...

The pharmacokinetics and quality of planar and SPECT brain imaging of two 99mTc-labeled brain perfusion agents, d,l-hexamethyl propylene amine oxime (HMPAO) and ethyl cysteinate dimer (ECD), were compared in seven healthy, normal subjects. Both radiopharmaceuticals showed rapid brain uptake and had a net brain washout of less than 5% during the fir...

99mTc-l,l-Ethyl cysteinate dimer (ECD) is a brain-perfusion imaging agent, which exhibits selective retention in brain and rapid renal excretion. The pharmacokinetics and metabolism of ECD were studied in vivo in healthy humans and its metabolism in vitro was evaluated in tissue from human brain. In vitro studies showed 99mTc-l,l-ECD to be metaboli...

Single photon emission computed tomography (SPECT) imaging of brain function provides novel information which often is of value in the diagnosis and prognosis of a number of neurological diseases [10,11,6]. The physical properties of the 99mTc-based SPECT brain agents makes them more available for routine clinical use than those labeled with other...

Increases in regional cerebral blood flow have been described in a variety of cerebral pathologic states, including stroke and seizure disorders. The usefulness of technetium-99m-labeled cysteinate dimer as a marker in the measurement of regional cerebral blood flow was tested in five cynomolgus monkeys. To expand the range of blood flow to beyond...

Technetium-99m ethyl cysteinate dimer ([99mTc]ECD) is a neutral, lipophilic complex which rapidly crosses the blood-brain barrier. Brain retention and tissue metabolism of [99mTc]ECD is dependent upon the stereochemical configuration of the complex. While both L,L and D,D enantiomers are extracted by the brain, only the L,L but not the D,D form, is...

The safety, biodistribution and kinetics of a new perfusion imaging agent [99mTc-L,L]-ethyl cysteinate dimer (ECD) was evaluated in normal volunteers. Technetium-99m-L,L-ECD is a neutral, lipophilic complex, which is radiochemically pure and stable. Twelve healthy adults were injected with 25-30 mCi of 99mTc-L,L-ECD and imaged periodically for up t...

The autoradiographic, 2-deoxy-D-[1-14C]glucose ([14C]DG) method was used to map the effects of intravenous (IV) naloxone (1.0, 10.0, and 20.0 mg/kg) on local cerebral glucose utilization (LCGU), an index of local brain function. Naloxone injected 5 min before [14C]DG did not alter LCGU in any of the fifty-six brain regions examined. Our findings su...

Aging is associated with a loss of cyclic gonadotropin release in female animals. This deficit may reflect dampened circadian rhythmicity of neuroendocrine events and/or altered function in hypothalamic nuclei important to regulation of cyclic female reproduction. The purpose of this study was to determine if diurnal periodicity and glucose metabol...

Degenerative kidney changes are associated with heroin use in human addicts, but it is not known whether these changes result from exposure to the opioid or from contaminants in street heroin. In the present study, 4-6-month-old rats each received 1 subcutaneous pellet containing 75 mg of morphine or placebo, followed 3 days later by implantation o...

The objective of this study was to determine the effect of co-dergocrine in rats on local cerebral glucose utilization and performance in a complex T-maze. Middle-aged (12-16 months) male Fischer-344 rats were given injections of co-dergocrine (3 or 10 mg/kg, IP) 35 min before behavioral testing or the administration of 2-deoxy-D-[1-14C]glucose ([1...

Elevated blood levels of prolactin increase the synthesis, turnover, and release of 3, 4-dihydroxyphenylethylamine (dopamine) from the tuberoinfundibular dopaminergic neurons, which project to the median eminence. The present study examined whether hyperprolactinemia also increases local cerebral glucose utilization, as determined by the 2-deoxy-D-...

Because glucose is the primary substrate for oxidative metabolism of the adult brain, measurements of glucose utilization provide information on cerebral energy metabolism, which ultimately is linked to neuronal activity. Early studies utilized in vitro techniques to measure carbohydrate oxidation as well as glycolytic and citric acid cycle enzymat...

Phenoxybenzamine (10 mg/kg, IP), an alpha-adrenoreceptor blocker, and bromocriptine (5 mg/kg, IP), a dopamine receptor stimulant, were administered to rats while the animals were being deprived of REM sleep by selective REM sleep deprivation method. We have shown recently that alpha-adrenoreceptor blockers and bromocriptine when administered to rat...

Bromocriptine mesylate (7.5 mg/kg, i.p.) and dihydroergotoxine mesylate (DHET); 3 mg/kg, i.p.) were administered 4 times at 9-hour intervals within a 27-hour period to rats polygraphically recorded for 84 h. Administration of bromocriptine resulted in increased wakefulness and reduced slow-wave sleep (SWS) and rapid eye movement sleep (REM) during...

The structure-activity relationship in a series of analogues of {sup 99m}{Tc}-bicisate ({sup 99m}{Tc}-N,Nâ²-1,2-ethylene-diylbis-L-cysteine diethyl ester dihydrochloride, RP-217) is described using in vivo studies in rodent and primate brain tissue. All analogues investigated were {sup 99m}{Tc}-diamine dithiol diesters, which were neutral and lipop...