Clovis Orlando da Fonseca

Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas

BACKGROUND Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. Perillyl alcohol has shown to have both chemopreventive and chemotherapeutic activities in preclinical studies. The underlying action mechanism(s) of POH has yet to be delineated but may involve effects on the TGF-beta and/or the Ras signaling pathways. The intranasal delivery allows drugs that do not cross the BBB to enter the CNS; moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. METHODS We are conducting a phase I/II study to evaluate the antitumoral activity of POH intranasal delivery in a 4x daily schedule in patients with recurrent MG. The objective was to determine PFS at 6 months and the safety for POH in adult patients who failed conventional treatment. Assessments were performed every 27 days. Thirty-seven patients with progressive disease after prior surgery, radiotherapy, and at least temozolomide-based chemotherapy were enrolled, 29 of whom had GBM, 5 who had anaplastic astrocytoma, and 3 had AO. RESULTS One patient (3.4%) with GBM and 1 patient (33.3%) with AO achieved partial response; 13 patients (44.8%) with GBM, 3 patients (60%) with AA, and 1 (33.3%) with AO achieved stable disease; 15 (51.7%) patients with GBM, 2 (40%) patients with AA, and 1 (33.3%) with AO showed progressive disease. Progression-free survival (partial response and stable disease) was 48.2% for patients with GBM, 60% for patients with AA, and 66.6% for patients with AO. CONCLUSIONS There were no toxicity events. Perillyl alcohol is well tolerated and regression of tumor size in some patients is suggestive of antitumor activity. This work discusses POH intranasal delivery as a potential adjuvant therapeutic strategy for patients with malignant gliomas.

Long-term Outcome in Patients with Recurrent Malignant Glioma Treated with Perillyl Alcohol Inhalation

As you begin the journey to understand the Emotional Core Therapy process please keep in mind the scientific method. The scientific method is a process for creating models of the natural world that can be verified experimentally. The scientific method requires making observations, recording data, and analyzing data in a form that can be duplicated by other scientists. The subject of a scientific experiment has to be observable and reproducible. Observations may be made with the unaided eye or any other apparatus suitable for detecting the desired phenomenon. The apparatus for making a scientific observation has to be comprised of well-known scientific principles. The scientific method requires that theories be testable. If a theory cannot be tested, it cannot be a scientific theory. The scientific method requires and relies on direct evidence. This means evidence that can be directly observed and tested. Scientific experiments are designed to be repeated by other scientists and to demonstrate unequivocally the point they are trying to prove by controlling all the factors that could influence the results. Source (Scientificpsychic.com/Scientific Method) Here are the four steps to the scientific method and the Emotional Core Therapy process. 1). Observation made both visually and with scientific equipment Stress affects both the mind and body. There exists a cause and effect relationship with stress. Oftentimes this stress can be uncomfortable for humans. 2) Formulation of a hypothesis to explain the phenomenon in the form of a causal mechanism/method/approach. Many psychology methods (REBT, CBT, ACT, DBT, etc.), religious approaches (Buddhism, 12 steps, etc.), and educational programs (Smart Recovery) have attempted to fully and completely explain via a model, how this cause and effect relationship with stress occurs. Up until this point in time, we have not had a model in the world that can successfully depict how this stress occurs each and every time. To their credit, many of these methods partially work and have contributed greatly to humanity. See Wiki.com for information on all the psychology methods and techniques mentioned in this book. With the invention/discovery of Emotional Core Therapy (ECT) we now have a psychology method that accurately can depict this causal relationship between stress and humans through my Eight Step Emotional Core Therapy Flowchart. With ECT, we now have a psychology approach that identifies and treats the root cause of psychological stress. The root cause is the temporary arousal of one of the four true emotions (joy, grief, fear, and relief). ECT also shares and borrows many psychological techniques from the aforementionedMethods: Adult male Wistar rats (225-275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 μg/10μl/ rat, ICV) or MFQ (50, 100 and 200 μg/10μl/rat, ICV) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes.D to the effect of thoracotomy on respiratory and circulatory systems, the anesthetic technique, one lung ventilation (OLV) is applied. With the consistent improvement and widespread application of double lumen endobronchial tube and novel endobronchial blockers, OLV is more popular for surgical performance. However, there are some issues of OLV, such as the dismatching of ventilation perfusion ratio, hypoxemia, SpO2 and increase of Pmax, which limited the use of OLV. Recently, many studies have been done in the advancement of safety of OLV and on the prevention and treatment of hypoxemia. This review briefly introduces the progress of OLV and discusses the function of OLV in anesthesia.BACKGROUND Treatment of patients with chronic conditions requiring hospitalization requires patient acceptance and cooperation and adoption of coping strategies. Inappropriate coping strategies such as substance abuse are concerning in the course of treatment. This study sought to explore the association of coping strategies with suicidal behavior in substance abusers and non substance abuser patients with chronic pulmonary diseases namely asthma and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS This comparative study was performed on 100 patients with asthma and COPD selected via convenience sampling. Subjects with and without substance abuse were separated into two groups of 50 patients each. Ways of Coping Questionnaire of Lazarus (WOCQ) and Suicide Behavior Questionnaire-Revised (SBQ-R) were completed by them. Five Persian speaking patients rated this questionnaire to be easily understandable in the pre-test stage. Cronbachs alpha was calculated to measure the internal consistency. RESULTS The mean (±standard deviation) age of participants was 40 (±14) years; 58% of individuals were men; 62% had chosen problem-focused coping. The most abused substances were cigarettes (78%) and opium (42%); 6% of substance abusers had thought about suicide five times or more in the past year; 5% of substance abusers had seriously attempted suicide. Tendency to commit suicide was greater in men, substance abusers and participants who had chosen emotion-focused coping strategies, based on a regression model. Average score of suicide tendency was significantly higher in substance abusers (B=2.196, P =0.007). CONCLUSION Chronic disease is a crisis and patients need to acquire appropriate coping strategies to deal with it, especially in substance abusers and suicidal patients. Precise recognition of coping strategies in chronic pulmonary patients with substance abuse is necessary via a team cooperation among psychiatrics, psychologists and an internal physician in hospitals because medical treatment alone is not sufficient in such cases.N oxide is a colorless and virtually odorless gas with a faint, sweet smell. It is a safe and effective tool used in dental clinics to reduce anxiety, produce analgesia, and cause the depression of the central nervous system (CNS), leading to the sensation of euphoria with little effect on the respiratory system. It also enhances effective communication between the patient and their healthcare provider. The decision to use nitrous oxide/oxygen must take into consideration the alternative behavioral guidance modalities, the patient’s dental needs, the effect on the quality of dental care, the patient’s emotional development, and the patient’s physical considerations.AIM This retrospective study aimed to evaluate the long-term response and toxicity of recurrent malignant glioma patients to inhalation chemotherapy with perillyl alcohol (POH). PATIENTS AND METHODS The cohort included 117 men and 81 women with primary glioblastoma multiforme (GBM; n=154), grade III astrocytoma (AA; n=26) and anaplastic oligodendroglioma (AO; n=5). POH inhalation schedule 4-times daily started with 66.7 mg/dose; 266 mg/day and escalated up to 133.4 mg/dose; 533.6 mg/day. Clinical toxicity and overall survival following treatment were compared with tumor size, topography, extent of peritumoral edema and histological classification. RESULTS Adhesion to the protocol was high (>95%), POH (533.6 mg/daily) occasionally caused nose soreness but rarely nosebleed. Tumor size, peritumoral edema and the oligodendroglial component influenced response to treatment. CONCLUSION After 4 years under exclusive POH treatment, 19% of patients still remain in clinical remission. Long-term POH inhalation chemotherapy is a safe and non-invasive strategy efficient for recurrent malignant glioma.

The anticancer drug perillyl alcohol is a Na/K-ATPase inhibitor

The monoterpene perillyl alcohol (POH) is a drug used in the treatment of several malignant tumors, including gliomas. The present study defines a POH inhibitory effect on Na/K-ATPase activity from kidney and brain guinea pig extracts and from a human glioblastoma cell line. This inhibition showed a high degree of selectivity toward the kidney enzyme expressing, as do glioblastoma cells, the α1 subunit. Kinetic studies with purified enzymes showed a noncompetitive POH inhibition profile to Na+ and K+ and an uncompetitive inhibition towards ATP. Furthermore, potassium activated p-nitrophenylphosfatase activity of these purified preparations was not inhibited by POH, suggesting that this drug, differently from the classical inhibitor ouabain, acted in the initial phase of the enzyme’s catalytic cycle. We suggest that POH antitumor action could be linked to its Na/K-ATPase binding properties.

Chemo-resistant protein expression pattern of glioblastoma cells (A172) to perillyl alcohol

Glioblastoma multiform (GBM) is by far the most malignant glioma. We have introduced a new treatment for GBMs that comprises the inhalation of a naturally occurring terpene with chemotherapeutic properties known as perillyl alcohol (POH). Clinical trial results on recurrent GBM patients showed that POH extends the average life by more than eight months, temporarily slows tumor growth, and in some cases even decreases tumor size. After approximately seven months, the tumor continues to grow and leads to a dismal prognosis. To investigate how these tumors become resistant to POH, we generated an A172 human glioblastoma cell culture tolerant to 0.06 mM of POH (A172r). We used Multidimensional Protein Identification Technology (MudPIT) to compare the protein expression profile of A172r cells to the established glioblastoma A172 cell line. Our results include a list of identified proteins unique to either the resistant or the nonresistant cell line. These proteins are related to cellular growth, negative apoptosis regulation, Ras pathway, and other key cellular functions that could be connected to the underlying mechanisms of resistance.

Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development

The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and proteoglycans that fills the intercellular space serving as scaffolding to provide structural framework for the tissue and regulate the behavior of cells via specific receptors - integrins. There is enormous structural diversity among proteoglycans due to variation in the core protein, the number of glycosaminoglycans chains, the extent and position of sulfation. The lectican family of proteoglycans interacts with growth factors, hyaluronan and tenascin forming a complex structure that regulates neuronal plasticity and ion homeostasis around highly active neurons. In this review, we will discuss the latest insights into the roles of brain glycoproteins as modulators of cell adhesion, migration, neurite outgrowth and glial tumor invasion.

Síndrome do túnel do carpo: estudo comparativo entre a medição ultrassonográfica e cirúrgica do nervo mediano nos casos moderados e severos da doença

OBJECTIVE: To compare sonographic and surgical measured perimeters of the median nerve; to evaluate the diagnosis of carpal tunnel syndrome by median nerve cross-sectional area; to verify the association between cross-sectional area of the median nerve and carpal tunnel syndrome severity. MATERIALS AND METHODS: Thirty patients with established carpal tunnel syndrome were studied. Cross-sectional area and sonographic perimeter of the median nerve were measured. The correlation between clinical and sonographic findings and association with carpal tunnel syndrome severity were evaluated. Sonographic and surgical perimeters were compared. Clinical classification, surgical perimeter, cross-sectional area and sonographic perimeter of the median nerve were compared. Statistical analysis utilized paired samples t-test, Pearsons correlation, Bland-Altmans diagram, Kolmogorov-Smirnovs test, Welchs and Wilcoxons tests. RESULTS: Five patients were excluded; 25 patients were studied; 60% of patients had moderated disease, and 60% presented cross-sectional area > 0.15 cm2. Distribution of surgical perimeter was not normal (p = 0.5); the sonographic perimeter distribution was normal (p = 0). There was a statistically significant difference between perimeters (paired samples t-test, p 0.09 cm2 was found in all the patients. CONCLUSION: No association was observed between median nerve sonographic and surgical perimeters. Median nerve cross-sectional area > 0.09 cm2 was valid for diagnosis of carpal tunnel syndrome. No association was observed between median nerve cross-sectional area and carpal tunnel syndrome severity.

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM.

Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals

Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage. Malignant tumors, such as glioblastoma multiforme, display elevated rates of oxygen consumption, necrosis and abnormal structural microvasculature. Alterations in the tumor microenvironment are tightly linked to tumor progression and occur as a result of activation of complex signaling networks involving inter-clonal cooperation, cell–matrix interactions and an ongoing inflammatory response leading to genetic and epigenetic alterations. This review will focus on the pro- and anti-oxidant activities of POH, which are greatly dependent on the respective ROS levels within the tumor microenvironment and involve the ER stress response system. As well, some critical aspects of tumor-associated metabolic changes and the consequences of endogenous ROS production for tumor progression will be discussed.

Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long‐term inhalational chemotherapy for gliomas

Background: Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may contribute to the development of drug resistance. Biophysical interactions between therapeutic agents and the lipid components at the outer plasma membrane interface are critical for effective drug uptake. Amphipathic molecules such as perillyl alcohol (POH) have a high partition coefficient and generally lead to altered lipid acyl tail dynamics near the lipid-water interface, impacting the lipid bilayer structure and transport dynamics. We therefore hypothesized that glioma cells may display enhanced sensitivity to POH-induced apoptosis due to plasma membrane alterations, while in non-transformed cells, POH may be expelled through thermal agitation. Methods: Interactions between POH and the plasma membrane was studied using molecular dynamics simulations. In this phase I/II trial, we set up to evaluate the clinical effectiveness of long-term (up to 5 years) daily intranasal administration of POH in a cohort of 19 patients with low-grade glioma (LGG). Importantly, in a series of clinical studies previously published by our group, we have successfully established that intranasal delivery of POH to patients with malignant gliomas is a viable and effective therapeutic strategy. Results: POH altered the plasma membrane potential of the lipid bilayer of gliomas and prolonged intranasal administration of POH in a cohort of patients with LGG halted disease progression with virtually no toxicity. Conclusion: Altogether, the results suggest that POH-induced alterations of the plasma membrane might be contributing to its therapeutic efficacy in preventing LGG progression.