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Pharmacotherapy, Jun 6, 2013
STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionali... more STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-b-cyclodextrin (HPbCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING Clinical research center. SUBJECTS Healthy adult volunteers. INTERVENTION Study 1: Subjects received HPbCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPbCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS Study 1: IV HPbCD-diclofenac had a higher peak plasma concentration (C max) and earlier time to reach maximum plasma concentration (T max), but equivalent plasma exposure (area under the curve from time zero to t [AUC 0-t ]) to IV Voltarol. The geometric mean ratio of HPbCD-diclofenac (IV) to Voltarol (IV) for AUC 0-t was 106.27%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IM) for AUC 0-t was 110.91%. The geometric mean ratio of HPbCD-diclofenac (IV) to HPbCD-diclofenac (IM) for AUC 0-t was 101.25%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IV) for AUC 0-t was 104.96%. Study 2: C max for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ngÁhour/ml) and 37.5 mg (1843 ngÁhour/ml) IV HPbCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ngÁhour/ml). CONCLUSIONS Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPbCD-diclofenac compared with Voltarol and after IM administration of HPbCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPbCD-diclofenac was equivalent to IV administration of HPbCD-diclofenac and IV administration of Voltarol. Study 2: HPbCDdiclofenac showed dose proportionality after single-and multiple-dose administration and no accumulation of HPbCD-diclofenac. HPbCD-diclofenac was safe and well tolerated following IV and IM administration.
PubMed, Dec 1, 1989
One of the more prominent clinical treatments for skin diseases such as psoriasis and vitiligo in... more One of the more prominent clinical treatments for skin diseases such as psoriasis and vitiligo involves the use of a combination of psoralens and UV light, a procedure referred to as PUVA chemotherapy. This drug regimen markedly alters epidermal cell growth and differentiation. In many cell types, an early cellular event following treatment of cells with PUVA is inhibition of binding of epidermal growth factor (EGF) to its receptor. To examine the mechanism underlying this effect, we used A431 cells, a human epidermal cell line known to express large numbers of EGF receptors. We found that exposure of A431 cells to PUVA caused a dramatic inhibition of EGF-stimulated EGF receptor tyrosine kinase activity. Inhibition required intact cells and did not appear to be mediated by protein kinase C, because this inhibition was apparent in cells in which the enzyme was down-regulated by phorbol ester pretreatment and in cells treated with inhibitors of protein kinase C. Inhibition of tyrosine kinase activity by PUVA was distinct from other inhibitors of EGF receptor function in that it was associated with a rapid increase in the amount of phosphate incorporated into serine residues of the EGF receptor. This suggested that PUVA-induced serine phosphorylation may mediate EGF receptor kinase activity. These results demonstrate that alterations in EGF receptor function may contribute to the therapeutic efficacy of PUVA in photo-chemotherapy.
Acute Pain, Dec 1, 2007
Background: Subanaesthetic doses of ketamine are analgesic. Intranasal administration offers a no... more Background: Subanaesthetic doses of ketamine are analgesic. Intranasal administration offers a non-invasive route for systemic drug delivery. We evaluated the safety and analgesic efficacy of intranasal ketamine in treating moderate-to-severe, acute postoperative pain in the molar extraction model. Methods: Intranasal ketamine (10 mg, 30 mg, and 50 mg) and placebo were evaluated in a randomised, double-blind, single-dose, parallel study in 40 patients undergoing removal of 2-4 impacted third molars. Analgesic efficacy was assessed over a 3 h period following drug administration. Safety was evaluated through adverse event reporting, vital signs, pulse oximetry, nasal assessments, and a standard dissociative side effects questionnaire. Results: Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics. Conclusion: Intranasal ketamine may offer a safe, nonopioid, well-tolerated, needlefree analgesic with efficacy in moderate-to-severe acute pain.
Regional Anesthesia and Pain Medicine, Jul 1, 2007
Pain Medicine, 2008
Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsur... more Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. Methods. In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a doseresponse assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. Results. A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. Conclusions. By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.
L'invention concerne des compositions pharmaceutiques composees de taux efficaces d'antag... more L'invention concerne des compositions pharmaceutiques composees de taux efficaces d'antagonistes du recepteur NMDA et d'un agent de conservation pour l'administration d'analgesiques et d'anesthesiques efficaces a un patient necessitant un tel traitement. Pour plus d'efficacite, les compositions selon l'invention n'induisent aucune neurotoxicite significative. De preference, l'antagoniste du recepteur NMDA est la ketamine et l'agent de conservation est le chlorure de benzalkonium.
A pharmaceutical composition comprising an effective amount of an NMDA receptor antagonist select... more A pharmaceutical composition comprising an effective amount of an NMDA receptor antagonist selected from the group consisting of ketamine, dextromethorphan, dextrophane, dextropropoxyphene, ketobemidone, budipine, quinurenic acid, 1-hydroxy-3-aminopyrrolidin-2-one, spermine and spermidine and an effective amount of a benzalkonium quaternary ammonium preservative in a suitable vehicle, in which the composition does not produce any significant neurotoxicity.
Nasal and Pulmonary Drug Delivery Conference, Barcelona, Spain, September 15-17, 2003. (Manuscrip... more Nasal and Pulmonary Drug Delivery Conference, Barcelona, Spain, September 15-17, 2003. (Manuscript also submitted for
PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATING SYMPTOMS OF atrophic vaginitis. The present in... more PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATING SYMPTOMS OF atrophic vaginitis. The present invention further provides pharmaceutical compositions containing compounds triphenylethylene derivatives and method for using the composition to treat symptoms associated with atrophic vaginitis. The pharmaceutical compositions are prepared for vaginal administration triphenylethylene derivative compounds alone or in combination therapy. Preferably, the triphenylethylene derivative is tamoxifen.
La presente invention concerne un procede et une composition pharmaceutique utiles dans le traite... more La presente invention concerne un procede et une composition pharmaceutique utiles dans le traitement d’une pathologie sensible a un traitement hormonal substitutif. La presente invention concerne particulierement le traitement a long terme de symptomes associes a une vaginite atrophique. La composition contient des quantites efficaces d’un œstrogene, un compose de progesterone et un vehicule pharmaceutiquement tolere, un excipient et/ou un diluant.
The compounds of the present invention is diclofenac effective unit dosage to induce anesthesia; ... more The compounds of the present invention is diclofenac effective unit dosage to induce anesthesia; And beta-cyclodextrin, and containing the compound; Here, the dosage of the compound diclofenac is directed to a pharmaceutical composition to be less than 10 mg. The invention also relates to a method of treating a subject in need of anesthesia in the pharmaceutical composition of the present invention.
Pharmacotherapy, Jun 6, 2013
STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionali... more STUDY OBJECTIVE To evaluate single-and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-b-cyclodextrin (HPbCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING Clinical research center. SUBJECTS Healthy adult volunteers. INTERVENTION Study 1: Subjects received HPbCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPbCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS Study 1: IV HPbCD-diclofenac had a higher peak plasma concentration (C max) and earlier time to reach maximum plasma concentration (T max), but equivalent plasma exposure (area under the curve from time zero to t [AUC 0-t ]) to IV Voltarol. The geometric mean ratio of HPbCD-diclofenac (IV) to Voltarol (IV) for AUC 0-t was 106.27%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IM) for AUC 0-t was 110.91%. The geometric mean ratio of HPbCD-diclofenac (IV) to HPbCD-diclofenac (IM) for AUC 0-t was 101.25%. The geometric mean ratio of HPbCD-diclofenac (IM) to Voltarol (IV) for AUC 0-t was 104.96%. Study 2: C max for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ngÁhour/ml) and 37.5 mg (1843 ngÁhour/ml) IV HPbCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ngÁhour/ml). CONCLUSIONS Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPbCD-diclofenac compared with Voltarol and after IM administration of HPbCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPbCD-diclofenac was equivalent to IV administration of HPbCD-diclofenac and IV administration of Voltarol. Study 2: HPbCDdiclofenac showed dose proportionality after single-and multiple-dose administration and no accumulation of HPbCD-diclofenac. HPbCD-diclofenac was safe and well tolerated following IV and IM administration.
PubMed, Dec 1, 1989
One of the more prominent clinical treatments for skin diseases such as psoriasis and vitiligo in... more One of the more prominent clinical treatments for skin diseases such as psoriasis and vitiligo involves the use of a combination of psoralens and UV light, a procedure referred to as PUVA chemotherapy. This drug regimen markedly alters epidermal cell growth and differentiation. In many cell types, an early cellular event following treatment of cells with PUVA is inhibition of binding of epidermal growth factor (EGF) to its receptor. To examine the mechanism underlying this effect, we used A431 cells, a human epidermal cell line known to express large numbers of EGF receptors. We found that exposure of A431 cells to PUVA caused a dramatic inhibition of EGF-stimulated EGF receptor tyrosine kinase activity. Inhibition required intact cells and did not appear to be mediated by protein kinase C, because this inhibition was apparent in cells in which the enzyme was down-regulated by phorbol ester pretreatment and in cells treated with inhibitors of protein kinase C. Inhibition of tyrosine kinase activity by PUVA was distinct from other inhibitors of EGF receptor function in that it was associated with a rapid increase in the amount of phosphate incorporated into serine residues of the EGF receptor. This suggested that PUVA-induced serine phosphorylation may mediate EGF receptor kinase activity. These results demonstrate that alterations in EGF receptor function may contribute to the therapeutic efficacy of PUVA in photo-chemotherapy.
Acute Pain, Dec 1, 2007
Background: Subanaesthetic doses of ketamine are analgesic. Intranasal administration offers a no... more Background: Subanaesthetic doses of ketamine are analgesic. Intranasal administration offers a non-invasive route for systemic drug delivery. We evaluated the safety and analgesic efficacy of intranasal ketamine in treating moderate-to-severe, acute postoperative pain in the molar extraction model. Methods: Intranasal ketamine (10 mg, 30 mg, and 50 mg) and placebo were evaluated in a randomised, double-blind, single-dose, parallel study in 40 patients undergoing removal of 2-4 impacted third molars. Analgesic efficacy was assessed over a 3 h period following drug administration. Safety was evaluated through adverse event reporting, vital signs, pulse oximetry, nasal assessments, and a standard dissociative side effects questionnaire. Results: Ketamine delivered intranasally was well tolerated. Statistically significant analgesia, superior to placebo, was observed with the highest dose tested, 50 mg, over a 3 h period. Rapid onset of analgesia was reported (<10 min), and meaningful pain relief was achieved within 15 min of the 50 mg dose. The majority of adverse events were mild/weak and transient. No untoward effects were observed on vital signs, pulse oximetry, and nasal examination. At the doses tested, no significant dissociative effects were evident using the Side Effects Rating Scale for Dissociative Anaesthetics. Conclusion: Intranasal ketamine may offer a safe, nonopioid, well-tolerated, needlefree analgesic with efficacy in moderate-to-severe acute pain.
Regional Anesthesia and Pain Medicine, Jul 1, 2007
Pain Medicine, 2008
Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsur... more Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. Methods. In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a doseresponse assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. Results. A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. Conclusions. By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.
L'invention concerne des compositions pharmaceutiques composees de taux efficaces d'antag... more L'invention concerne des compositions pharmaceutiques composees de taux efficaces d'antagonistes du recepteur NMDA et d'un agent de conservation pour l'administration d'analgesiques et d'anesthesiques efficaces a un patient necessitant un tel traitement. Pour plus d'efficacite, les compositions selon l'invention n'induisent aucune neurotoxicite significative. De preference, l'antagoniste du recepteur NMDA est la ketamine et l'agent de conservation est le chlorure de benzalkonium.
A pharmaceutical composition comprising an effective amount of an NMDA receptor antagonist select... more A pharmaceutical composition comprising an effective amount of an NMDA receptor antagonist selected from the group consisting of ketamine, dextromethorphan, dextrophane, dextropropoxyphene, ketobemidone, budipine, quinurenic acid, 1-hydroxy-3-aminopyrrolidin-2-one, spermine and spermidine and an effective amount of a benzalkonium quaternary ammonium preservative in a suitable vehicle, in which the composition does not produce any significant neurotoxicity.
Nasal and Pulmonary Drug Delivery Conference, Barcelona, Spain, September 15-17, 2003. (Manuscrip... more Nasal and Pulmonary Drug Delivery Conference, Barcelona, Spain, September 15-17, 2003. (Manuscript also submitted for
PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATING SYMPTOMS OF atrophic vaginitis. The present in... more PHARMACEUTICAL COMPOSITION AND METHOD FOR TREATING SYMPTOMS OF atrophic vaginitis. The present invention further provides pharmaceutical compositions containing compounds triphenylethylene derivatives and method for using the composition to treat symptoms associated with atrophic vaginitis. The pharmaceutical compositions are prepared for vaginal administration triphenylethylene derivative compounds alone or in combination therapy. Preferably, the triphenylethylene derivative is tamoxifen.
La presente invention concerne un procede et une composition pharmaceutique utiles dans le traite... more La presente invention concerne un procede et une composition pharmaceutique utiles dans le traitement d’une pathologie sensible a un traitement hormonal substitutif. La presente invention concerne particulierement le traitement a long terme de symptomes associes a une vaginite atrophique. La composition contient des quantites efficaces d’un œstrogene, un compose de progesterone et un vehicule pharmaceutiquement tolere, un excipient et/ou un diluant.
The compounds of the present invention is diclofenac effective unit dosage to induce anesthesia; ... more The compounds of the present invention is diclofenac effective unit dosage to induce anesthesia; And beta-cyclodextrin, and containing the compound; Here, the dosage of the compound diclofenac is directed to a pharmaceutical composition to be less than 10 mg. The invention also relates to a method of treating a subject in need of anesthesia in the pharmaceutical composition of the present invention.