Pharmacofiles

Christmas Hiatus

2008-12-08T11:49:00.000-08:00

Work has caught up with me, and I will need to continue the blog starting with the first Monday in January. Merry Christmas and happy holidays!

Bromelain

2008-11-14T10:51:00.000-08:00

Bromelain is an enzyme, or group of enzymes, contained in the stems and fruit of pineapples. The enzymes are called proteases because they degrade proteins. Bromelain is concentrated in the stem; eating pineapple is not a good dietary source. The extract is most often used in powder form as a meat tenderizer. However, it has also been used since the late 1950s as a herbal medicine.

Bromelain is an anti-inflammatory. It has been used to treat many conditions, including arthritis, sinusitis, or any type of swelling. Often supplements are prepared in combination with other proteolytic enzymes. Good clinical evidence for its effectiveness is lacking however,. Small studies have suggested that it may help alleviate pain following running, but data show little benefit in people with osteoarthritis or multiple sclerosis. A diet rich in pineapples and other fruits would probably be more beneficial to overall health. .

Coming Up On Monday…Hallucinogens

Proliferative Injection Therapy

2008-11-12T08:17:00.000-08:00

Proliferative injection therapy, or prolotherapy, was first investigated in the 1940s. It is a procedure designed to strengthen connective tissue, such as ligaments and tendons, and relieve pain. The therapy involves injecting a solution of proliferants, sometimes called irritants, into areas where ligaments or tendons attach to bone. The irritant is most often a solution of either dextrose, lidocaine (an anesthetic), cod liver oil, or glycerine. The theory is that the solution will promote inflammation in the injection site and that this would, in turn, promote repair of the tissue. Ankles, knees, and loer back are some of the sites considered for the treatment. The technique is still under investigation, however. Some data suggest that, by itself, the therapy is ineffective but may have some benefit when used in combination with other approaches.

A recent study funded by the U.S. National Center for Complementary and Alternative Medicine showed that the act of inserting a needle itself is sufficient to cause inflammation similar to that seen with and irritant. (1) These results suggest that any benefits of prolotherapy are due to the act of injection and not the proliferant. The authors of the study point out that clinical investigations of the procedure should account for this confounder.

Reference

1. Jensen KT, Rabago DP, Best TM, Patterson JJ, Vanderby R Jr. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008 Jun;26(6):816-23.

Coming Up On Friday…Pineapples

Anthocyanins

2008-11-10T10:21:00.000-08:00

Recently, researchers have developed purple tomatoes. The colour is due to compounds called anthocyanins. Anthocyanins are antioxidants, those molecules that reduce cellular damage caused by free radicals. Anthocyanins give many fruits their red, orange, or blue colour; cherries, blueberries, and red raspberries are also good, natural sources. Anthocyanins may have many healthy effects on the body.

Anthocyanins have shown potential as cancer chemotherapy. They prevent healthy cells from turning cancerous (transformation) as well as encourage apoptosis, which is a form of cell death. One way the compounds prevent malignant transformation is enhancement of DNA repair. All of these mechanisms would help reduce the proliferation and number of cancer cells. The antiangiogenic (prevents blood vessel formation) properties of the antioxidant may also help fight cancer. Anthocyanins also have anti-inflammatory properties; they inhibit cyclooxygenase, which is the same mechanism of action as aspirin. A mixture of bberry extracts containing anthocyanisn is available commercially as OptiBerry. Its makers suggest that the supplement supports many bodily functions. In other words, its effectiveness for treating or preventing any disorder has not been proven.

The purple tomatoes have been developed in the hopes of providing developing countries a dietary source of antioxidants because the fruit is very popular in many of these nations.

Coming Up On Wednesday…Prolotherapy

Valproic Acid for Cognition

2008-11-07T11:22:00.000-08:00

Valproic acid, or valproate, is an anticonvulsant used to treat epilepsy and bipolar disorder. Its antiepileptic properties were discovered by accident: valproic acid was used as a vehicle during investigations of other drugs for epilepsy. Vehicles are chemicals mixed in with the drug under study to improve solubility or some other property; vehicles themselves should not have any biologic activity. Valproic acid reduces electrical activity in the brain by “blocking” sodium channels. It actually slows the channels from reactivating the neuron after an electrical impulse. The drug also prevents calcium influx into neurons, which would also inhibit neuronal firing. All types of seizures can be treated with valproic acid. For bipolar disorder, the drug medicine is effective in reucing mania, probably because of a sedative effect. New research, however, has suggested that the antiseizure medications could also help in Alzheimer disease.(1)

Researchers studied the effects of valproic acid on the accumulation of beta amyloid protein in the brains of mice. This protein forms the basis of the plaques seen in the brains of people with Alzheimer disease. The study found that the drug reduced accumulation of the protein and prevented death and destruction of neurons when given in the early stages of Alzheimer-like manifestations in the model animals. Further, treatment prevented some of the decline in memory and performance usually seen in these meice. The results were promising enough to initiate a small clinical trial in people with Alzheimer disease.

Reference

1. Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W. Valproic acid inhibits A{beta} production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med. 2008 Oct 27.

Coming Up On Monday…Purple Tomatoes

Caffeine and Fetal Growth Restriction

2008-11-05T12:19:00.000-08:00

In the last post, I described research showing that flaxseed oil may cause premature birth. Continuing with the pregnancy theme, today I will describe some data that show caffeine can restrict fetal growth. The study was published in the British Medical Journal.(1)

In the study, researchers in the united Kingdom (UK) recruited 2635 low risk pregnant women. Caffeine intake from any source was determined for four weeks before and throughout pregnancy. Consumption of 100-199 mg caffeine per day (one to two cups of coffee), relative to less than 100 mg/day, was associated with a 20% increase in the risk of having children with growth restriction (a low birth weight). The risk increased 50% for those women who consumed 200-299 mg/day. The risk was increased 40% with over 300 mg/day of caffeine.

The authors of the study suggest that pregnant women minimize their caffeine consumption. The growth restriction is small, however, and is probably not significant for babies with average weights. The concern is more with babies who would be born small. The UK Food Standards Agency have paid attention to the results: they lowered their recommendation for caffeine intake for pregnant women from 300 mg/day to 200 mg/day.

Reference

1. CARE Study Group. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. 2008 Nov 3;337:a2332.

Coming Up On Friday…Epilepsy and Alzheimer Disease

Flaxseed Oil and Pregnancy

2008-11-03T10:42:00.000-08:00

Complementary and alternative medicine can be dangerous. The idea that natural products are safe is a misconception. One example comes immediately to mind: kava. This plant is used for depression and many other neurological disorders because of its sedative effects. However, the Food and Drug Administration has labeled it harmful to the liver. And now, recent research in women living in Quebec has shown that flaxseed oil may adversely influence pregnancy.

The study looked at natural product use during pregnancy. It found that The most commonly used products included chamomile (19$), green tea (17%), peppered mint (12%), and flaxseed oil (12%). The risk of premature birth in women taking flaxseed oil was 12%, whereas the risk in the general population is approximately 2%. The flaxseed seed and the other products examined did not influence gestation.

The authors suggest that more study is needed, but that the correlation is strong enough that women should reconsider flaxseed oil use if pregnant.

Coming Up On Wednesday…Caffeine and Pregnancy

The Clozapine Story

2008-10-31T07:34:00.000-07:00

Chlorpromazine, a modified antihistamine, was the first drug designed solely for people with schizophrenia. Schizophrenia is thought to result from an overactivation of dopamine receptors, and chlorpromazine blocks this system. The disorder has both negative and positive symptoms. The former consist of social withdrawal and the latter delusions and hallucinations. Chlorpromazine does not alleviate both these symptoms equally. The search for vbetter antipsychotics continued.

In 1959, a small Swiss company (the same one that invented Ovaltine) synthesized a new antipsychotic called clozapine. Clinical trials showed that the drug was a sedative and also reduced psychotic symptoms. However, clozapine also caused some liver toxicity. This side effect was so dangerous that the producers of clozapine almost halted research on the drug. The physicians who participated in the clinical trials, however, urged the company to provide more samples because the drug had been effective in patients who did not respond to typical antipsychotics like chlorpromazine. In 1971, a few European countries approved clozapine, but widespread acceptance was limited because of toxicity. In 1975, clozapine was removed from the market after rare reports of agranulocytosis, or abnormally low levels of white blood cells. Some patients had died as a result of infections subsequent to the impaired immune system. Research in the late 1980s persisted however, and clozapine had consistently shown to be effective in patients for whom other treatments had failed. The U.S. Food and Drug Administration, as well as many other countries, re-instated clozapine for use in treatment-resistant schizophrenia. Patients need to be closely monitored while taking the drug, and this includes weekly blood tests. Another potentially serious side effect is cardiac damage, including inflammation, arrythmias and cardiac failure. Clozapine is also used to reduce suicidal tendancies in people at risk.

Clozapine blocks dopamine receptors as well as many others. One advantage of the drug is that it alleviates both positive and negative symptoms. The latter is probably due to activation of serotonin receptors. Many atypical antipsychotics have followed after clozapine, including olanzapine and risperidone, but many physicians still consider clozapine the most effective.

Coming Up On Monday…Flaxseed and Pregnancy

Discovery of Chlorpromazine

2008-10-29T07:15:00.000-07:00

Chlorpromazine (Thorazine) was the first drug developed to treat schizophrenia. Schizophrenia had been treated in several different ways before the drug was synthesized. Some methods included induction of prolonged sleep – narcosis for psychosis – and electroconvulsive therapy. Julius Wagner von Jauregg won the 1927 Nobel Prize in Medicine for his approach: shock caused by injection of malarial parasites. Lobotomies followed, its pioneer also won a Nobel Prize.

Chlorpromazine was synthesized based on the structure of antihistamines such as Benadryl. Antihistamines had been discovered by 1937, but better versions had been sought. This lead to the synthesis of promethazine. This drug had a side effect though; it showed some antipsychotic properties. At the same time, a French naval surgeon had been looking for a treatment for surgical shock. The surgeon investigated promethazine, but it was not effective enough against shock. The drug needed to be modified to increase its effects on the central nervous system. The structure of promethazine was altered slightly to produce chlorpromazine. Animal testing of chlorpromazine 1950s showed the the drug made mice indifferent to learned activities. Chlorpromazine had the same effect on participants in clinical trials; they had become subdued and apathetic and psychotic patients experienced fewer hallucinaitons. Chlorpromazien entered thesd American market in 1954 and over two million patients were prescribed it in the first eight months after approval.

Chlorpromazine reduces the symptoms of schizophrenia by blocking dopamine recpeotrs in the brain. It has numerous side effects; one is Parkinsonisonism (Parkinson disease is caused by a lack of dopamine). Subsequent generations of antipsychotics are more potent and safe, and thus have largely replaced chlorpromazine.

Coming Up On Friday…More Antipsychotics

Black Cohosh

2008-10-24T10:39:00.000-07:00

Black cohosh is a perennial plant native to wooded areas of eastern North America. It grows approximately 0.5 metres tall and flowers in late spring. Native Americans used the plant for various ailments, including depression, sore throats, and gynecological symtoms (especially those associated with menopause or premenstrual syndromes). Potentially serious side effects include liver damage and excessive bleeding during menstruation. A lot of attention has focused on the use of the plant for alleviating the symptoms of menopause. Two of the best designed studies however, have cast doubt on its effectiveness in this regard.

The effects of black cohosh on hot flashes during menopause were studied in 132 women.(1) Four weeks of treatment with black cohosh reduced hot flash scores by 20% compared to baseline; placebo, 27%. The frequency of hot flashes also did not differ between the two treatments. In another study, 351 women undergoing the menopausawl transition or already in menopause were treated with one of five treatments for one year: black cohosh alone, block cohosh with mixed botanicals, mixed botanical with soy, hormones, or placebo. Symptoms and symptoms intensity did not differ after three, six, or 12 months of treatment for any group, except that the soy group had more severe symptoms at one year.

The evidence seems fairly clear: black cohosh is ineffective in treating menopausal symptoms. However, proponents of complementary medicine generally don’t accept defeat easily. The latter study mentioned above states in its conldusion “The whole-person approach used by most naturopathic physicians differs significantly from the treatments selected for our study, and this might have affected response to therapy. Time spent with the patient on counseling about diet, exercise, and emotional issues related to menopause; dose revisions; and additional supplements are important aspects of the naturopathic strategy for managing menopausal symptoms.” In other words, black cohosh might work if it is used with other strategies. Maybe, but that remains to be seen. And somehow I doubt it given that black cohosh is ineffective by itself.

References

1. Pockaj BA, Gallagher JG, Loprinzi CL, Stella PJ, Barton DL, Sloan JA, Lavasseur BI, Rao RM, Fitch TR, Rowland KM, Novotny PJ, Flynn PJ, Richelson E, Fauq AH. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol. 2006 Jun 20;24(18):2836-41.

2. Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006 Dec 19;145(12):869-79. Summary for

A New Use for Artemisinin

2008-10-22T06:57:00.000-07:00

Artemisinin is a popular antimalarial, and it is used primarily in African and Asian countries. It is extracted from a Chinese plant, the wormwood. The drug may have other medicinal applications however, especially for the treatment of cancer. In fact, it could be up to 1,200 times more specific for cancer cells than are other chemotherapeutic agents.

Artemisinin probably kills cancer cells in the same way it affects parasites. Cancer cells are loaded with iron, moreso than are normal, healthy cells. Malignant cells need the extra iron because of their high rate of dibision. The unusually high iron content helps guide artemisinin to cancerous cells. Much like in parasites, artemisinin attaches to iron inside the cancerous cells. The iron splits the drug into two and initiates a cascade of free radical production. The consequent damage to macromolecules I nthe cell leads to cellular death. In cell cultures, artemisinin reduces the growth of new blood vessels, which growing tumours need to thrive.

Artemisinin is fairly selective for tumour cells, but even greater specificity has been achieved recently by complexing the drug with another molecule.(1) This molecule binds to special receptors on both cancerous and healthy cells. However, they are more abundant on the former. The protein is designed to bind iron in the blood and internalize it within the cell. Thus, the new artemisinin complex attaches with greater specificity to cancer cells. The research showed that this new drug composite targeted leukemia cells in culture with better specificity than artemsinin alone. The new drug should be potent against many different malignancies because they all need high amounts of iron to survive.

Reference

1. Oh S, Kim BJ, Singh NP, Lai H, Sasaki T. Synthesis and anti-cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett. 2008 Oct 4.

Artemisinin and its Derivatives

2008-10-20T07:51:00.000-07:00

Malaria is a major health concern in many countries, especially those of Africa. One of the mainstays of malaria treatment is artemisinin and related compounds. Artemisinin is extracted from the sweet wormwood, or annual wormwood, plant. This piece of greenry has been used for over 2,000 years as a medicine in China. Today, the Chinese often add it to salads. As early as 340, the wormwood was used to treat fevers, and in 1596 the antimalarial properties had been recognized. The Chinese army took an interest in the plant in the 1960s, and by 1972 the medicinal component of the plant was isolated and called artemisinin. Three derivatives have since been synthesized and have largely replaced the natural product in North America. Artemisinin itself is still widely used in Africa and several Asian countries.

All artemisinin drugs act the same way. They are called endoperoxidases. They are attracted to iron, especially in malarial parasites that have consumed the heme in red blood cells. This iron causes the drug to cleave in two, which forms free radicals. These radicals are the same types of molecules that antioxidants are designed to eliminate. They wreak havoc on molecules within the parasite. The destruction of intracellular organelles, such as the energy-producing mitochondria, ultimately leads to the death of the parasite.

Parasitic resistance is a problem for many antimalarials. However, resistance to artemisinin has not developed. This lack of resistance is surprising because the drug has been used for thousands of years. Some researchers think that resistance will never develop because the drug does not stay in the body lon enough for the parasite to prepare defenses.

Coming Up On Wednesday...Artemisinin for Cancer

Fetal Anticonvulsant Syndrome

2008-10-17T10:07:00.000-07:00

Women with epilepsy who want to have a child face a tough dilemma: should they discontinue their anticonvulsant medicine and risk the pregnancy or continue with treatment and put the fetus at risk for birth defects? Drugs that cause birth defects are called teratogens, which literally means “monster maker.” I am surprised that, in this politically-correct world, that this term is still tolerated. The study of birth defects is called teratology. Alcohol is a teratogen, and so are anticonvulsants such as carbamazepine and phenytoin. The former puts less than 10% of fetuses at risk; the latter, 10%. Fetal exposure to anticonvulsants can cause the fetal anticonvulsant syndrome, or fetal hydantoin syndrome. The fetal anticonvulsant syndrome can manifest as facial abnormalities, growth restriction, heart dysfunction, and mild to moderate cognitive deficiencies.

Many anticonvulsants are converted in the body to molecules called epoxides. These molecules are harmful to cells and are thought to contribute to the fetal harm attributed to the drugs. Epoxides are inactivated by enzymes called epoxide hydrolases. Some studies have shown that the severity of the syndrome is associated with epoxide hydrolase activity in the fetus. Currently, no preventative measures are available.

Coming Up On Monday…An Antimalarial for Cancer

Vitamin C Reduces Effectiveness of Chemotherapy…in Mice

2008-10-08T06:37:00.000-07:00

Several weeks ago I mentioned in a post some of the anecdotal evidence for the use of vitamin C use in the treatment of cancer. The data is far from convincing, but many proponents of complementary medicine have suggested that more research is justified. Indeed, the effects of vitamin C, or ascorbic acid, on people with cancer are justified, but not necessarily to determine its benefit. A recent study has reported that vitamin C may actually reduce the effectiveness of cancer chemotherapy.(1)

The researchers treated cell cultures of lymphoma or leukemia with one of several chemotherapeutic drugs (doxorubicin, cisplatin, vincristine, methotrexate, and imatinib) with and without dehydroascorbic acid. This is the form of vitamin C that is readily taken up into cells. Vitamin C reduced the ability of the drugs to kill the cancer cells. In addition, the vitamin reduced the effectiveness of doxorubicin in mice with implanted cancer cells. The nutrient acted by stabilizing mitochondria, the part of the cell that produces energy. When this organelle is destabilized by chemotherapeutic drugs, the cell dies. This is thought to underlie the actions of many of these drugs. Vitamin C prevents this mode of cell death.

The results certainly need more investigation, and the researchers stress that the data probably only apply to large doses of vitamin C, such as those achieved when taking many supplements. Regardless, The results show that nutrient supplementation may not always be beneficial. The data are particularly important given the popularity of vitamin and mineral supplements that act as antioxidants.

Reference

1. Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O'Connor OA. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008 Oct 1;68(19):8031-8.

Coming Up On Friday…Teratogeneicity of Phenytoin

Neuroleptic Malignant Syndrome

2008-10-06T08:27:00.000-07:00

Antipsychotics, also called neuroleptics, are used to reduce the psychosis associated with schizophrenia. They were developed in the 1950s, and newer versions have slightly different mechanisms of actions than do their older counterparts. All these drugs are thought, at least in part, to act by blocking dopamine receptors in the brain. Schizophrenia may result from overactivation of these receptors; side effects of levodopa (the dopamine supplement used to reduce the symptoms of Parkinson disease) often mimic psychosis. One rare, but life-threatening, side effect of single or multiple antipsychotic use is the neuroleptic malignant syndrome.

The neuroleptic malignant syndrome is characterized by rigid muscles, fever, and sweating. As it progresses, blood pressure and mental status change. The latter include agitation and confusion, sometimes leading to coma. In addition to these symptoms, physicians use elevated creatine phosphokinase as a marker of the syndrome. This enzyme converts ADP into ATP, the energy molecule of the cell. Elevated levels indicate increased muscle activity, which is caused by the muscle rigidity. This enzyme is also used as a marker of a heart attack. Many symptoms are caused by deactivation of the dopamine recepotrs by either a direct action on the protein or by reducing dopamine concentrations in the brain. However, newer antipsychotics influence other neurotransmitter systems, so the role of other receptors cannot be ruled out. Sometimes discontinuation of the antipsychotic is enough to relieve symptoms, but in other cases benzodiazepines and drugs that activate dopemine receptors (such as bromocriptine) are used.

The syndrome is caused by any antipsychotic and other drugs that block dopamine receptors. Some drutgs that have been reported to cause the adverse events include risperidone, clozapine, prochlorperazine , and promethazine. casue t

Coming Up On Wednesday…Vitamin C and Cancer

The Serotonin Syndrome

2008-10-03T11:51:00.000-07:00

Serotonin, which is also called 5-hydroxytryptophan, is a neurotransmitter that regulates many bodily functions. It primarily influences the gastrointestinal tract, but is also important for brain function. For the latter, low levels of the chemical may contribute to depressive states. Thus, the selective serotonin reuptake inhibitors (SSRIs) antidepressants relieve the symtoms of depression by elevating the amount of serotonin available to activate neurons in the brain. A potentially life-threatening side effect associated with these drugs, and others that elevate serotonin levels, is the serotonin syndrome.

The serotonin syndrome occurs when the serotonergic system in the brain is overstimulated. This can occur because serotonin levels are too high, or because the serotonin receptors are activated. Drugs that cause the syndrome either increase serotonin levels or activate the receptors directly. For example,some drugs, like the SSRIs, increase the amount of serotonin in the synapse, which increases neuronal activity. Other compounds prevent neurotransmitter degradation. Triptans, which are used for migraines, activate serotonin receptors. Symptoms of the syndrome range from mild to severe. Some mild manifestations include shivering, rapid heartbeat, tremors, and sweating. More severe symptoms include high blood pressure, fever, confusion, altered mental states, and agitation. In severe cases these symptoms worsen and seizures, renal failure, coma, and death can result.

Most commonly the serotonin syndrome results from excessive SSRIs, use. These drugs include citalopram, fluoxetine, paroxetine, and fluvoxamine. Use of triptans (e.g., sumatriptan, almotriptan), tricyclic antidepressants (e.g., amitriptyline), stimulants (e.g., amphetamine, methylphenidate), and serotonin norepinephrine reuptake inhibitors (e.g., venlafaxine) can also precipitate symptoms. Any combinations of these drugs, for example paroxetine with sumatriptan, can also cause the syndrome.

Coming Up On Monday…Another Rare But Serious Syndrome

Detergent Suicide

2008-10-01T07:48:00.000-07:00

Japan is ranked among the top ten countries with respect to suicides. Now, the Japanese have found a new way to do the deed, thanks to the internet. A recent news story in the Canadian Medical Association Journal has described the new fad.(1)

Several websites have popped up that describe how to make hydrogen sulfide from common household cleaners. Hydrogen sulfide is similar to hydrogen cyanide, the gas that was used by the Nazis to kill millions of Jews in the concentration camps in World War II. The colourless vapour prevents ATP production, which is the energy used by all body cells. Inhalation causes death by suffocation or brain damage. Often these sucide attempts, which are called detergent suicides, produce a fog or poisonous gas that can harm individuals in the immediate vicinity, including rescue workers. Fortunately the fad has not caught on in North America and is unlikely to do so. Japanese officials are urging internet service providers to remove the websites.

Reference

1. Truscott A. Suicide fad threatens neighbours, rescuers. CMAJ. 2008 Aug 12;179(4):312-3.

Coming Up On Friday…Too Much of a Good Thing

Pot in the Periphery

2008-09-19T09:49:00.000-07:00

Cannabis would be a great therapeutic drug for pain and appetite if it was not for the psychoactive effects. Well, the smoke is harmful too, so a pill would be nice. Marijuana acts on proteins called the cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Stimulation of the latter does not elicit a mind-altering effect. Accordingly, researchers are trying to develop medications for pain that target only the CB2 receptor. A recent study in the journal Pain has presented some results of this research.

The researchers isolated and supported human dorsal root ganglion cells in culture. The dorsal root ganglion sends pain signals to the brain from areas outside the central nervous system (brain and spinal cord). These cells expressed CB1 and CB2 receptors as well as receptors for capsaicin. Capsaicin is used to provoke a pain response; it is the hot component of chili peppers. Addition of a drug that stimulated CB2 reduced the cellular response to capsaicin. The drug acted like morphine, but did not activate opioid receptors. Clinical trials are being planned in patients with chronic pain. Drugs that activate CB2 could be used in a number of pain conditions, such as arthritis or nerve damage.

Coming in Two Weeks…I am taking a week off. I will be back in two weeks.

Reference

1. Anand U, Otto WR, Sanchez-Herrera D, et al.
Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008 Sep 15;138(3):667-80. Epub 2008 Aug 9.

Coming Up In Two Weeks...I Will be back in two weeks.

Expanding the Antidepressant Market

2008-09-17T12:09:00.000-07:00

Pharmaceutical companies usually try to find new uses for their aging drugs. This holds off the companies that prepare generic forms and sell them at cheaper prices. Besides, expanding the market for a medicine fattens the wallet. Anticonvulsants, typically used to treat the seizures of epilepsy, have found a new use as mood stabilizers for the treatment of bipolar disorder (formerly called manic-depressive disorder). The only mood stabilizer that is not an anticonvulsant is lithium. Lithium is the oldest of these drugs and is considered standard treatment even today.

The awnticonvulsant mood staiblizers used for bipolar disorder include lamotrigine, carbamazepine, and valproic acid. These drugs prevent seizures by blocking sodium channels on neurons, but their actions as stabilizers is thought to be due to other actions, such as on intracellular signaling. Carbamazepine and valproic acid treat the manic phase of the disorder, whereas lamotrigine treats both the manic and depressive states. In fact, this drug is the only mood stabilizer approved for the long-term prevention of the two emotional states.

Lamotrigine seems fairly effective as maintenance treatment of bipolar disorder. The first multicenter, randomized, placebo-controlled study of the drug for the disorder found that 51% of patients responded at the highest dose.(1) Similarly designed studies have found that 42% and 48% of patients responded to carbamazepine or valproic acid, respectively.(2)(3) The JAMA trial (3) found that valproates were no more effective than the older drug lithium, however. This is actually very common; newer drugs are not necessarily better. Diuretics, for example, are just as effective in maintaining healthy blood pressure as is newer agents. But alas, this a a topic for a future post.

References

1. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999 Feb;60(2):79-88.

2. Weisler RH, Kalali AH, Ketter TA; SPD417 Study Group. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004 Apr;65(4):478-84.

3. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 1994 Mar 23-30;271(12):918-24. Erratum in: JAMA 1994 Jun 15;271(23):1830.

Coming Up On Friday…Marijuana for Pain

Pharmacogenetics and Breast Cancer

2008-09-15T16:08:00.000-07:00

Pharmacogenetics is the study of how genes influence the effectiveness and safety of drugs. One example is the effect of mutations in genes encoding the cyochrome P450 system of enzymes. These proteins metabolize numerous drugs, and any change in the DNA encoding them may change how our bodies react. Many antidepressants, for example, are susceptivle to genetic changes in the CYP2D6 enzyme. Mutations are also a problem for cancer treatment. They underlie resistance to therapy and a poorer outcome. A recent study in pLOS One is a good example of how genes can affect breast cancer treatment.(1)

The TP53gene encodes p53. This protein helps induce cells to die (apoptosis) when DNA is damaged. Mutaitons in the gene are associated with the uncontrolled clellular growth of cancer. They also increase the risk of treatment resistance. However, this does not explain all cases of failed therapy. The study in PLOS One looked at biopsied breast tissue of women about to undergo treatment with epirubicin. The research found that mutations in TP53 or another gene, CHEK2, were associated with the likelihood of disease progression. The CHEK2 gene encodes a protein that turns on p53, and is therefore part of the same cancerous pathway. Recognition of the genes involved in treatment resistance helps guide therapy choices and identify patients who will most benefit from the drugs.

Reference

1. Chrisanthar R, Knappskog S, Løkkevik E, Anker G, Østenstad B, Lundgren S, Berge EO, Risberg T, Mjaaland I, Maehle L, Engebretsen LF, Lillehaug JR, Lønning
PE. CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary
breast cancer. PLoS ONE. 2008 Aug 26;3(8):e3062.

Coming Up On Wednesday…Mood Stabilizers

Folate and Colon Cancer

2008-09-12T12:32:00.000-07:00

Folatte (folic acid, vitamin B9) is an essential vitamin. Essential means that it is not made by our bodies and we must acquire it from food. Folate participates in growth and division of cells. It helps DNA replication, particularly synthesis of the DNA base thymine. Deficiencies can result in anemia, depression, and, during pregnancy, it can cause neural tube defects in a fetus. Folate can also reduce levels of homocysteine, an amino acid implicated in cardiovascular disease. However, studies have shown that folate supplementation does not reduce the risk of cardiovascular-related adverse events such as heart attack or stroke. In contrast, folate does xseem to reduce the risk of cancer, particularly that of the colon. A new study has shed some light on how folate fights uncontrolled cellular growth.(1)

The study was performed in colon cells grown in media that was either enriched or deficient in folate. The latter condition produced cells that were more susceptible to DNA damage caused by free radicals than were cells in the former media. Folate had facilitated DNA repair and improved fidelity (the ability to incorporate the proper base into a growing DNA strand). It had also increased expression of genes involved in DNA repair and apoptosis, a process by which cells die, whereas expression of genes involved in cancer development was downregulated.

Reference

1. Duthie SJ, Mavrommatis Y, Rucklidge G, Reid M, Duncan G, Moyer MP, Pirie LP, Bestwick CS. The response of human colonocytes to folate deficiency in vitro: functional and proteomic analyses. J Proteome Res. 2008 Aug;7(8):3254-66.

Coming Up On Monday…Predicting Success of Breast Cancer Treatment

A Nicotine Vaccine

2008-09-10T06:21:00.000-07:00

Nicotine is the compound in tobacco that keeps addicts coming back for more. Many of the harmful effects of cigarette smoking, however, may be attributed to other compounds in the tobacco such as carbon monoxide and arsenic. The pharmacologic approaches to smoking cessation include nicotine replacement products (gums, patches, etc) and the prescription drugs bupropion and varenicline. But, as I showed in a previous blog post, these interventions have had limited success. In an effort to improve outcome, vaccines based on nicotine have been developed and are currently being tested. These vaccines are designed to create antibodies directed against nicotine. These antibodies would bind to nicotine and prevent it from entering the brain. In theory, this should reduce or eliminate addictive behaviours. Animal testing has shown that these vaccines can reduce nicotine craving, and phase I trials have shown that the drugs are safe and produce antibodies in human subjects. Recently, the results of a one year phase II trial of a nicotine vaccine in 229 smokers wishing to quit have been reported.(1)

The researchers gave smokers either the nicotine vaccine or a placebo as monthly injections (into a muscle). All participants produced antibodies to nicotine during treatment with the vaccine. After two months, significantly more smokers given the vaccine (47%) compared to those given a placebo (35%) had remained abstinent. However, the difference in these rates did not differ after two months. Further analysis of the data showed that rates over 12 months had been significantly higher in smokers with the highest concentrations of antibodies. The authours concluded that nicotine vaccine may be useful in smokers who can develop high antibody concentrations.

Despite the apparent success of the secondary analysis, the study’s results are negative. The first analysis was performed on the intent-to-treat population. The secondary analysis was performed on the per protocol population. The former analysis is preferred because it reduces bias in the results. Not surprisingly, the authours (who work for the vaccine manufacturer) suggest that the vaccine does work but only in people who achieve high antibody concentrations. This is a good example of a positive spin placed on a study with negative results. Much more research is needed before the potential of a nicotine vaccine is realized.

Reference

1. Cornuz J, Zwahlen S, Jungi WF, Osterwalder J, Klingler K, van Melle G, Bangala Y, Guessous I, Müller P, Willers J, Maurer P, Bachmann MF, Cerny T. A vaccine against nicotine for smoking cessation: a randomized controlled trial. PLoS ONE. 2008 Jun 25;3(6):e2547.

Coming Up On Friday...Folate and Cancer

Jimson Weed

2008-09-08T07:04:00.000-07:00

Jimson weed is a popular hallucinogen, especially for teenagers searching for a cheap thrill. In fact, the weed is sometimes celebrated at parties. In some people, the effects of the weed do not manifest immediately, and this can result in severe poisoning. For example, one recent report detailed the overdose experienves of two teenagers who visited a Vancouver hospital.(1) The teenagers had attended a party where one partygoer presented some pods of the jimson weed. Each teenager consumed between 100 and 300 seeds. Of course, alcohol had been take nwith the seeds. At the hospital, the male user had dilated pupils, was disoriented, was verbally incoherent, and had visual hallucinations. He had a fever and rapid heart beat. He needed to be restrained to prevent him from fighting the doctors. His hallucinations subsided over the next two days. The female user had many of the same symptoms but also spit and swore at the attending doctors. She needed catheterization because of urinary retention. She was discharged three days later. Six other partyers required medical attention for less severe symptoms such as confusion, sedationt, and dry mouth. These are typical symptoms of jimson weed poisoning, some others include extreme thirst, high or low blood pressure, seizures, and coma.

Jimson weed is also called ditch weed, stink weed, Jamestown weed, thorn apple, angel's trumpet, and devil's trumpet. Its scientific name is Datura stramonium. Itt is an annual herb with a purple stem and distinctive trumpet-shaped flowers. The flower opens and closes throughout the night. The pods are egg-shaped and about the size of a walnut. Many black seeds are contained in the pods. When damaged, the flowers emit a malodourous smell, hence the stink weed moniker. The weed grows along roadways and in pastures of North America, but is native to India or Central America.

Jimson weed contains three active alkaloids: atropine, scopolamine, and hyoscyamine. These alkaloids are distributed throughout all parts of the plant, but they are concentrated in the seeds. These alkaloids are anticholinergic, that is they block the effects of the neurotransmitter acetylcholine by binding to muscarinic receptors. These receptors are distributed throughout the body and regulate many physiologic functions. Thus, jimson weed ingestion can have numerous effects both within and without the central nervous system. Each of atropine, hyoscyamine, and scopolamine are available individually for medicinal purposes. At one time, an alkaloid extract from the weed, called aturine was also sold as a muscle relaxant designed to work in the lungs. It was used to treat asthmatic conditions. Physostigmine, a drug that prevents acetylcholine breakdown, is often used to treat jimson weed overdose.

Reference

1. Spina SP, Taddei A. Teenagers with Jimson weed (Datura stramonium) poisoning. CJEM. 2007 Nov;9(6):467-8.

Coming Up On Wednesday...Preventing Smoking

Killer Caterpillars

2008-09-05T07:52:00.000-07:00

A case report recently appeared in the Canadian Medical Association Journal of a 22-year-old woman with discoloured blotches on her skin.(1) These patches had been spreading over her skin, primarily on the legs, for the past four days. The patches suggested internal bleeding, but she was otherwise healthy. Upon questioning, doctors discovered that a week earlier she had returned from a trip to Peru. In Peru, she had stepped barefoot on five caterpillars. The caterpillars had caused pain throughout her legs and a headache, but the pain disappeared and the incident was dismissed. The doctors suspected she had been invenomated by the caterpillars, and they began to give her blood and coagulation factors to help treat the excessive bleeding. The doctors then ordered antivenin to be flown in from Brazil because no Canadian facility is prepares for poisoning by caterpillars. Anemia and other complications developed before the antivenin could be administered. She received one dose of antivenin but died from multiorgan failure. This occurred ten days after stepping on the caterpillars.

Only one of the 12 potentially harmful caterpillar families produces excessive bleeding like the kind seen in this woman: two species of the genus Lonomia. Lonomia oblique produces the toxins losac and lopap. These toxins exhaust the ability of the blood to coagulate; they cause excessive bleeding by depleting clotting factors. The other species, L achelous, contains numerous proteins that promote and prevent blood coagulation. However, anticoagulation predominates and the effects are very similar to those produced by the other species.

The treatment is the antivenin, which is only produced in Brazil. The antivenin is usually effective if given within 24 hours of invenomation. Fresh frozen plasma, which was initially used in this woman, is contraindicated because it could worsen symptoms.

Reference

1. Chan K, Lee A, Onell R, Etches W, Nahirniak S, Bagshaw SM, Larratt LM. Caterpillar-induced bleeding syndrome in a returning traveller. CMAJ. 2008 Jul 15;179(2):158-61.

Coming Up On Monday...Cheap Weed

Antidepressant Publication Bias

2008-09-03T10:36:00.000-07:00

An argument has been made that antidepressants don’t work. Often trials of antidepressants show small effect sizes and the influence of confounders cannot always be ruled out. Another problem, which doesn’t necessarily only affect antidepressant trials, is publication bias. Publication bias occurs when researchers submit only positive studies for publication, or put a positive spin on the results. The problem of publication bias in antidepressawnt research was the subject of a paper published in the New England Journal of Medicine earlier this year.(1)

The study compared the effectiveness of antidepressants in published studies to data submitted to the Food and Drug Administration (FDA). Nearly one-third of trials submitted to the FDA had not been published in the scientific literature. Of the 74 trials registered with the FDA, 51% showed positive results and all but one had been published. The FDA had considered the remaining 34 studies to have negative or at least questionable results. Of these, only three had been published with a negative spin, 11 had been reported in the literature as having positive results, and 22 results had not been published. This publication bias made it appear as though 91% of studies on antidepressants had been positive, whereas ony 51%of the FDA data showed an effect.

Some studies with a positive spin used methods that differed from those reported to the FDA. Trials are supposed to report a “primary outcome” that represents the major finding or significant outcome that would suggest a positive result. Many of the studies that had non-significatn primary outcomes neglected to include the data in the published paper, or relegated the finding to secondary outcome status and used a secondary result as a positive primary outcome.

The authors point out that the reasons for the publication bias are not known. Did sponsors and authors fail to submit negative trials for publication? Were these negative trials more likely to be rejected by journal editors? Regardless of the reason however, publication bias appears to be a major problem, and could be hindering the treatment of many people. And how many drugs are available that don’t really work well? Many people could be at risk for drug-related complications unnecessarily. I am not sure of a solution to the problem. Perhaps the FDA data should be made more accessible to patients and doctors. In addition, researchers and editors should be encouraged to publish all results, but perhaps this is impossible.

Reference

1. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008 Jan 17;358(3):252-60.

Coming Up On Friday...A Deadly Hike